• AKEEGA™ (niraparib and abiraterone acetate film-coated tablets)

    INDICATION

    AKEEGA™ (niraparib and abiraterone acetate film-coated tablets) with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA™.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA™ in combination with prednisone in BRCAm patients in Cohort 1 (N=113) of MAGNITUDE.

    Myelodysplastic Syndrome/Acute Myeloid Leukemia

    AKEEGA™ may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

    MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA™.

    All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

    For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA™ if MDS/AML is confirmed.

    Myelosuppression

    AKEEGA™ may cause myelosuppression (anemia, thrombocytopenia, or neutropenia).

    In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA™. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients.

    Monitor complete blood counts weekly during the first month of AKEEGA™ treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA™ until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA™ and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.

    Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

    AKEEGA™ may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA™. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA™.

    In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA™, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA™ arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA™ arm.

    The safety of AKEEGA™ in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE.

    Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA™.

    Discontinue AKEEGA™ in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

    Hepatotoxicity

    AKEEGA™ may cause hepatotoxicity.

    Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA™, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths.

    In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA™ in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE.

    Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA™, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring and may require dosage modifications.

    Permanently discontinue AKEEGA™ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA™.

    Adrenocortical Insufficiency

    AKEEGA™ may cause adrenal insufficiency.

    Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA™, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

    Hypoglycemia

    AKEEGA™ may cause hypoglycemia in patients being treated with other medications for diabetes.

    Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA™, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide.

    Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA™. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

    Increased Fractures and Mortality in Combination with Radium 223 Dichloride

    AKEEGA™ with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials.

    The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

    At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone.

    It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA™, in combination with prednisone.

    Posterior Reversible Encephalopathy Syndrome

    AKEEGA™ may cause Posterior Reversible Encephalopathy Syndrome (PRES).

    PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA™.

    Monitor all patients treated with AKEEGA™ for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA™ and administer appropriate treatment. The safety of reinitiating AKEEGA™ in patients previously experiencing PRES is not known.

    Embryo-Fetal Toxicity

    The safety and efficacy of AKEEGA™ have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA™ can cause fetal harm and loss of pregnancy when administered to a pregnant female.

    Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow).

    In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose.

    Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA™. Females who are or may become pregnant should handle AKEEGA™ with protection, e.g., gloves.

    Based on animal studies, AKEEGA™ may impair fertility in males of reproductive potential.

    ADVERSE REACTIONS

    The safety of AKEEGA™ in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE.

    The most common adverse reactions (≥10%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia.

    Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA™, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%).

    DRUG INTERACTIONS

    Effect of Other Drugs on AKEEGA™

    Avoid coadministration with strong CYP3A4 inducers.

    Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone.

    Effects of AKEEGA™ on Other Drugs

    Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug.

    Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA™ increases the concentration of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates.

    Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions.

    Abiraterone is a CYP2C8 inhibitor. AKEEGA™ increases the concentration of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates.

    Please see the full Prescribing Information for AKEEGA™.

    cp-401051v1

    INDICATION
  • DARZALEX® (daratumumab)

    INDICATIONS

    • DARZALEX® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:
    • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
    • In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
    • In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
    • In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
    • In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
    • In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
    • As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

    WARNINGS AND PRECAUTIONS

    Infusion-Related Reactions

    DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision.

    When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

    Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

    To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

    Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®.

    Interference With Serological Testing

    Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®.

    Neutropenia and Thrombocytopenia

    DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets.

    Interference With Determination of Complete Response

    Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

    Embryo-Fetal Toxicity

    Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose.

    The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

    ADVERSE REACTIONS

    The most frequently reported adverse reactions (incidence ≥20%) were upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

    Please click here to see the full Prescribing Information.

    cp-60862v8

    INDICATIONS
  • DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

    INDICATIONS

    DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

    • In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
    • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
    • In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
    • In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
    • In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
    • In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
    • As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

    DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide, and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    Limitations of Use

    DARZALEX FASPRO® is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    DARZALEX FASPRO® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.

    WARNINGS AND PRECAUTIONS

    Hypersensitivity and Other Administration Reactions

    Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®.

    Systemic Reactions

    In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as monotherapy or in combination, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO® administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

    Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.

    Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

    Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®.

    Local Reactions

    In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO®. Monitor for local reactions and consider symptomatic management.

    Cardiac Toxicity in Patients With AL Amyloidosis

    Serious or fatal cardiac adverse reactions occurred in patients with AL amyloidosis who received DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide, and dexamethasone. Serious cardiac disorders occurred in 16% of patients, and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of AL amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

    Neutropenia

    Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO® until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed.

    Thrombocytopenia

    Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO® until recovery of platelets.

    Embryo-Fetal Toxicity

    Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose.

    The combination of DARZALEX FASPRO® with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy.

    Interference With Serological Testing

    Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.

    Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®. Type and screen patients prior to starting DARZALEX FASPRO®.

    Interference With Determination of Complete Response

    Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO®-treated patients with IgG kappa myeloma protein.

    ADVERSE REACTIONS

    In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.

    The most common adverse reactions (≥20%) in patients with AL amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

    The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

    Please click here to see the full Prescribing Information.

    cp-205671v6

    INDICATIONS
  • EDURANT® (rilpivirine)

    Indication

    Treatment of HIV-1 in Treatment-Naïve Patients

    EDURANT® (rilpivirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35 kg with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.

    Limitations of Use:

    • More EDURANT®-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT®-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL

    Treatment of HIV-1 in Combination With Cabotegravir

    EDURANT® is indicated in combination with VOCABRIA (oral cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as:

    • Oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir, rilpivirine) extended-release injectable suspensions
    • Oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions

    Important Safety Information

    Contraindications

    • Coadministration of EDURANT® with the following drugs is contraindicated because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance and cross-resistance: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, systemic dexamethasone (more than single dose), and products containing St. John’s wort (Hypericum perforatum)
    • Coadministration of rifabutin with cabotegravir [VOCABRIA (cabotegravir) tablets, CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended‑release injectable suspension), co-packaged for intramuscular use] is contraindicated. Consult the Prescribing Information for CABENUVA and VOCABRIA

    Warnings and Precautions

    • Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. EDURANT® should be discontinued immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated
    • Hepatotoxicity: Hepatic adverse events were reported. Patients with underlying hepatic disease, including hepatitis B or C, or marked elevations in transaminases before treatment may be at increased risk for worsening or development of transaminase elevations. Monitor liver function tests (LFTs) before and during treatment. A few hepatotoxicity cases occurred in patients with no pre-existing hepatic disease or other identifiable risk factors; therefore, monitoring of LFTs should be considered in all patients
    • Depressive Disorders: Severe depressive disorders, defined as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation, have been reported with EDURANT®. Immediate medical evaluation is recommended for severe depressive symptoms
    • Immune Reconstitution Syndrome has been reported in patients treated with combination ARV therapy, including EDURANT®. Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barré syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment

    Drug Interactions

    • EDURANT® is primarily metabolized by cytochrome P450 (CYP)3A.
      • Coadministration of EDURANT® and drugs that induce CYP3A may result in decreased plasma concentrations, loss of virologic response and possible resistance to EDURANT® or to the class of NNRTIs
      • Coadministration of EDURANT® and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine
    • Coadministration of EDURANT® with drugs that increase gastric pH may result in decreased plasma concentrations, loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs
    • EDURANT® should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes
    • EDURANT® should not be used in combination with NNRTIs

    This is not a complete list of potential drug interactions.

    Please see full Prescribing Information for more details.

    Use in Specific Populations

    • Hepatic Impairment: No dosage adjustment of EDURANT® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. EDURANT® has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C)
    • Pregnancy: In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period
    • Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission
    • Pediatric Use: Safety and effectiveness in pediatric patients less than 12 years of age or weighing less than 35 kg have not been established
    • Renal Impairment: Use with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. EDURANT® concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. EDURANT® is highly bound to plasma proteins; it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis
    • Geriatric Use: Clinical studies of EDURANT® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT® in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy

    Adverse Reactions

    • The most common adverse drug reactions reported (incidence >2%) of at least moderate intensity (≥ Grade 2) in patients taking EDURANT® through 96 weeks were depressive disorders (5%), headache (3%), insomnia (3%), and rash (3%)

    Please read the full Prescribing Information for EDURANT®.

    cp-51575v8

    INDICATION
  • ERLEADA® (apalutamide)

    INDICATIONS

    ERLEADA® (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with:

    • Metastatic castration-sensitive prostate cancer (mCSPC)
    • Non-metastatic castration-resistant prostate cancer (nmCRPC)

    IMPORTANT Safety Information

    WARNINGS AND PRECAUTIONS

    Cerebrovascular and Ischemic Cardiovascular Events In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA® and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA® and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

    In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA® and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA®, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.

    Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events.

    Fractures In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

    Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly. Evaluate patients for fall risk.

    Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

    Severe Cutaneous Adverse Reactions Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens‑Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA®.

    Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA® until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA® [see Dosage and Administration (2.2)].

    Embryo-Fetal Toxicity The safety and efficacy of ERLEADA® have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)].

    ADVERSE REACTIONS

    The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

    Laboratory Abnormalities — All Grades (Grade 3-4)

    • Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (1.8%), placebo 21% (1.6%)
    • Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA® 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA® 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (1.9%), placebo 22% (0.5%)

    Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%).

    The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA®.

    Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA® and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted.

    DRUG INTERACTIONS

    Effect of Other Drugs on ERLEADA® Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)].

    Effect of ERLEADA® on Other Drugs

    CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA® with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA® and evaluate for loss of activity.

    P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA® and evaluate for loss of activity if medication is continued.

    Please see the full Prescribing Information for ERLEADA®.

    cp-50507v6

    INDICATIONS
  • Infliximab

    INDICATIONS

    Crohn’s Disease

    Infliximab is indicated for:

    • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response to conventional therapy.
    • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD.

    Pediatric Crohn’s Disease

    Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy.

    Ulcerative Colitis

    Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy.

    Pediatric Ulcerative Colitis

    Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

    Rheumatoid Arthritis

    Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA).

    Ankylosing Spondylitis

    Infliximab is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).

    Psoriatic Arthritis

    Infliximab is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA).

    Plaque Psoriasis

    Infliximab is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Infliximab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

    IMPORTANT SAFETY INFORMATION FOR Infliximab

    SERIOUS INFECTIONS

    Patients treated with Infliximab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Infliximab if a patient develops a serious infection or sepsis.

    Reported infections include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with Infliximab.1,2 Treatment for latent infection should be initiated prior to treatment with Infliximab.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella, Listeria, and Salmonella.

    The risks and benefits of treatment with Infliximab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Infliximab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with Infliximab included pneumonia, cellulitis, abscess, and skin ulceration.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Infliximab. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    Post-marketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including Infliximab. These cases have had a very aggressive disease course and have been fatal. The majority of reported Infliximab cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with Infliximab at or prior to diagnosis. Carefully assess the risks and benefits of treatment with Infliximab, especially in these patient types.

    In clinical trials of all TNF blockers, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF blockers, including Infliximab, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with Infliximab was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use. As the potential role of TNF blockers in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including Infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    A population-based retrospective cohort study found a 2- to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with Infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between Infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with Infliximab.

    CONTRAINDICATIONS

    The use of Infliximab at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. Infliximab is contraindicated in patients with a previous severe hypersensitivity reaction to Infliximab or any of the inactive ingredients of Infliximab or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

    HEPATITIS B REACTIVATION

    TNF blockers, including Infliximab, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating Infliximab. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing Infliximab for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with Infliximab. Discontinue Infliximab in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of Infliximab and monitor patients closely.

    HEPATOTOXICITY

    Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported in patients receiving Infliximab post-marketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, Infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken.

    HEART FAILURE

    In a randomized, placebo-controlled study in patients with moderate or severe heart failure (NYHA Functional Class III/IV), higher mortality rates and a higher risk of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors. Patients with moderate or severe heart failure taking Infliximab (≤5 mg/kg) or patients with mild heart failure should be closely monitored and treatment should be discontinued if new or worsening symptoms appear.

    HEMATOLOGIC EVENTS

    Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to Infliximab therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of Infliximab in patients who develop significant hematologic abnormalities.

    HYPERSENSITIVITY

    Infliximab has been associated with hypersensitivity reactions that differ in their time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in association with infusions of Infliximab. Medications for the treatment of hypersensitivity reactions should be available.

    CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

    Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of Infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of Infliximab infusion. Monitor patients during infusion and if a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

    NEUROLOGIC EVENTS

    TNF blockers, including Infliximab, have been associated with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering Infliximab in patients with these disorders and consider discontinuation if these disorders develop.

    CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS

    Concurrent use of Infliximab with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as Infliximab is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

    AUTOIMMUNITY

    Treatment with Infliximab may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

    Prior to initiating Infliximab, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with Infliximab due to the possibility of clinical infections, including disseminated infections.

    At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to Infliximab.

    ADVERSE REACTIONS

    In clinical trials, the most common adverse reactions occurring in >10% of Infliximab-treated patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

    For more information, please see the full Prescribing Information, including Boxed Warning, and Medication Guide for Infliximab. Provide the Medication Guide to your patients and encourage discussion.

    References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

    cp-253862v1

    INDICATIONS
  • INTELENCE® (etravirine)

    INDICATION STATEMENT

    INTELENCE® (etravirine), in combination with other antiretroviral (ARV) agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in ARV treatment-experienced adults and pediatric patients ages 2 years and older.

    IMPORTANT SAFETY INFORMATION

    WARNINGS & PRECAUTIONS

    • Severe Skin and Hypersensitivity Reactions:
      • Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking INTELENCE®. In clinical trials, these include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme.
      • Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving INTELENCE® in combination with other HIV-1 ARV agents in an observational study.
      • Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.

    Discontinue INTELENCE® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema).

      • Monitor clinical status including liver transaminases, and initiate appropriate therapy.
      • Delay in stopping INTELENCE® treatment after the onset of severe rash may result in a life-threatening reaction.
    • Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:
      • The concomitant use of INTELENCE® and other drugs may result in potentially significant drug interactions, some of which may lead to the loss of therapeutic effect of INTELENCE® and possible development of resistance or possible clinically significant adverse reactions from greater exposures of INTELENCE® or concomitant drugs.
      • Consult the full Prescribing Information for potential drug interactions prior to and during INTELENCE® therapy; review concomitant medications during INTELENCE® therapy.
    • Immune Reconstitution Syndrome has been reported in patients treated with ARV therapy, including INTELENCE®. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

    ADVERSE REACTIONS

    • The most common adverse drug reactions (≥2%) of at least moderate intensity (≥Grade 2) reported in adult patients taking INTELENCE® and that occurred at a higher rate compared with placebo were rash (10% vs 3%) and peripheral neuropathy (4% vs 2%). The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea.

    DRUG INTERACTIONS

    • Consult the full Prescribing Information for INTELENCE® for more information on significant drug interactions, including clinical comments.
    • Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P‑glycoprotein (P-gp). Therefore, co‑administration of INTELENCE® and drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp may alter the therapeutic effect or adverse reaction profile of the co‑administered drug(s).

    USE IN SPECIFIC POPULATIONS

    • Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. Patients should not breastfeed if they are receiving INTELENCE®.
    • Hepatic Impairment: INTELENCE® should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics of INTELENCE® have not been evaluated in these patients.
    • Pediatric Use: In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving INTELENCE® have been reported (see Warnings & Precautions).

    Please see full Prescribing Information for INTELENCE®.

    cp-63695v3

    INDICATION
  • INVEGA HAFYERA™ (paliperidone palmitate)

    INDICATION

    INVEGA HAFYERA™, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

    • A once-a-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA SUSTENNA®) for at least four months or
    • An every-three-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA TRINZA®) for at least one three-month cycle.

    IMPORTANT SAFETY INFORMATION

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA HAFYERA™ is not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA HAFYERA™ is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone or INVEGA HAFYERA™ in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse of blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA HAFYERA™ and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA HAFYERA™, drug discontinuation should be considered. However, some patients may require treatment with INVEGA HAFYERA™ despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA HAFYERA™ may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA HAFYERA™ should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA HAFYERA™, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA HAFYERA™. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA HAFYERA™ at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA HAFYERA™ in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA HAFYERA™ elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA HAFYERA™. INVEGA HAFYERA™ has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA HAFYERA™ does not adversely affect them.

    Seizures: INVEGA HAFYERA™ should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For gluteal intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA HAFYERA™ kits. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA HAFYERA™. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA HAFYERA™ may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA HAFYERA™. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA HAFYERA™ during pregnancy. INVEGA HAFYERA™ can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA HAFYERA™ and any potential adverse effect on the breastfed infant from INVEGA HAFYERA™ or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA HAFYERA™: The most common adverse reactions (incidence at least 5% in the double-blind phase) in the INVEGA HAFYERA™ clinical trial were upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA HAFYERA™.

    cp-256050v1

    INDICATION
  • INVEGA SUSTENNA® (paliperidone palmitate)

    INDICATION

    INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of:

    • Schizophrenia in adults.
    • Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants in adults.

    IMPORTANT SAFETY INFORMATION FOR INVEGA SUSTENNA® (paliperidone palmitate)

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA SUSTENNA® is not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA SUSTENNA® is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the INVEGA SUSTENNA® formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA SUSTENNA® and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA SUSTENNA® elevates prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA®.

    INVEGA SUSTENNA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA SUSTENNA® does not adversely affect them.

    Seizures: INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA SUSTENNA® kit. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g. carbamazepine, rifampin, St. John’s Wort) during a dosing interval for INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA SUSTENNA® during pregnancy. INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA SUSTENNA® and any potential adverse effects on the breastfed infant from INVEGA SUSTENNA® or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5% and twice placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. No adverse events occurred at a rate of ≥5% and twice placebo during the 15-month double-blind, placebo-controlled study in patients with schizoaffective disorder. The following adverse reactions occurred more frequently (a ≥2% difference vs. placebo) in the long-term study in patients with schizoaffective disorder: weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA®.

    cp-64202v3

    INDICATION
  • INVEGA TRINZA® (paliperidone palmitate)

    INDICATION

    INVEGA TRINZA® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate) for at least four months.

    INVEGA SUSTENNA® (paliperidone palmitate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

    IMPORTANT SAFETY INFORMATION

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA SUSTENNA® and INVEGA TRINZA® are not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA TRINZA® and INVEGA SUSTENNA® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA SUSTENNA® or INVEGA TRINZA® and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA® or INVEGA TRINZA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA® or INVEGA TRINZA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA TRINZA® and INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA TRINZA® and INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA TRINZA® and INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® and INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA TRINZA® and INVEGA SUSTENNA® elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® and INVEGA SUSTENNA®. INVEGA TRINZA® and INVEGA SUSTENNA® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA TRINZA® and INVEGA SUSTENNA® do not adversely affect them.

    Seizures: INVEGA TRINZA® and INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA TRINZA® or INVEGA SUSTENNA® kits. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA TRINZA® or INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA TRINZA® and INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA® or INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA TRINZA® or INVEGA SUSTENNA® during pregnancy. INVEGA TRINZA® and INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® or INVEGA SUSTENNA® and any potential adverse effect on the breastfed infant from INVEGA TRINZA® or INVEGA SUSTENNA® or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA TRINZA®: The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism.

    Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA® and click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA®.

    cp-64206v3

    INDICATION
  • INVOKAMET® (canagliflozin/metformin HCl)

    indications

    INVOKAMET® and INVOKAMET® XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

    Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

    Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular death (CV), and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

    Limitations of Use

    INVOKAMET® or INVOKAMET® XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    IMPORTANT SAFETY INFORMATION for INVOKAMET® (canagliflozin/metformin HCl) and INVOKAMET® XR (canagliflozin/metformin HCl extended-release)

    WARNING: LACTIC ACIDOSIS

    • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
    • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
    • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
    • If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET® or INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    CONTRAINDICATIONS

    INVOKAMET® or INVOKAMET® XR is contraindicated in patients with:

    • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
    • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    • Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET® or INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.

    Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET® or INVOKAMET® XR and report these symptoms to their healthcare provider.

    Recommendations to reduce the risk include:

    Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).

    Age 65 or Greater: Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Stop INVOKAMET® or INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET® or INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Discontinue INVOKAMET® or INVOKAMET® XR while patients have restricted food and fluid intake.

    Hypoxic States: Discontinue INVOKAMET® or INVOKAMET® XR in conditions associated with hypoxemia.

    Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    Hepatic Impairment: Avoid use of INVOKAMET® or INVOKAMET® XR in patients with evidence of hepatic disease.

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKAMET® or INVOKAMET® XR.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. INVOKAMET® or INVOKAMET® XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET® or INVOKAMET® XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET® or INVOKAMET® XR; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET® or INVOKAMET® XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET® or INVOKAMET® XR.

    Withhold INVOKAMET® or INVOKAMET® XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET® or INVOKAMET® XR when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET® or INVOKAMET® XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET® or INVOKAMET® XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving canagliflozin. Treatment with INVOKAMET® or INVOKAMET® XR increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use of Sulfonylurea or Insulin: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET® or INVOKAMET® XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET® or INVOKAMET® XR.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET® or INVOKAMET® XR.
    • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET® or INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
    • Vitamin B12 Levels: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2‑ to 3‑year intervals and manage any abnormalities.

    DRUG INTERACTIONS

    Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET® or INVOKAMET® XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

    Drugs That Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, and cimetidine) involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

    Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    UGT Enzyme Inducers: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET® or INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET® or INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg.

    Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET® or INVOKAMET® XR is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

    Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for hypoglycemia.

    Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKAMET® or INVOKAMET® XR with concomitant digoxin for a need to adjust dose of digoxin.

    Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKAMET® or INVOKAMET® XR initiation and dosage changes.

    Drug/Laboratory Test Interference

    Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKAMET® or INVOKAMET® XR is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKAMET® or INVOKAMET® XR is not recommended while breastfeeding.
    • Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
    • Pediatric Use: Safety and effectiveness of INVOKAMET® or INVOKAMET® XR in patients <18 years of age have not been established.
    • Geriatric Use: Frequently monitor renal function after initiating INVOKAMET® or INVOKAMET® XR in elderly patients and adjust dose accordingly.

    Canagliflozin

    Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300‐mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.

    Metformin HCl

    The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.

    Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: Metformin HCl use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET® or INVOKAMET® XR is not recommended in patients with hepatic impairment.

    OVERDOSAGE

    • In the event of an overdose with INVOKAMET® or INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common (≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
    • The most common (≥5%) adverse reactions due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

    Please read full Prescribing Information for INVOKAMET® and INVOKAMET® XR, including Boxed WARNING, and Medication Guide for INVOKAMET® and INVOKAMET® XR.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68815v6

    INDICATIONS
  • INVOKAMET® XR (canagliflozin/metformin HCl extended-release tablets)

    indications

    INVOKAMET® and INVOKAMET® XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

    Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

    Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular death (CV), and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

    Limitations of Use

    INVOKAMET® or INVOKAMET® XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    IMPORTANT SAFETY INFORMATION for INVOKAMET® (canagliflozin/metformin HCl) and INVOKAMET® XR (canagliflozin/metformin HCl extended-release)

    WARNING: LACTIC ACIDOSIS

    • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
    • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
    • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
    • If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET® or INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    CONTRAINDICATIONS

    INVOKAMET® or INVOKAMET® XR is contraindicated in patients with:

    • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
    • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    • Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET® or INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.

    Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET® or INVOKAMET® XR and report these symptoms to their healthcare provider.

    Recommendations to reduce the risk include:

    Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).

    Age 65 or Greater: Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Stop INVOKAMET® or INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET® or INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Discontinue INVOKAMET® or INVOKAMET® XR while patients have restricted food and fluid intake.

    Hypoxic States: Discontinue INVOKAMET® or INVOKAMET® XR in conditions associated with hypoxemia.

    Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    Hepatic Impairment: Avoid use of INVOKAMET® or INVOKAMET® XR in patients with evidence of hepatic disease.

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKAMET® or INVOKAMET® XR.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. INVOKAMET® or INVOKAMET® XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET® or INVOKAMET® XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET® or INVOKAMET® XR; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET® or INVOKAMET® XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET® or INVOKAMET® XR.

    Withhold INVOKAMET® or INVOKAMET® XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET® or INVOKAMET® XR when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET® or INVOKAMET® XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET® or INVOKAMET® XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving canagliflozin. Treatment with INVOKAMET® or INVOKAMET® XR increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use of Sulfonylurea or Insulin: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET® or INVOKAMET® XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET® or INVOKAMET® XR.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET® or INVOKAMET® XR.
    • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET® or INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
    • Vitamin B12 Levels: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2‑ to 3‑year intervals and manage any abnormalities.

    DRUG INTERACTIONS

    Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET® or INVOKAMET® XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

    Drugs That Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, and cimetidine) involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

    Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    UGT Enzyme Inducers: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET® or INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET® or INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg.

    Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET® or INVOKAMET® XR is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

    Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for hypoglycemia.

    Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKAMET® or INVOKAMET® XR with concomitant digoxin for a need to adjust dose of digoxin.

    Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKAMET® or INVOKAMET® XR initiation and dosage changes.

    Drug/Laboratory Test Interference

    Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKAMET® or INVOKAMET® XR is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKAMET® or INVOKAMET® XR is not recommended while breastfeeding.
    • Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
    • Pediatric Use: Safety and effectiveness of INVOKAMET® or INVOKAMET® XR in patients <18 years of age have not been established.
    • Geriatric Use: Frequently monitor renal function after initiating INVOKAMET® or INVOKAMET® XR in elderly patients and adjust dose accordingly.

    Canagliflozin

    Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300‐mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.

    Metformin HCl

    The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.

    Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: Metformin HCl use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET® or INVOKAMET® XR is not recommended in patients with hepatic impairment.

    OVERDOSAGE

    • In the event of an overdose with INVOKAMET® or INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common (≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
    • The most common (≥5%) adverse reactions due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

    Please read full Prescribing Information for INVOKAMET® and INVOKAMET® XR, including Boxed WARNING, and Medication Guide for INVOKAMET® and INVOKAMET® XR.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68815v6

    INDICATIONS
  • INVOKANA® (canagliflozin)

    INDICATIONS

    INVOKANA® (canagliflozin) is indicated:

    • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
    • To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD)
    • To reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day

    Limitations of Use

    INVOKANA® is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    INVOKANA® is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. INVOKANA® is likely to be ineffective in this setting based upon its mechanism of action.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    • Serious hypersensitivity reaction to INVOKANA®, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKANA®. INVOKANA® is not indicated for glycemic control in patients with type 1 diabetes mellitus.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA®.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKANA®; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKANA®, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA®.

    Withhold INVOKANA®, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA® when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with INVOKANA® use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA® in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA® in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating INVOKANA®, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: INVOKANA® can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA® in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving INVOKANA®. Treatment with INVOKANA® increases this risk. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA® may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA®.
    • Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with INVOKANA®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA®, treat, and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA®. Prior to initiation, consider factors that contribute to fracture risk.

    DRUG INTERACTIONS

    • UGT Enzyme Inducers: UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) decrease canagliflozin exposure which may reduce the effectiveness of INVOKANA®. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs is administered with INVOKANA®, increase the dosage to 200 mg daily (taken as two 100-mg tablets) in patients currently tolerating INVOKANA® 100 mg daily. The total daily dosage may be increased to 300 mg daily in patients currently tolerating INVOKANA® 200 mg daily who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is administered with INVOKANA®, increase the dose to 200 mg daily (taken as two 100-mg tablets) in patients currently tolerating INVOKANA® 100 mg daily. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

    • Insulin or Insulin Secretagogues: The risk of hypoglycemia is increased when INVOKANA® is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue of insulin to reduce the risk of hypoglycemia.
    • Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKANA® with concomitant digoxin for a need to adjust the dosage of digoxin.
    • Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKANA® initiation and dosage changes.

    Drug/Laboratory Test Interference

    • Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
    • Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKANA® is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKANA® is not recommended while breastfeeding.
    • Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.
    • Geriatric Use: Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300-mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years.
    • Renal Impairment: The efficacy and safety of INVOKANA® for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using INVOKANA® for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: INVOKANA® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

    OVERDOSAGE

    • In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common adverse reactions (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination.

    Please read full Prescribing Information and Medication Guide for INVOKANA®.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68813v8

    INDICATIONS
  • OPSUMIT® (macitentan)

    INDICATION

    OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

    Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

    IMPORTANT SAFETY INFORMATION

    BOXED WARNING: EMBRYO-FETAL TOXICITY

    • Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
    • Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
    • For all female patients, OPSUMIT® is available only through a restricted program called the Macitentan Risk Evaluation and Mitigation Strategy (REMS).

    CONTRAINDICATIONS

    Pregnancy: OPSUMIT® may cause fetal harm when administered to a pregnant woman. OPSUMIT® is contraindicated in females who are pregnant. If OPSUMIT® is used during pregnancy, advise the patient of the potential risk to a fetus.

    Hypersensitivity: OPSUMIT® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product.

    WARNINGS AND PRECAUTIONS

    Embryo-fetal Toxicity and Macitentan REMS Program

    Due to the risk of embryo-fetal toxicity, OPSUMIT® is available for females only through a restricted program called the Macitentan REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.

    Notable requirements of the Macitentan REMS Program include:

    • Prescribers must be certified with the program by enrolling and completing training.
    • All females, regardless of reproductive potential, must enroll in the Macitentan REMS Program prior to initiating OPSUMIT®. Male patients are not enrolled in the REMS.
    • Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
    • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT®.

    Hepatotoxicity

    • ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 x ULN was 3.4% for OPSUMIT® vs 4.5% for placebo, and >8 x ULN was 2.1% vs 0.4%, respectively. Discontinuations for hepatic adverse events were 3.3% for OPSUMIT® vs 1.6% for placebo.
    • Obtain liver enzyme tests prior to initiation of OPSUMIT® and repeat during treatment as clinically indicated.
    • Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).
    • If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT®. Consider re-initiation of OPSUMIT® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

    Fluid Retention

    • Peripheral edema and fluid retention are known consequences of PAH and ERAs. In the pivotal PAH study SERAPHIN, edema was reported in 21.9% of the OPSUMIT® group vs 20.5% for placebo.
    • Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of pulmonary hypertension due to left ventricular dysfunction, more patients in the OPSUMIT® group developed significant fluid retention and had more hospitalizations due to worsening heart failure compared to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT®, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.
    • Monitor for signs of fluid retention after OPSUMIT® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the possible need to discontinue OPSUMIT®.

    Hemoglobin Decrease

    • Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and in clinical studies with OPSUMIT®. These decreases occurred early and stabilized thereafter.
    • In the SERAPHIN study, OPSUMIT® caused a mean decrease in hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® group vs 3.4% for placebo. Decreases in hemoglobin seldom require transfusion.
    • Initiation of OPSUMIT® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.

    Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

    Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT®.

    Decreased Sperm Counts

    OPSUMIT®, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.

    ADVERSE REACTIONS

    Most common adverse reactions (more frequent than placebo by ≥3%) were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infection (9% vs 6%).

    DRUG INTERACTIONS

    • Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT® with strong CYP3A4 inducers should be avoided.
    • Strong inhibitors of CYP3A4 like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT® with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
    • Moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole and amiodarone are predicted to increase macitentan exposure. Avoid concomitant use of OPSUMIT® with moderate dual inhibitors of CYP3A4 and CYP2C9.
    • Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT® should also be avoided.

    Please see accompanying full Prescribing Information, including BOXED WARNING, for OPSUMIT®.

    cp-113979v6

    INDICATION
  • PONVORY® (ponesimod)

    INDICATION

    PONVORY® is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    PONVORY® is contraindicated in patients who:

    • In the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure.
    • Have presence of Mobitz Type II second-degree, third-degree atrioventricular (AV) block, or sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker.

    WARNINGS AND PRECAUTIONS

    Risk of Infections

    PONVORY® causes a dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. PONVORY® may increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators. Before initiating treatment with PONVORY®, results from a recent complete blood count including lymphocyte count should be reviewed.

    Herpes Viral Infections

    Cases of herpes viral infection have been reported in the development program of PONVORY®; herpes simplex encephalitis and varicella zoster meningitis have been reported with other S1P receptor modulators. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination should be tested for antibodies to VZV prior to initiating PONVORY®.

    Cryptococcal Infections

    Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. PONVORY® treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

    Progressive Multifocal Leukoencephalopathy (PML)

    PML has been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with PONVORY® should be suspended until PML has been excluded.

    If PML is confirmed, treatment with PONVORY® should be discontinued.

    Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

    Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies

    Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects.

    Vaccinations

    Patients without a confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY® treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with PONVORY®, following which initiation of treatment should be postponed for 4 weeks to allow the full effect of vaccination to occur.

    No clinical data are available on the efficacy and safety of vaccinations in patients taking PONVORY®. Vaccinations may be less effective if administered during PONVORY® treatment. If live attenuated vaccines are required, administer at least 1 month prior to initiation of PONVORY®. Avoid the use of live attenuated vaccines during and for 1 to 2 weeks after treatment of PONVORY®.

    Bradyarrhythmia and Atrioventricular Conduction Delays

    Since initiation of PONVORY® treatment results in a transient decrease in heart rate and atrioventricular (AV) conduction delays, an up-titration scheme must be used to reach the maintenance dosage of PONVORY® (20 mg).

    Reduction in Heart Rate

    Initiation of PONVORY® may result in a transient decrease in heart rate. After the first titration dose of PONVORY®, the decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration.

    Atrioventricular Conduction Delays

    Initiation of PONVORY® treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. If treatment with PONVORY® is considered, advice from a cardiologist should be sought for individuals:

    • With significant QT prolongation (QTc greater than 500 msec).
    • With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs.
    • With unstable ischemic heart disease, cardiac decompensated failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension.
    • With a history of Mobitz Type II second degree AV block or higher-grade AV block, sick-sinus syndrome, or sino-atrial heart block.

    Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. For patients taking other drugs that decrease heart rate, treatment with PONVORY® should generally not be initiated without consultation from a cardiologist because of the potential effect on heart rate. In all patients, a dose titration is recommended for initiation of PONVORY® treatment to help reduce cardiac effects.

    Respiratory Effects

    Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide (DLCO) were observed in PONVORY®-treated patients mostly occurring in the first month after treatment initiation. Spirometric evaluation of respiratory function should be performed during therapy with PONVORY® if clinically indicated.

    Liver Injury

    Elevations of transaminases may occur in PONVORY®-treated patients. Obtain transaminase and bilirubin levels, if not recently available (i.e., within last 6 months) before initiation of PONVORY® therapy.

    Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have hepatic enzymes checked. PONVORY® should be discontinued if significant liver injury is confirmed.

    No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). PONVORY® is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C, respectively).

    Increased Blood Pressure

    PONVORY®-treated patients had an average increase of 2.9 mmHg in systolic blood pressure and 2.8 mmHg in diastolic blood pressure. Blood pressure should be monitored during treatment with PONVORY® and managed appropriately.

    Cutaneous Malignancies

    Cases of basal cell carcinoma and other skin malignancies have been reported in patients treated with S1P receptor modulators, including PONVORY®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking PONVORY®.

    Fetal Risk

    Based on animal studies, PONVORY® may cause fetal harm. Because it takes approximately 1 week to eliminate PONVORY® from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 1 week after stopping PONVORY® treatment.

    Macular Edema

    S1P receptor modulators, including PONVORY®, have been associated with an increased risk of macular edema. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and again at any time if a patient reports any change in vision while on PONVORY® therapy. Continuation of therapy in patients with macular edema has not been evaluated.

    Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

    Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during therapy with S1P receptor modulators, including PONVORY®. Therefore, these patients should have regular follow-up examinations of the fundus, including the macula, during treatment with PONVORY®.

    Posterior Reversible Encephalopathy Syndrome

    Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for PONVORY®-treated patients in the development program. However, should a PONVORY®-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, PONVORY® should be discontinued.

    Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies

    When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive effects on the immune system while at the same time minimizing risk of disease reactivation, when initiating PONVORY®. Initiating treatment with PONVORY® after treatment with alemtuzumab is not recommended.

    Severe Increase in Disability After Stopping PONVORY®

    Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping PONVORY® treatment. Patients should be observed for a severe increase in disability upon PONVORY® discontinuation and appropriate treatment should be instituted, as required.

    After stopping PONVORY® in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

    Immune System Effects After Stopping PONVORY®

    After stopping PONVORY® therapy, ponesimod remains in the blood for up to 1 week.

    Starting other therapies during this interval will result in concomitant exposure to ponesimod. Lymphocyte counts returned to the normal range in 90% of patients within 1 week of stopping therapy, however, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for 1 to 2 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 1 to 2 weeks after the last dose of PONVORY®.

    OVERDOSAGE

    In patients with overdosage of PONVORY®, especially upon initiation/re-initiation of treatment, it is important to observe for signs and symptoms of bradycardia as well as AV conduction blocks, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed.

    There is no specific antidote to ponesimod. Neither dialysis nor plasma exchange would result in meaningful removal of ponesimod from the body. The decrease in heart rate induced by PONVORY® can be reversed by atropine.

    In the event of overdose, PONVORY® should be discontinued, and general supportive treatment given until clinical toxicity has been diminished or resolved. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose.

    ADVERSE REACTIONS

    Most common adverse reactions (incidence at least 10%) are upper respiratory tract infection, hepatic transaminase elevation, and hypertension.

    Please see full Prescribing Information and Medication Guide.

    cp-214886v6

    INDICATION
  • PREZCOBIX® (darunavir 800 mg/cobicistat 150 mg)

    Indication

    PREZCOBIX® is indicated in combination with other antiretroviral agents for the treatment of Human Immunodeficiency Virus (HIV-1) infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

    Important Safety Information

    Contraindications

    • Darunavir and cobicistat are both inhibitors and substrates of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX® should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). In addition, co-administration of PREZCOBIX® with CYP3A inducers may lead to lower exposures of darunavir and cobicistat, and potential loss of efficacy of darunavir and possible resistance.

    Examples of drugs that are contraindicated for co-administration with PREZCOBIX® are: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, ivabradine, lomitapide, lovastatin, lurasidone, methylergonovine, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

    Warnings and Precautions

    • Hepatotoxicity: Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions. Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported.

    Appropriate laboratory testing should be conducted prior to initiating and during therapy with PREZCOBIX®. Evidence of new or worsening liver dysfunction in patients on PREZCOBIX® should prompt consideration of interruption or discontinuation of treatment.

    • Severe Skin Reactions: Severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported in patients receiving darunavir coadministered with ritonavir. Mild-to-moderate rash was also reported and often occurred and resolved with continued dosing. Discontinue PREZCOBIX® immediately if signs or symptoms of severe skin reaction develop.
    • Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX®.
    • Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. Prior to starting PREZCOBIX®, assess estimated CrCl. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
    • Renal Impairment When Used With Tenofovir Disoproxil Fumarate (DF): Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported with the use of tenofovir DF and cobicistat. Coadministration with tenofovir DF is not recommended in patients who have an estimated CrCl <70 mL/min. In all patients, monitor estimated CrCl, urine glucose, and urine protein prior to initiating and during therapy. Measure serum phosphorus in patients at risk of renal impairment. Coadministration of PREZCOBIX® and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
    • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Initiation of PREZCOBIX®, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX® may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX®. These interactions may lead to clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications; clinically significant adverse reactions from higher exposures of PREZCOBIX®; loss of therapeutic effect of concomitant medications from lower exposures of active metabolite(s); or loss of therapeutic effect of PREZCOBIX® and possible development of resistance from lower exposures of PREZCOBIX®.
    • Antiretrovirals Not Recommended: Do not use PREZCOBIX® in combination with other antiretroviral drugs that require pharmacokinetic boosting or which contain the individual components of PREZCOBIX® (darunavir and cobicistat) or with ritonavir.
    • Diabetes Mellitus/Hyperglycemia and Hemophilia: New onset or exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. Increased bleeding in hemophiliacs has been reported in patients receiving protease inhibitors.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.
    • Immune Reconstitution Syndrome including the occurrence of autoimmune disorders with variable time to onset has been reported.

    Adverse Reactions

    • The most common clinical adverse reactions (incidence ≥5%) of at least moderate intensity (≥Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting during the darunavir clinical development program, where darunavir was coadministered with ritonavir.

    This is not a complete list of all adverse drug reactions reported with the use of PREZCOBIX®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

    Drug Interactions

    • Consult the full Prescribing Information for PREZCOBIX® for information on potentially significant drug interactions, including clinical comments.

    Use in Specific Populations

    • PREZCOBIX® is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.
    • PREZCOBIX® should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with PREZCOBIX®.

    Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

    • The safety and effectiveness of PREZCOBIX® have not been established and is not recommended in pediatric patients weighing less than 40 kg.
    • Consult the full Prescribing Information for PREZCOBIX® for additional information on the Uses in Specific Populations.

    Please see full Prescribing Information for more details.

    cp-08641v12

    INDICATION
  • PREZISTA® (darunavir)

    Indication

    PREZISTA® (darunavir), coadministered with ritonavir (PREZISTA®/r), in combination with other antiretroviral agents (ARVs), is indicated for the treatment of Human Immunodeficiency Virus (HIV-1) infection in adult patients.

    Important Safety Information

    Contraindications

    • Co-administration of PREZISTA®/ritonavir (PREZISTA®/r) is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below. Due to the need for co-administration of PREZISTA® with ritonavir, please refer to ritonavir Prescribing Information for a description of ritonavir contraindications.
      • alfuzosin, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, ivabradine, lomitapide, lovastatin, lurasidone, methylergonovine, oral midazolam, naloxegol, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil (for the treatment of pulmonary arterial hypertension), simvastatin, and triazolam.

    Warnings & Precautions

    • PREZISTA® must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA® with ritonavir and food may result in a loss of efficacy of darunavir.
    • Hepatotoxicity: Drug-induced hepatitis has been reported with PREZISTA®/r. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA®/r. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

    Post-marketing cases of liver injury, including some fatalities, have been reported. A causal relationship with PREZISTA®/r therapy has not been established.

    Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA®/r and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA®/r treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA®/r should prompt consideration of interruption or discontinuation of treatment.

    • Severe Skin Reactions: Severe skin reactions (0.4%), accompanied by fever and/or elevations of transaminases in some cases, and Stevens-Johnson Syndrome (<0.1%) have been reported in patients receiving PREZISTA®/r. During post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported in patients receiving PREZISTA®/r. Discontinue PREZISTA®/r immediately if signs or symptoms of severe skin reactions develop (including, but not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).

    In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of patients receiving PREZISTA®/r. Discontinuation due to rash was 0.5%.

    Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA®/r + raltegravir compared to subjects receiving either drug regimen alone. However, rash that was considered drug-related occurred at similar rates. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

    • Sulfa Allergy: PREZISTA® should be used with caution in patients with known sulfonamide allergy.
    • Risk of Serious Adverse Reactions Due to Drug Interactions: Initiation of PREZISTA®/r, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA®/r, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA®/r, respectively. These interactions may lead to:
      • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
      • Clinically significant adverse reactions from greater exposures of PREZISTA®/r.
      • Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).
      • Loss of therapeutic effect of PREZISTA®/r and possible development of resistance from lower exposures of PREZISTA®/r.

    Consider the potential for drug interactions prior to and during PREZISTA®/r therapy, review concomitant medications during PREZISTA®/r therapy, and monitor for the adverse reactions associated with the concomitant drugs.

    • Diabetes Mellitus/Hyperglycemia and Hemophilia: New-onset or exacerbations of preexisting diabetes mellitus, hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. A causal relationship between protease inhibitors and these events has not been established.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
    • Immune Reconstitution Syndrome: Patients receiving PREZISTA®/r may develop new onset or exacerbations of immune reconstitution syndrome.

    Adverse Reactions

    • In treatment-naïve adult patients, the most common adverse drug reactions (≥5%) reported of at least moderate intensity (≥Grade 2) in the PREZISTA®/r arm through 192 weeks were diarrhea (9%), headache (7%), abdominal pain (6%), and rash (6%).
    • In treatment-experienced adult patients, the most common adverse drug reactions (≥5%) reported of at least moderate intensity (≥Grade 2) in the PREZISTA®/r arm through 96 weeks were diarrhea (14%), nausea (7%), rash (7%), abdominal pain (6%), and vomiting (5%).

    This is not a complete list of all adverse drug reactions reported with the use of PREZISTA®/r.

    Drug Interactions

    • Consult the full Prescribing Information for PREZISTA® for information on potentially significant drug interactions, including clinical comments.

    Use in Specific Populations

    • Hepatic Impairment: PREZISTA®/r is not recommended for use in patients with severe hepatic impairment. There are no pharmacokinetic or safety data available in patients with severe hepatic impairment.

    This list of uses in specific populations is not complete.

    Please refer to the ritonavir Prescribing Information for additional safety information.

    Please see full Prescribing Information for more details.

    cp-07779v7

    INDICATION
  • REMICADE® (infliximab)

    INDICATIONS

    Crohn's Disease

    REMICADE® is indicated for:

    • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy.
    • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD.

    Pediatric Crohn's Disease

    REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy.

    Ulcerative Colitis

    REMICADE® is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy.

    Pediatric Ulcerative Colitis

    REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

    Rheumatoid Arthritis

    REMICADE®, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA).

    Ankylosing Spondylitis

    REMICADE® is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).

    Psoriatic Arthritis

    REMICADE® is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA).

    Plaque Psoriasis

    REMICADE® is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

    IMPORTANT SAFETY INFORMATION FOR REMICADE® (infliximab)

    SERIOUS INFECTIONS

    Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.

    Reported infections include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®.1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella, Listeria, and Salmonella.

    The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including REMICADE®. These cases have had a very aggressive disease course and have been fatal. The majority of reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.

    In clinical trials of all TNF blockers, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF blockers, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF blockers in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    A population-based retrospective cohort study found a 2- to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with REMICADE® compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between REMICADE® and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMICADE®.

    CONTRAINDICATIONS

    The use of REMICADE® at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. REMICADE® is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab or any of the inactive ingredients of REMICADE® or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

    HEPATITIS B REACTIVATION

    TNF blockers, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.

    HEPATOTOXICITY

    Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.

    HEART FAILURE

    In a randomized, placebo-controlled study in patients with moderate or severe heart failure (NYHA Functional Class III/IV), higher mortality rates and a higher risk of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been postmarketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors. Patients with moderate or severe heart failure taking REMICADE® (≤5 mg/kg) or patients with mild heart failure should be closely monitored and treatment should be discontinued if new or worsening symptoms appear.

    HEMATOLOGIC EVENTS

    Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.

    HYPERSENSITIVITY

    REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Medications for the treatment of hypersensitivity reactions should be available.

    CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

    Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of REMICADE® infusion. Cases of transient visual loss have been reported during or within 2 hours of REMICADE® infusion. Monitor patients during infusion and if a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

    NEUROLOGIC EVENTS

    TNF blockers, including REMICADE®, have been associated with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE® in patients with these disorders and consider discontinuation if these disorders develop.

    CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS

    Concurrent use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as REMICADE® is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

    AUTOIMMUNITY

    Treatment with REMICADE® may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

    Prior to initiating REMICADE®, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with REMICADE® due to the possibility of clinical infections, including disseminated infections.

    At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to REMICADE®.

    ADVERSE REACTIONS

    In clinical trials, the most common adverse reactions occurring in >10% of REMICADE®-treated patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

    For more information, please see the full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.

    References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

    cp-62063v2

    INDICATIONS
  • RISPERDAL CONSTA® (risperidone)

    INDICATION

    RISPERDAL CONSTA® (risperidone) long-acting injection is indicated for the treatment of schizophrenia.

    IMPORTANT SAFETY INFORMATION FOR RISPERDAL CONSTA® (risperidone)

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL CONSTA® is not approved for use in patients with dementia-related psychosis.

    Contraindications: RISPERDAL CONSTA® is contraindicated in patients with a known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL CONSTA®.

    Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL CONSTA® is not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue RISPERDAL CONSTA® and provide symptomatic treatment and monitoring.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possible masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on RISPERDAL CONSTA®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL CONSTA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL CONSTA®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Monitor glucose regularly in patients with diabetes or at risk for diabetes. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Orthostatic Hypotension and Syncope: RISPERDAL CONSTA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. RISPERDAL CONSTA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL CONSTA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL CONSTA®. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL CONSTA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL CONSTA® and have their WBC followed until recovery.

    Potential for Cognitive and Motor Impairment: Somnolence was reported in multiple trials in subjects treated with RISPERDAL CONSTA®. Since RISPERDAL CONSTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL CONSTA® does not adversely affect them.

    Seizures: RISPERDAL CONSTA® should be used cautiously in patients with a history of seizures.

    Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Use cautiously in patients at risk for aspiration pneumonia.

    Priapism has been reported. Severe priapism may require surgical intervention.

    Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with RISPERDAL CONSTA® use.

    Thrombotic Thrombocytopenic Purpura (TTP) has been reported.

    Administration: For intramuscular injection only. Care should be taken to avoid inadvertent injection into a blood vessel.

    Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS.

    Use RISPERDAL CONSTA® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g., recent myocardial infarction or unstable cardiac disease).

    Pregnancy/Nursing: RISPERDAL CONSTA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with RISPERDAL CONSTA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to RISPERDAL CONSTA® during pregnancy. RISPERDAL CONSTA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for RISPERDAL CONSTA® and any potential adverse effect on the breastfed infant from RISPERDAL CONSTA® or the mother’s underlying condition.

    Fertility: RISPERDAL CONSTA® may cause a reversible reduction in fertility in females.

    Commonly Observed Adverse Reactions for RISPERDAL CONSTA®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5%) were headache, Parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities, and dry mouth.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for RISPERDAL CONSTA®.

    cp-64212v3

    INDICATIONS
  • RYBREVANT® (amivantamab-vmjw)

    INDICATION

    RYBREVANT® (amivantamab-vmjw) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

    This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Infusion-Related Reactions

    RYBREVANT® can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

    Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT®. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT® due to IRR.

    Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT® based on severity.

    Interstitial Lung Disease/Pneumonitis

    RYBREVANT® can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT®, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT® due to ILD/pneumonitis.

    Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

    Dermatologic Adverse Reactions

    RYBREVANT® can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT®, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT® was permanently discontinued due to rash in 0.7% of patients.

    Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT®.

    Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT®. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol‑free emollient cream is recommended for dry skin.

    If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

    Ocular Toxicity

    RYBREVANT® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

    Embryo-Fetal Toxicity

    Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT®.

    Adverse Reactions

    The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

    Please read full Prescribing Information for RYBREVANT®.

    cp-213274v2

    INDICATION
  • SIMPONI® (golimumab)

    INDICATIONS

    SIMPONI® is a tumor necrosis factor (TNF) blocker indicated for the treatment of adult patients with:

    • Moderately to severely active rheumatoid arthritis (RA), in combination with methotrexate (MTX)
    • Active psoriatic arthritis (PsA) alone, or in combination with MTX
    • Active ankylosing spondylitis (AS)
    • Moderately to severely active ulcerative colitis (UC) who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine for:
      • Inducing and maintaining clinical response
      • Improving endoscopic appearance of the mucosa during induction
      • Inducing clinical remission
      • Achieving and sustaining clinical remission in induction responders

    IMPORTANT SAFETY INFORMATION

    SERIOUS INFECTIONS

    Patients treated with SIMPONI® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI® if a patient develops a serious infection.

    Reported infections with TNF blockers, of which SIMPONI® is a member, include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI® use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI® use.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

    The risks and benefits of treatment with SIMPONI® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI® included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI® is a member.

    Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI®, more cases of lymphoma have been observed among patients receiving TNF-blocking treatment compared with control patients. In the Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), and Ankylosing Spondylitis (AS) clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI® group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI® and was similar to what would be expected in the general population. In controlled and uncontrolled portions of the Phase 2/3 studies in ulcerative colitis (UC) with a mean follow-up of approximately 1 year, there were no cases of lymphoma with SIMPONI®. Short follow-up periods, such as those of 1 year or less in the studies above, may not adequately reflect the true incidence of malignancies. Cases of acute and chronic leukemia have been reported with TNF-blocker use, including SIMPONI®. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

    Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or UC, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for HSTCL in patients treated with TNF blockers cannot be excluded.

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocking agents, including SIMPONI®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    HEPATITIS B REACTIVATION

    The use of TNF-blocking agents including SIMPONI® has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

    All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI®. Discontinue SIMPONI® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI®, and monitor patients closely.

    HEART FAILURE

    Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers, including SIMPONI®. Some cases had a fatal outcome. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI® if new or worsening symptoms of heart failure appear.

    DEMYELINATING DISORDERS

    TNF-blocking agents, of which SIMPONI® is a member, have been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported with SIMPONI®. Exercise caution in considering the use of SIMPONI® in patients with these disorders. Consider discontinuation if these disorders develop.

    AUTOIMMUNITY

    Treatment with TNF blockers, including SIMPONI®, may result in the formation of antinuclear antibodies and, rarely, in the development of a lupus-like syndrome. Discontinue treatment if symptoms suggestive of a lupus-like syndrome develop.

    HEMATOLOGIC CYTOPENIAS

    There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia in patients receiving SIMPONI®. Exercise caution when using SIMPONI® in patients who have or had significant cytopenias.

    USE WITH OTHER DRUGS

    The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the use of SIMPONI® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI® with biologics approved to treat RA, PsA, or AS is not recommended because of the possibility of an increased risk of infection.

    VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS

    People receiving SIMPONI® can receive vaccinations, except for live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Administration of live vaccines to infants exposed to SIMPONI® in utero is not recommended for 6 months following the mother’s last SIMPONI® injection during pregnancy due to an increased risk of infection. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI® due to the possibility of clinical infections, including disseminated infections.

    HYPERSENSITIVITY REACTIONS

    Serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported with SIMPONI®, some occurring after the first dose. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI® immediately and institute appropriate therapy.

    ADVERSE REACTIONS

    The most serious adverse reactions were serious infections and malignancies.

    Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI® as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI® compared with 2% of patients in the control group.

    In the Phase 2/3 trials in UC evaluating SIMPONI®-treated patients, no new adverse drug reactions were identified, and the frequency of adverse drug reactions was similar to the safety profile observed in patients with RA, PsA, and AS.

    Please see the full Prescribing Information and Medication Guide for SIMPONI®. Provide the Medication Guide to your patients and encourage discussion.

    cp-51205v1

    INDICATIONS
  • SIMPONI ARIA® (golimumab)

    INDICATIONS

    SIMPONI ARIA® (golimumab) is a tumor necrosis factor (TNF) blocker indicated for the treatment of:

    • Adult patients with moderately to severely active Rheumatoid Arthritis (RA) in combination with methotrexate
    • Active Psoriatic Arthritis (PsA) in patients 2 years of age and older
    • Adult patients with active Ankylosing Spondylitis (AS)
    • Active polyarticular Juvenile Idiopathic Arthritis (pJIA) in patients 2 years of age and older

    IMPORTANT SAFETY INFORMATION

    SERIOUS INFECTIONS

    Patients treated with SIMPONI ARIA® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI ARIA® if a patient develops a serious infection.

    Reported infections with TNF blockers, of which SIMPONI ARIA® is a member, include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before SIMPONI ARIA® use and during therapy. Initiate treatment for latent infection prior to SIMPONI ARIA® use.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

    Consider the risks and benefits of treatment with SIMPONI ARIA® prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI ARIA® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI ARIA® included sepsis, pneumonia, cellulitis, and abscess.

    MALIGNANCIES

    Malignancies, some fatal, have been reported in children, adolescents, and young adult patients treated with golimumab. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    In the controlled portions of clinical trials of TNF blockers including the subcutaneous formulation of golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. In clinical trials, the incidence of malignancies other than lymphoma and non-melanoma skin cancer per 100 patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA® group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group. Cases of acute and chronic leukemia have been reported with TNF-blocker use, including SIMPONI ARIA®. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

    Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for HSTCL in patients treated with TNF blockers cannot be excluded.

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocking agents, including SIMPONI ARIA®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    HEPATITIS B REACTIVATION

    The use of TNF blockers, of which SIMPONI ARIA® is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

    All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI ARIA® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI ARIA®. Discontinue SIMPONI ARIA® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI ARIA®, and monitor patients closely.

    CONGESTIVE HEART FAILURE

    Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers, including SIMPONI ARIA®. Some cases had a fatal outcome. Exercise caution in CHF patients receiving SIMPONI ARIA® and monitor them closely during therapy. Discontinue SIMPONI ARIA® if new or worsening symptoms of heart failure appear.

    DEMYELINATING DISORDERS

    Use of TNF blockers, including SIMPONI ARIA®, has been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with golimumab. Exercise caution in considering the use of SIMPONI ARIA® in patients with these disorders. Consider discontinuation if these disorders develop.

    AUTOIMMUNITY

    Treatment with TNF blockers, including SIMPONI ARIA®, may result in the formation of antinuclear antibodies. Rarely, treatment with TNF blockers may result in a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    USE WITH OTHER DRUGS

    The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI ARIA® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI ARIA® with biologics approved to treat RA is not recommended because of the possibility of an increased risk of infection.

    HEMATOLOGIC CYTOPENIAS

    There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia in patients receiving SIMPONI ARIA®. Exercise caution when using SIMPONI ARIA® in patients who have or had significant cytopenias.

    VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS

    Live vaccines or therapeutic infectious agents should not be given with SIMPONI ARIA® due to the possibility of clinical infections, including disseminated infections.

    Update vaccinations prior to initiation of treatment in accordance with current vaccination guidelines. Advise patients to discuss with the physician before seeking any immunizations. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to SIMPONI ARIA®.

    HYPERSENSITIVITY REACTIONS

    Serious systemic hypersensitivity reactions (including anaphylaxis) have been reported following administration of the subcutaneous formulation of golimumab and SIMPONI ARIA®, some occurring after the first dose. Hypersensitivity reactions including hives, pruritus, dyspnea, and nausea, were reported in association with infusions of SIMPONI ARIA®. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI ARIA® immediately and institute appropriate therapy.

    ADVERSE REACTIONS

    The most serious adverse reactions were serious infections and malignancies.

    The most common adverse reactions (incidence ≥ 3%) reported in clinical trials were: upper respiratory tract infection, alanine aminotransferase increase, viral infection, aspartate aminotransferase increase, neutrophil count decrease, bronchitis, hypertension, and rash. In the controlled phase of Trial RA, the rate of infusions associated with an infusion reaction was reported in 1.1% of SIMPONI ARIA® infusions compared with 0.2% of infusions in the control group.

    The adverse reactions observed in pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA) were consistent with the established safety profile of SIMPONI ARIA® in adult patients with RA and PsA.

    Please see the full Prescribing Information and Medication Guide for SIMPONI ARIA®. Provide the Medication Guide to your patients and encourage discussion.

    cp-51207v3

    INDICATIONS
  • SPRAVATO® (esketamine) CIII Nasal Spray

    Indications and Limitations of Use:

    SPRAVATO® (esketamine) CIII Nasal Spray is indicated, in conjunction with an oral antidepressant, for the treatment of:

    • Treatment-resistant depression (TRD) in adults.
    • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

    Limitations of Use:

    • The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO® does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO®.
    • SPRAVATO® is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO® as an anesthetic agent have not been established.

    Important Safety Information

    WARNING: SEDATION, DISSOCIATION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS

    See full prescribing information for complete boxed warning

    • Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration (5.1, 5.2).
    • Potential for abuse and misuse. Consider the risks and benefits of using SPRAVATO® prior to use in patients at higher risk of abuse. Monitor for signs and symptoms of abuse and misuse (5.3).
    • SPRAVATO® is only available through a restricted program called the SPRAVATO® REMS (5.4).
    • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO® is not approved for use in pediatric patients (5.5).

    CONTRAINDICATIONS

    SPRAVATO® is contraindicated in patients with:

    • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
    • History of intracerebral hemorrhage.
    • Hypersensitivity to esketamine, ketamine, or any of the excipients.

    WARNINGS AND PRECAUTIONS

    Sedation: In clinical trials, 48% to 61% of SPRAVATO®-treated patients developed sedation and 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness.

    Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

    Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants (e.g., benzodiazepines, opioids, alcohol).

    Dissociation: The most common psychological effects of SPRAVATO® were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO®-treated patients developed dissociative or perceptual changes). Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.

    Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

    Abuse and Misuse: SPRAVATO® contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient’s risk for abuse or misuse prior to prescribing and monitor all patients for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence.

    SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO® is available only through a restricted program called the SPRAVATO® REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.

    Important requirements of the SPRAVATO® REMS include the following:

    • Healthcare settings must be certified in the program and ensure that SPRAVATO® is:
      • Only dispensed and administered in healthcare settings.
      • Patients treated in outpatient settings (e.g., medical offices and clinics) must be enrolled in the program.
      • Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO®.
    • Pharmacies must be certified in the REMS and must only dispense SPRAVATO® to healthcare settings that are certified in the program.

    Further information, including a list of certified pharmacies, is available at www.SPRAVATOrems.com/ or 1-855-382-6022.

    Suicidal Thoughts and Behaviors in Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included adult and pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. SPRAVATO® is not approved in pediatric (<18 years of age) patients.

    There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

    Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO® and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

    Increase in Blood Pressure: SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO® administration and last approximately 4 hours.

    Approximately 8% to 19% of SPRAVATO®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risk.

    Assess BP prior to administration of SPRAVATO®. In patients whose BP is elevated prior to SPRAVATO® administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO® therapy should take into account the balance of benefit and risk in individual patients.

    BP should be monitored for at least 2 hours after SPRAVATO® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.

    Closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) or monoamine oxidase inhibitors (MAOIs).

    In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.

    Cognitive Impairment

    Short-Term Cognitive Impairment: In a study in healthy volunteers, a single dose of SPRAVATO® caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO®-treated subjects required a greater effort to complete the cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO® and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.

    Long-Term Cognitive Impairment: Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. No adverse effects of SPRAVATO® nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO® have not been evaluated beyond one year.

    Impaired Ability to Drive and Operate Machinery: Before SPRAVATO® administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO®.

    Ulcerative or Interstitial Cystitis: Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO® nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO®-treated patients than in placebo-treated patients. No cases of esketamine-related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year.

    Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO® and refer to an appropriate healthcare provider as clinically warranted.

    PREGNANCY, EMBRYO-FETAL TOXICITY, AND LACTATION

    SPRAVATO® is not recommended during pregnancy. SPRAVATO® may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO® in utero. Advise women of reproductive potential to consider pregnancy planning and prevention.

    There are risks to the mother associated with untreated depression in pregnancy. If a woman becomes pregnant while being treated with SPRAVATO®, treatment with SPRAVATO® should be discontinued and the patient should be counseled about the potential risk to the fetus.

    Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

    SPRAVATO® is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO®.

    SELECT USE IN SPECIFIC POPULATIONS

    Geriatric Use: No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age. At the end of a 4-week, randomized, double-blind study, there was no statistically significant difference between groups on the primary efficacy endpoint.

    Hepatic Impairment: SPRAVATO®-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.

    SPRAVATO® has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.

    ADVERSE REACTIONS

    The most common adverse reactions with SPRAVATO® plus oral antidepressant (incidence ≥5% and at least twice that of placebo nasal spray plus oral antidepressant) were:

    TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

    Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.

    Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO®.

    cp-361448v1

    INDICATIONS AND LIMITATIONS OF USE:
  • STELARA® (ustekinumab)

    INDICATIONS

    STELARA® (ustekinumab) is indicated for the treatment of patients 6 years and older with active psoriatic arthritis.

    STELARA® (ustekinumab) is indicated for the treatment of patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

    STELARA® (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

    STELARA® (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

    IMPORTANT SAFETY INFORMATION

    STELARA® (ustekinumab) is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients.

    Infections

    STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections requiring hospitalization or otherwise clinically significant infections were reported. In patients with psoriasis, these included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. In patients with psoriatic arthritis, this included cholecystitis. In patients with Crohn’s disease, these included anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and Listeria meningitis. In patients with ulcerative colitis, these included gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

    Treatment with STELARA® should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STELARA® in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA® and consider discontinuing STELARA® for serious or clinically significant infections until the infection resolves or is adequately treated.

    Theoretical Risk for Vulnerability to Particular Infections

    Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® may be susceptible to these types of infections. Appropriate diagnostic testing should be considered (eg, tissue culture, stool culture) as dictated by clinical circumstances.

    Pre-Treatment Evaluation of Tuberculosis (TB)

    Evaluate patients for TB prior to initiating treatment with STELARA®. Do not administer STELARA® to patients with active tuberculosis infection. Initiate treatment of latent TB before administering STELARA®. Closely monitor patients receiving STELARA® for signs and symptoms of active TB during and after treatment.

    Malignancies

    STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had risk factors for developing non-melanoma skin cancer (NMSC). All patients receiving STELARA®, especially those >60 years or those with a history of PUVA or prolonged immunosuppressant treatment, should be monitored for the appearance of NMSC.

    Hypersensitivity Reactions

    Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA®. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®.

    Posterior Reversible Encephalopathy Syndrome (PRES)

    Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.

    Monitor all patients treated with STELARA® for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA®.

    Immunizations

    Prior to initiating therapy with STELARA®, patients should receive all age-appropriate immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.

    Concomitant Therapies

    The safety of STELARA® in combination with other biologic immunosuppressive agents or phototherapy was not evaluated in clinical studies of psoriasis. Ultraviolet-induced skin cancers developed earlier and more frequently in mice. In psoriasis studies, the relevance of findings in mouse models for malignancy risk in humans is unknown. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease and ulcerative colitis induction studies, concomitant use of 6-mercaptopurine, azathioprine, methotrexate, and corticosteroids did not appear to influence the overall safety or efficacy of STELARA®.

    Noninfectious Pneumonia

    Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and, in certain cases, administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment.

    Allergen Immunotherapy

    STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

    Most Common Adverse Reactions

    The most common adverse reactions (≥3% and higher than that with placebo) in adults from psoriasis clinical studies for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively. The safety profile in pediatric patients with plaque psoriasis was similar to that of adults with plaque psoriasis. In psoriatic arthritis (PsA) studies, a higher incidence of arthralgia and nausea was observed in patients treated with STELARA® when compared with placebo (3% vs 1% for both). In Crohn’s disease induction studies, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 8 for STELARA® 6 mg/kg intravenous single infusion or placebo included: vomiting (4% vs 3%). In the Crohn’s disease maintenance study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 44 for STELARA® 90 mg subcutaneous injection or placebo were: nasopharyngitis (11% vs 8%), injection site erythema (5% vs 0%), vulvovaginal candidiasis/mycotic infection (5% vs 1%), bronchitis (5% vs 3%), pruritus (4% vs 2%), urinary tract infection (4% vs 2%) and sinusitis (3% vs 2%). In the ulcerative colitis induction study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 8 for STELARA® 6 mg/kg intravenous single infusion or placebo included: nasopharyngitis (7% vs 4%). In the ulcerative colitis maintenance study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 44 for STELARA® 90 mg subcutaneous injection or placebo included: nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

    Please click to see the full Prescribing Information and Medication Guide for STELARA®. Provide the Medication Guide to your patients and encourage discussion.

    cp-124933v5

    INDICATIONS
  • SYMTUZA® (darunavir/​cobicistat/​emtricitabine/​tenofovir alafenamide)

    INDICATION

    SYMTUZA® is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg:

    • who have no prior antiretroviral treatment history or
    • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

    IMPORTANT SAFETY INFORMATION

    BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

    • Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of SYMTUZA®.

    Action: Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA®. If appropriate, anti-hepatitis B therapy may be warranted.

    CONTRAINDICATIONS

    • Darunavir and cobicistat are both inhibitors and substrates of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA® should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events. In addition, co-administration of SYMTUZA® with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance.

    Action: Examples of drugs that are contraindicated for co-administration with SYMTUZA® due to the potential for serious and/or life-threatening events or loss of therapeutic effect are listed below: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

    WARNINGS AND PRECAUTIONS

    • Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA®. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

    Action: Monitor liver function prior to initiating and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases. Patients with evidence of new or worsening liver function should consider discontinuing SYMTUZA®. SYMTUZA® is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

    • Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA®, severe skin reactions may occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These include conditions accompanied by fever and/or elevations of transaminases.

    Action: Discontinue SYMTUZA® immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

    • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
    • Immune Reconstitution Syndrome: Patients receiving SYMTUZA® may develop new onset or exacerbations of immune reconstitution syndrome.
    • New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events. SYMTUZA® is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

    Action: Prior to initiating or during treatment, on a clinically appropriate schedule, monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA® in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

    • Sulfa Allergy: Darunavir contains a sulfonamide moiety. The incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

    Action: Monitor patients with a known sulfonamide allergy.

    • Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA®, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals.

    Action: Discontinue SYMTUZA® in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

    • Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors.

    Action: Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.
    • Hemophilia: Patients with hemophilia may develop an increase in bleeding events.

    ADVERSE REACTIONS

    • The most common clinical adverse reactions (all grades) occurring in at least 2% of treatment-naïve patients were diarrhea, rash,* nausea, fatigue, headache, abdominal discomfort, and flatulence.

    *Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.

    Grade 2-4 laboratory abnormalities have been reported in patients receiving SYMTUZA®, including elevations in serum creatinine, liver function tests, triglycerides, total cholesterol, low-density lipoproteins, and glucose levels. This is not a complete list of all adverse reactions reported with the use of SYMTUZA®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: SYMTUZA® is not recommended for use during pregnancy and should not be initiated in pregnant individuals because of substantially lower exposures of darunavir and cobicistat during pregnancy.

    Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

    • Pediatric Use: The safety and effectiveness of SYMTUZA® have not been established and is not recommended in pediatric patients weighing less than 40 kg.
    • Consult the full Prescribing Information for SYMTUZA® for additional information on the Uses in Specific Populations.

    Please see full Prescribing Information, including Boxed WARNING for SYMTUZA®.

    cp-62076v10

    INDICATION
  • TALVEY™ (talquetamab-tgvs)

    INDICATION AND USAGE

    TALVEY™ (talquetamab-tgvs) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

    This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    IMPORTANT SAFETY INFORMATION

    WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

    Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY™. Initiate TALVEY™ treatment with step-up dosing to reduce the risk of CRS. Withhold TALVEY™ until CRS resolves or permanently discontinue based on severity.

    Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and serious and life-threatening or fatal reactions, can occur with TALVEY™. Monitor patients for signs and symptoms of neurologic toxicity including ICANS during treatment. Withhold or discontinue TALVEY™ based on severity.

    Because of the risk of CRS and neurologic toxicity, including ICANS, TALVEY™ is available only through a restricted program called the TECVAYLI® and TALVEY™ Risk Evaluation and Mitigation Strategy (REMS).

    CONTRAINDICATIONS: None.

    WARNINGS AND PRECAUTIONS

    Cytokine Release Syndrome (CRS): TALVEY™ can cause cytokine release syndrome, including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 76% of patients who received TALVEY™ at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

    Initiate therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY™ in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next TALVEY™ dose.

    Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity, and consider further management per current practice guidelines. Withhold TALVEY™ until CRS resolves or permanently discontinue based on severity.

    Neurologic Toxicity including ICANS: TALVEY™ can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including fatal reactions. In the clinical trial, neurologic toxicity occurred in 55% of patients who received the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).

    ICANS was reported in 9% of 265 patients where ICANS was collected and who received the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

    Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue TALVEY™ based on severity and consider further management per current practice guidelines. [see Dosage and Administration (2.5)].

    Due to the potential for neurologic toxicity, patients receiving TALVEY™ are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule, and in the event of new onset of any neurological symptoms, until symptoms resolve.

    TECVAYLI® and TALVEY™ REMS: TALVEY™ is available only through a restricted program under a REMS, called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.

    Further information about the TECVAYLI® and TALVEY™ REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.

    Oral Toxicity and Weight Loss: TALVEY™ can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis. In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.

    TALVEY™ can cause weight loss. In the clinical trial, 62% of patients experienced weight loss of 5% or greater, regardless of having an oral toxicity, including 28% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported weight loss.

    Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice, including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold TALVEY™ or permanently discontinue based on severity.

    Infections: TALVEY™ can cause infections, including life-threatening or fatal infections. Serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis and COVID-19 (2.7%).

    Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY™ and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or permanently discontinue TALVEY™ as recommended, based on severity.

    Cytopenias: TALVEY™ can cause cytopenias, including neutropenia and thrombocytopenia. In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received TALVEY™. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold TALVEY™ as recommended, based on severity.

    Skin Toxicity: TALVEY™ can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash. In the clinical trial, skin reactions occurred in 62% of patients, with grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to grade 1 or less was 33 days.

    Monitor for skin toxicity, including rash progression. Consider early intervention and treatment to manage skin toxicity. In the clinical trial, supportive care included topical steroids (15%). Oral steroid tapers (4.4%) were typically administered for Grade 3 skin reactions. Withhold or permanently discontinue TALVEY™, based on severity.

    Hepatotoxicity: TALVEY™ can cause hepatotoxicity. Elevated ALT occurred in 33% of patients, with grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.

    Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TALVEY™ or consider permanent discontinuation of TALVEY™, based on severity [see Dosage and Administration (2.5)].

    Embryo-Fetal Toxicity: Based on its mechanism of action, TALVEY™ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TALVEY™ and for 3 months after the last dose.

    Adverse Reactions: The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.

    The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.

    Please read full Prescribing Information, including Boxed WARNING, for TALVEY™.

    cp-394174v2

    INDICATION
  • TECVAYLI® (teclistamab-cqyv)

    INDICATION AND USAGE

    TECVAYLI® (teclistamab-cqyv) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

    This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

    IMPORTANT SAFETY INFORMATION

    WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

    Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI®. Initiate treatment with TECVAYLI® step-up dosing schedule to reduce risk of CRS. Withhold TECVAYLI® until CRS resolves or permanently discontinue based on severity.

    Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI®. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment. Withhold TECVAYLI® until neurologic toxicity resolves or permanently discontinue based on severity.

    TECVAYLI® is available only through a restricted program called the TECVAYLI® and TALVEY™ Risk Evaluation and Mitigation Strategy (REMS).

    WARNINGS AND PRECAUTIONS

    Cytokine Release Syndrome - TECVAYLI® can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI® at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI®. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).

    Initiate therapy according to TECVAYLI® step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI® accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI® based on severity.

    TECVAYLI® is available only through a restricted program under a REMS.

    Neurologic Toxicity including ICANS - TECVAYLI® can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

    In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI® at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI®.

    In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI® at the recommended dose. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI®. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

    Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or permanently discontinue TECVAYLI® based on severity per recommendations and consider further management per current practice guidelines.

    Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI® step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.

    TECVAYLI® is available only through a restricted program under a REMS.

    TECVAYLI® and TALVEY™ REMS - TECVAYLI® is available only through a restricted program under a REMS called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.

    Hepatotoxicity - TECVAYLI® can cause hepatotoxicity, including fatalities. In patients who received TECVAYLI® at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.

    Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Infections - TECVAYLI® can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI® at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI® and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Monitor immunoglobulin levels during treatment with TECVAYLI® and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

    Neutropenia - TECVAYLI® can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI® at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.

    Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines. Monitor patients with neutropenia for signs of infection. Withhold TECVAYLI® based on severity.

    Hypersensitivity and Other Administration Reactions - TECVAYLI® can cause both systemic administration-related and local injection-site reactions. Systemic Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients, with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Embryo-Fetal Toxicity - Based on its mechanism of action, TECVAYLI® may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI® and for 5 months after the last dose.

    ADVERSE REACTIONS

    The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

    Please read full Prescribing Information, including Boxed WARNING, for TECVAYLI®.

    cp-322928v3

    INDICATION
  • TRACLEER® (bosentan)

    INDICATION

    TRACLEER® is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):

    • in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%).
    • in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.

    IMPORTANT SAFETY INFORMATION

    BOXED WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY

    Because of the risks of hepatotoxicity and birth defects, TRACLEER® is available only through a restricted program called the Bosentan REMS Program, which is a component of the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program

    Hepatotoxicity

    Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER®. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged (>12 months) treatment. In general, avoid using TRACLEER® in patients with elevated aminotransferases (>3 × ULN) at baseline. Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue TRACLEER® if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 × ULN.

    Embryo-Fetal Toxicity

    TRACLEER® is likely to cause major birth defects if used by pregnant females. Therefore, pregnancy must be excluded before the start of treatment with TRACLEER®. Throughout treatment and for one month after stopping TRACLEER®, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving TRACLEER®. Obtain monthly pregnancy tests.

    CONTRAINDICATIONS

    Pregnancy: Use of TRACLEER® is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER®

    Use with Cyclosporine A: Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER® and cyclosporine A is contraindicated

    Use with Glyburide: An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER® is contraindicated

    Hypersensitivity: TRACLEER® is contraindicated in patients who are hypersensitive to bosentan or any component of the product.

    WARNINGS AND PRECAUTIONS

    Hepatotoxicity

    • In clinical trials, ALT/AST elevation (>3 × ULN) were observed in 11% of patients treated with TRACLEER®, accompanied by elevated bilirubin in a few cases. In a pooled analysis of pediatric studies conducted in PAH, elevations in liver aminotransferases ≥3 × ULN were observed in 2% of patients.
    • The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥2 × ULN) is a marker for potential serious hepatotoxicity.
    • Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly. Discontinue TRACLEER® if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity or increases in bilirubin ≥2 × ULN.
    • Avoid initiation of TRACLEER® in patients with elevated aminotransferases (>3 × ULN).

    Embryo-fetal Toxicity

    • TRACLEER® may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus.
    • Obtain a pregnancy test prior to TRACLEER® treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with TRACLEER® and for at least one month after the last dose.
    • TRACLEER® is only available for females through a restricted program under REMS.

    Prescribing and Distribution Program for Bosentan

    Because of the risks of hepatotoxicity and birth defects, TRACLEER® is available only through a restricted program called the Bosentan REMS Program.

    Required components of the Bosentan REMS are:

    • Healthcare professionals who prescribe TRACLEER® must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements.
    • Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
    • To receive TRACLEER®, all patients must understand the risks and benefits, and complete a patient enrollment form.
    • Pharmacies that dispense TRACLEER® must enroll in the program and agree to comply with the Bosentan REMS Program requirements.

    Fluid Retention

    • Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of TRACLEER® and other endothelin receptor antagonists.
    • If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as TRACLEER® or underlying heart failure, and the possible need for treatment or discontinuation of TRACLEER®.

    Pulmonary Veno-Occlusive Disease

    • If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER® should be discontinued.

    Decreased Sperm Counts

    • Decreased sperm counts have been observed in patients receiving TRACLEER®.
    • Preclinical data also suggest that TRACLEER®, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.

    Decreases in Hemoglobin and Hematocrit

    • Treatment with TRACLEER® can cause a dose-related decrease in hemoglobin and hematocrit.
    • It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.

    ADVERSE REACTIONS

    In TRACLEER® pivotal trials, the most common adverse events occurring more often in TRACLEER®-treated patients than in patients taking placebo were respiratory tract infection (22% vs 17%), headache (15% vs 14%), edema (11% vs 9%), chest pain (5% vs 5%), syncope (5% vs 4%), flushing (4% vs 3%), hypotension (4% vs 2%), sinusitis (4% vs 2%), arthralgia (4% vs 2%), abnormal serum aminotransferases (4% vs 2%), palpitations (4% vs 2%), and anemia (3% vs 0%). TRACLEER® was evaluated for safety in pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH.

    DRUG INTERACTIONS

    • TRACLEER® is contraindicated for use with cyclosporine A and with glyburide.
    • TRACLEER® is metabolized by CYP2C9 and CYP3A and an inducer of CYP3A and CYP2C9.
      • Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents.
      • When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of TRACLEER® is necessary.
      • When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered.
      • When co-administered with rifampin, a CYP3A inducer, liver function should be monitored weekly.
      • When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of TRACLEER® is necessary, but increased effects of TRACLEER® may need to be considered.
    • Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER® is co-administered.
    • There are no clinically relevant interactions between TRACLEER® and warfarin, digoxin, nimodipine, losartan, sildenafil, or tadalafil.
      • Dose adjustments are not necessary when TRACLEER® and sildenafil or tadalafil are co-administered.

    LIVER ENZYME ELEVATIONS

    • Measure liver aminotransferases prior to initiation of treatment and then monthly.
    • Use of TRACLEER® should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.
    • It is important to adhere strictly to the monthly monitoring schedule for the duration of treatment.
      • Changes in aminotransferases may occur early or late in treatment.
      • There have been rare postmarketing reports of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring; the contribution of TRACLEER® could not be excluded.
    • For patients whose monthly LFTs are ≤3 x ULN, no change in monitoring schedule or dosage is required.
    • For patients whose monthly LFTs are >3 x ULN, close monitoring and either dose reduction or treatment cessation are necessary.

    MONITORING

    It is important to adhere strictly to the monthly monitoring schedule for LFTs and, if applicable, pregnancy for the duration of treatment.

    Please read full Prescribing Information, including BOXED WARNING.

    cp-113987v3

    INDICATION
  • TREMFYA® (guselkumab)

    INDICATIONS

    TREMFYA® (guselkumab) is indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

    TREMFYA® is indicated for the treatment of adults with active psoriatic arthritis.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    TREMFYA® is contraindicated in patients with a history of serious hypersensitivity reaction to guselkumab or to any of the excipients.

    WARNINGS AND PRECAUTIONS

    Hypersensitivity Reactions

    Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of TREMFYA®. Some cases required hospitalization. If a serious hypersensitivity reaction occurs, discontinue TREMFYA® and initiate appropriate therapy.

    Infections

    TREMFYA® may increase the risk of infection. Treatment with TREMFYA® should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated.

    Consider the risks and benefits of treatment prior to prescribing TREMFYA® in patients with a chronic infection or a history of recurrent infection. Instruct patients receiving TREMFYA® to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection, or is not responding to standard therapy, closely monitor and discontinue TREMFYA® until the infection resolves.

    Pre-Treatment Evaluation for Tuberculosis (TB)

    Evaluate patients for TB infection prior to initiating treatment with TREMFYA®. Initiate treatment of latent TB prior to administering TREMFYA®. Monitor patients for signs and symptoms of active TB during and after TREMFYA® treatment. Do not administer TREMFYA® to patients with active TB infection.

    Immunizations

    Prior to initiating TREMFYA®, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TREMFYA®.

    ADVERSE REACTIONS

    Most common (≥1%) adverse reactions associated with TREMFYA® include upper respiratory infections, headache, injection site reactions, arthralgia, bronchitis, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections.

    The overall safety profile observed in patients with psoriatic arthritis is generally consistent with the safety profile in patients with plaque psoriasis, with the addition of bronchitis and neutrophil count decreased.

    Please read the full Prescribing Information and Medication Guide for TREMFYA®. Provide the Medication Guide to your patients and encourage discussion.

    cp-82625v3

    INDICATIONS
  • UPTRAVI® (selexipag)

    INDICATION

    UPTRAVI® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

    Effectiveness of UPTRAVI® Tablets was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.

    Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI® is contraindicated.

    Hypersensitivity to the active substance or to any of the excipients is contraindicated.

    WARNINGS AND PRECAUTIONS

    Pulmonary Edema with Pulmonary Veno-Occlusive Disease (PVOD)

    Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue UPTRAVI®.

    ADVERSE REACTIONS

    Adverse reactions more frequent compared to placebo (≥3%) seen with UPTRAVI® Tablets are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 8%).

    These adverse reactions are more frequent during the dose titration phase.

    Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI® Tablets and in none of the patients on placebo.

    DRUG INTERACTIONS

    CYP2C8 Inhibitors

    Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI® with strong inhibitors of CYP2C8 is contraindicated.

    Concomitant administration of UPTRAVI® with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold. Reduce the dosing of UPTRAVI® to once daily in patients on a moderate CYP2C8 inhibitor.

    CYP2C8 Inducers

    Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI® dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI® when rifampin is stopped.

    DOSAGE AND ADMINISTRATION

    Recommended Dosage

    Recommended starting dose is 200 mcg twice daily for UPTRAVI® Tablets. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

    Patients With Hepatic Impairment

    For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI® Tablets is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI® in patients with severe hepatic impairment (Child-Pugh class C).

    Co-administration With Moderate CYP2C8 Inhibitors

    When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI® to once daily.

    Dosage Strengths

    UPTRAVI® tablet strengths:

    200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.

    Additional Important Safety Information for UPTRAVI® IV

    Use UPTRAVI® for injection in patients who are temporarily unable to take oral therapy.

    Administer UPTRAVI® for injection twice daily by intravenous infusion at a dose that corresponds to the patient’s current dose of UPTRAVI® Tablets (see Table 1 in full Prescribing Information). Administer UPTRAVI® for injection as an 80-minute intravenous infusion.

    Adverse Reactions: Infusion-site reactions (infusion-site erythema/redness, pain and swelling) were reported with UPTRAVI® for injection.

    Please see full Prescribing Information.

    cp-126160v5

    INDICATION
  • VELETRI® (epoprostenol)

    INDICATION

    VELETRI® is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    VELETRI® is contraindicated in patients with congestive heart failure due to severe left ventricular systolic dysfunction.

    VELETRI® should not be used chronically in patients who during dose initiation develop pulmonary edema, which may be associated with pulmonary veno-occlusive disease.

    VELETRI® is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

    WARNINGS AND PRECAUTIONS

    General

    Reconstitute VELETRI® only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not mix VELETRI® with any other parenteral medications or solutions prior to or during administration. Each vial is for single use only; discard any unused solution. Use after reconstitution and immediate dilution to final concentration. Use at room temperature (77°F/25°C). Do not expose VELETRI® to direct sunlight.

    VELETRI® should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension.

    Dose Initiation

    VELETRI® is a potent pulmonary and systemic vasodilator. Initiate VELETRI® in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

    Chronic Use and Dose Adjustment

    During chronic use, deliver VELETRI® continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving VELETRI® to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of VELETRI® and in routine catheter care.

    Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of VELETRI® may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with VELETRI® will likely be needed for prolonged periods, possibly years, so consider the patient’s capacity to accept and care for a permanent intravenous catheter and infusion pump.

    Dosage of VELETRI® during chronic use should be adjusted at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

    Withdrawal Effects

    Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of VELETRI® may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. Abrupt withdrawal should be avoided.

    ADVERSE REACTIONS

    The most common and dose-limiting adverse events during dose initiation and escalation (≥1%) were flushing (58%), headache (49%), nausea/vomiting (32%), hypotension (16%), anxiety/nervousness/agitation (11%), chest pain (11%), dizziness (8%), bradycardia (5%), abdominal pain (5%), musculoskeletal pain (3%), dyspnea (2%), back pain (2%), sweating (1%), dyspepsia (1%), hypesthesia/paresthesia (1%), and tachycardia (1%).

    Adverse events occurring in patients with idiopathic or heritable PAH with ≥10% difference between epoprostenol and conventional therapy alone were chills/fever/sepsis/flu-like symptoms (25% vs 11%), tachycardia (35% vs 24%), flushing (42% vs 2%), diarrhea (37% vs 6%), nausea/vomiting (67% vs 48%), jaw pain (54% vs 0%), myalgia (44% vs 31%), nonspecific musculoskeletal pain (35% vs 15%), anxiety/nervousness/tremor (21% vs 9%), dizziness (83% vs 70%), headache (83% vs 33%), and hypesthesia/hyperesthesia/paresthesia (12% vs 2%).

    Adverse events occurring in patients with PAH/CTD with ≥10% difference between epoprostenol and conventional therapy alone were flushing (23% vs 0%), hypotension (13% vs 0%), anorexia (66% vs 47%), nausea/vomiting (41% vs 16%), diarrhea (50% vs 5%), jaw pain (75% vs 0%), pain/neck pain/arthralgia (84% vs 65%), headache (46% vs 5%), skin ulcer (39% vs 24%), and eczema/rash/urticaria (25% vs 4%).

    Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.

    Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.

    DRUG INTERACTIONS

    Additional reductions in blood pressure may occur when VELETRI® is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for VELETRI® to increase the risk of bleeding. However, patients receiving infusions of epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol, which may be clinically significant in patients prone to digoxin toxicity.

    Please read full Prescribing Information.

    cp-115420v3

    INDICATION
  • VENTAVIS® (iloprost)

    INDICATION

    VENTAVIS® is a prostacyclin mimetic indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%).

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    RISK OF SYNCOPE

    • Monitor vital signs while initiating VENTAVIS®. Do not initiate VENTAVIS® in patients with systolic blood pressure below 85 mmHg.
    • Syncope can also occur in association with pulmonary arterial hypertension, particularly in association with physical exertion. The occurrence of exertional syncope may reflect a therapeutic gap or insufficient efficacy, and the need to adjust dose or change therapy should be considered.

    PULMONARY VENOUS HYPERTENSION

    • Stop VENTAVIS® immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension.

    BRONCHOSPASM

    • VENTAVIS® inhalation can induce bronchospasm. Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways.
    • VENTAVIS® has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.

    ADVERSE REACTIONS

    SERIOUS ADVERSE EVENTS

    • Serious adverse events reported include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

    ADVERSE EVENTS

    • Adverse events reported in a Phase 3 clinical trial occurring with a ≥3% difference between VENTAVIS® patients and placebo patients were vasodilation (flushing) (27% vs 9%), increased cough (39% vs 26%), headache (30% vs 20%), trismus (12% vs 3%), insomnia (8% vs 2%), nausea (13% vs 8%), hypotension (11% vs 6%), vomiting (7% vs 2%), alkaline phosphatase increased (6% vs 1%), flu syndrome (14% vs 10%), back pain (7% vs 3%), tongue pain (4% vs 0%), palpitations (7% vs 4%), syncope (8% vs 5%), GGT increased (6% vs 3%), muscle cramps (6% vs 3%), hemoptysis (5% vs 2%), and pneumonia (4% vs 1%).

    DRUG INTERACTIONS

    ANTIHYPERTENSIVES AND VASODILATORS

    • VENTAVIS® has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents.

    ANTICOAGULANTS AND PLATELET INHIBITORS

    • VENTAVIS® has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.

    USE IN SPECIFIC POPULATIONS

    LACTATION

    • Advise not to breastfeed during treatment with VENTAVIS®.

    Please read full Prescribing Information.

    cp-134777v3

    INDICATION
  • XARELTO® (rivaroxaban tablets)

    INDICATIONS

    XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF).

    There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

    XARELTO® is indicated for the treatment of deep vein thrombosis (DVT). XARELTO® is indicated for the treatment of pulmonary embolism (PE). XARELTO® is indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

    XARELTO® is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.

    XARELTO® is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE, and not at high risk of bleeding.

    XARELTO®, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease (CAD).

    XARELTO®, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with peripheral artery disease (PAD), including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.

    XARELTO® is indicated for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.

    XARELTO® is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

    IMPORTANT SAFETY INFORMATION

    WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS,

    (B) SPINAL/EPIDURAL HEMATOMA

    A. Premature discontinuation of XARELTO® increases the risk of thrombotic events

    Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

    B. Spinal/epidural hematoma

    Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

    • Use of indwelling epidural catheters
    • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions
    • A history of traumatic or repeated epidural or spinal punctures
    • A history of spinal deformity or spinal surgery
    • Optimal timing between the administration of XARELTO® and neuraxial procedures is not known

    Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

    Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

    CONTRAINDICATIONS

    • Active pathological bleeding
    • Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

    WARNINGS AND PRECAUTIONS

    • Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
    • Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage.
      • An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable.
      • Concomitant use of other drugs that impair hemostasis increases risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).
      • Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding: Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO® for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (ie, undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer or history of bleeding in the three months prior to treatment; or dual antiplatelet therapy. XARELTO® is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.
    • Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with concurrent use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO®. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®. The next dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
    • Use in Patients with Renal Impairment:
      • Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute renal failure while on XARELTO®. Clinical efficacy and safety studies with XARELTO® did not enroll patients with CrCl <30 mL/min or end-stage renal disease (ESRD) on dialysis.
      • Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment.
      • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment.
      • Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment.
      • Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients after Recent Lower Extremity Revascularization Due to Symptomatic PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO® twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose efficacy and safety outcomes were similar to those with preserved renal function. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis.
      • Pediatric Patients: There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid use of XARELTO® in these patients.

    There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO® in these patients.

    • Use in Patients with Hepatic Impairment: No clinical data are available for adult patients with severe hepatic impairment. Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased. No clinical data are available in pediatric patients with hepatic impairment.
    • Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers.
    • Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
    • Patients with Prosthetic Heart Valves: Use of XARELTO® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the GALILEO study, which reported higher rates of death and bleeding in patients randomized to XARELTO® compared to those randomized to an antiplatelet regimen. Safety and efficacy of XARELTO® have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO® is not recommended in patients with prosthetic heart valves.
    • Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
    • Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome: Direct-acting oral anticoagulants (DOACs), including XARELTO®, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS).  For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

    DRUG INTERACTIONS

    • Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding.
    • Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events.
    • XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.
    • Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding.
    • Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO® for the mother and possible risks to the fetus when prescribing to a pregnant woman.
      • Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.
      • Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting.
      • There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage.
    • Lactation: Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for XARELTO® and any potential adverse effects on the breastfed infant from XARELTO® or from the underlying maternal condition.
    • Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants, including XARELTO®, should be assessed in females of reproductive potential and those with abnormal uterine bleeding.
    • Pediatric Use: XARELTO® was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth, had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.

    Clinical studies that evaluated safety, efficacy, and pharmacokinetic/pharmacodynamic data support the use of XARELTO® 10-mg, 15-mg, and 20-mg tablets in pediatric patients. For the XARELTO® 2.5-mg tablets, there are no safety, efficacy, and pharmacokinetic/pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO® 2.5-mg tablets are not recommended for use in pediatric patients.

    Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

    • Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients.

    OVERDOSAGE

    • Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

    ADVERSE REACTIONS

    • Most common adverse reactions in adult patients with XARELTO® were bleeding complications.
    • Most common adverse reactions in pediatric patients were bleeding, cough, vomiting, and gastroenteritis.

    Please read full Prescribing Information, including Boxed WARNINGS for XARELTO®.

    cp-62551v9

    INDICATIONS
  • YONDELIS® (trabectedin)

    INDICATION

    YONDELIS® (trabectedin) is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline‑containing regimen.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS YONDELIS® is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.

    WARNINGS AND PRECAUTIONS

    Neutropenic sepsis, including fatal cases, can occur. In Trial ET743-SAR-3007, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, was 43% (161/378). Median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months). Median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with YONDELIS®. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS® and periodically throughout the treatment cycle. Withhold or reduce dose of YONDELIS® based on severity of adverse reaction.

    Rhabdomyolysis YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial ET743-SAR-3007, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving YONDELIS®. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS®, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS® with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). Median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). Median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS®. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

    Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 x upper limit of normal were not enrolled in Trial ET743-SAR-3007. In Trial ET743-SAR-3007, the incidence of Grade 3‑4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving YONDELIS®. Median time to development of Grade 3‑4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial ET743-SAR-3007, the incidence of drug‑induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving YONDELIS®. ALT or AST elevation greater than eight times the upper limit of normal occurred in 18% (67/378) of patients receiving YONDELIS®. Assess LFTs prior to each administration of YONDELIS® and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality.

    Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur. In Trial ET743-SAR-3007, a significant decrease in left ventricular ejection fraction (LVEF) was defined as an absolute decrease of ≥15% or below the lower limit of normal with an absolute decrease of ≥5%. Patients with a history of New York Heart Association Class II to IV heart failure or abnormal LVEF at baseline were ineligible. In Trial ET743-SAR-3007, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS® and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS® and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS® and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS® was 5.3 months (range: 26 days to 15.3 months). Patients with LVEF < lower limit of normal, prior cumulative anthracycline dose of ≥300 mg/m2, age ≥65 years, or a history of cardiovascular disease may be at increased risk of cardiac dysfunction. Assess LVEF by echocardiogram (ECHO) or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2‑ to 3‑month intervals thereafter until YONDELIS® is discontinued. Discontinue treatment with YONDELIS® based on severity of adverse reaction.

    Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia has been reported with YONDELIS®, including serious CLS resulting in death. Monitor for signs and symptoms of CLS. Discontinue YONDELIS® and promptly initiate standard management for patients with CLS, which may include a need for intensive care.

    Extravasation Resulting in Tissue Necrosis Extravasation of YONDELIS®, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS®. Administer YONDELIS® through a central venous line.

    Embryo-Fetal Toxicity Based on its mechanism of action, YONDELIS® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS®. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS®.

    Adverse Reactions The most common (≥20%) adverse reactions are nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%), and headache (25%).

    The most common (≥5%) grades 3-4 laboratory abnormalities are: neutropenia (43%), increased ALT (31%), thrombocytopenia (21%), anemia (19%), increased AST (17%), and increased creatine phosphokinase (6.4%).

    ­­DRUG INTERACTIONS

    Effect of Cytochrome CYP3A Inhibitors Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS®. If a strong CYP3A inhibitor for short‑term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS® infusion, and discontinue it the day prior to the next YONDELIS® infusion.

    Effect of Cytochrome CYP3A Inducers Avoid using strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) in patients taking YONDELIS®.

    Please click here to read the full Prescribing Information for YONDELIS®.

    cp-63569v2

    INDICATION
  • ZYTIGA® (abiraterone acetate)

    INDICATION

    ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with:

    • metastatic castration-resistant prostate cancer (CRPC)
    • metastatic high-risk castration-sensitive prostate cancer (CSPC)

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions Due to Mineralocorticoid Excess - ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment.

    Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. In postmarketing experience, QT prolongation, and Torsades de Pointes have been observed in patients who develop hypokalemia while taking ZYTIGA®.

    The safety of ZYTIGA® in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)].

    Adrenocortical Insufficiency - Adrenocortical insufficiency was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency if prednisone is stopped or withdrawn, if the prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if clinically indicated, to confirm adrenocortical insufficiency. Increased dosages of corticosteroids may be used before, during, and after stressful situations [see Warnings and Precautions (5.1)].

    Hepatotoxicity - In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure, and deaths. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA® dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Re-treatment with ZYTIGA® at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5 x ULN [see Dosage and Administration (2.4)].

    Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

    The safety of ZYTIGA® re-treatment of patients who develop AST or ALT greater than or equal to 20 x ULN and/or bilirubin greater than or equal to 10 x ULN is unknown.

    Increased Fractures and Mortality in Combination With Radium Ra 223 Dichloride - ZYTIGA® plus prednisone/prednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials. Increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received ZYTIGA® plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with ZYTIGA® plus prednisone/prednisolone [see Warnings and Precautions (5.4)].

    Embryo-Fetal Toxicity - The safety and efficacy of ZYTIGA® have not been established in females. Based on animal reproductive studies and mechanism of action, ZYTIGA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with ZYTIGA® and for 3 weeks after the last dose of ZYTIGA® [see Use in Specific Populations (8.1, 8.3)]. ZYTIGA® should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].

    Hypoglycemia - Severe hypoglycemia has been reported when ZYTIGA® was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with ZYTIGA®. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

    ADVERSE REACTIONS

    Adverse Reactions - The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory tract infection, cough, and headache.

    Laboratory Abnormalities - The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

    DRUG INTERACTIONS

    Drugs That Inhibit or Induce CYP3A4 Enzymes - Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.5)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3)].

    Effects of Abiraterone on Drug-Metabolizing Enzymes - ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA® [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.6)].

    USE IN SPECIFIC POPULATIONS

    Females and Males of Reproductive Potential - ZYTIGA® can cause fetal harm and potential loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of ZYTIGA® [see Use in Specific Populations (8.1)]. ZYTIGA® may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

    Hepatic Impairment - In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA® to 250 mg once daily. Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5 x ULN or total bilirubin >3 x ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA® treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

    For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

    Please read the full Prescribing Information and Patient Information for ZYTIGA®.

    cp-54013v6

    INDICATION
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INDICATIONS

IMPORTANT SAFETY INFORMATION

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Important Safety Information For

  • AKEEGA™

    INDICATION

    AKEEGA™ (niraparib and abiraterone acetate film-coated tablets) with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA™.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA™ in combination with prednisone in BRCAm patients in Cohort 1 (N=113) of MAGNITUDE.

    Myelodysplastic Syndrome/Acute Myeloid Leukemia

    AKEEGA™ may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

    MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA™.

    All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

    For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA™ if MDS/AML is confirmed.

    Myelosuppression

    AKEEGA™ may cause myelosuppression (anemia, thrombocytopenia, or neutropenia).

    In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA™. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients.

    Monitor complete blood counts weekly during the first month of AKEEGA™ treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA™ until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA™ and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.

    Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

    AKEEGA™ may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA™. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA™.

    In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA™, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA™ arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA™ arm.

    The safety of AKEEGA™ in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE.

    Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA™.

    Discontinue AKEEGA™ in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

    Hepatotoxicity

    AKEEGA™ may cause hepatotoxicity.

    Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA™, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths.

    In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA™ in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE.

    Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA™, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring and may require dosage modifications.

    Permanently discontinue AKEEGA™ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA™.

    Adrenocortical Insufficiency

    AKEEGA™ may cause adrenal insufficiency.

    Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA™, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

    Hypoglycemia

    AKEEGA™ may cause hypoglycemia in patients being treated with other medications for diabetes.

    Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA™, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide.

    Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA™. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

    Increased Fractures and Mortality in Combination with Radium 223 Dichloride

    AKEEGA™ with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials.

    The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

    At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone.

    It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA™, in combination with prednisone.

    Posterior Reversible Encephalopathy Syndrome

    AKEEGA™ may cause Posterior Reversible Encephalopathy Syndrome (PRES).

    PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA™.

    Monitor all patients treated with AKEEGA™ for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA™ and administer appropriate treatment. The safety of reinitiating AKEEGA™ in patients previously experiencing PRES is not known.

    Embryo-Fetal Toxicity

    The safety and efficacy of AKEEGA™ have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA™ can cause fetal harm and loss of pregnancy when administered to a pregnant female.

    Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow).

    In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose.

    Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA™. Females who are or may become pregnant should handle AKEEGA™ with protection, e.g., gloves.

    Based on animal studies, AKEEGA™ may impair fertility in males of reproductive potential.

    ADVERSE REACTIONS

    The safety of AKEEGA™ in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE.

    The most common adverse reactions (≥10%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia.

    Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA™, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%).

    DRUG INTERACTIONS

    Effect of Other Drugs on AKEEGA™

    Avoid coadministration with strong CYP3A4 inducers.

    Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone.

    Effects of AKEEGA™ on Other Drugs

    Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug.

    Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA™ increases the concentration of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates.

    Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions.

    Abiraterone is a CYP2C8 inhibitor. AKEEGA™ increases the concentration of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates.

    Please see the full Prescribing Information for AKEEGA™.

    cp-401051v1

    INDICATION
  • DARZALEX®

    INDICATIONS

    • DARZALEX® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:
    • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
    • In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
    • In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
    • In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
    • In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
    • In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
    • As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

    WARNINGS AND PRECAUTIONS

    Infusion-Related Reactions

    DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision.

    When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

    Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

    To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

    Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®.

    Interference With Serological Testing

    Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®.

    Neutropenia and Thrombocytopenia

    DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets.

    Interference With Determination of Complete Response

    Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

    Embryo-Fetal Toxicity

    Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose.

    The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

    ADVERSE REACTIONS

    The most frequently reported adverse reactions (incidence ≥20%) were upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

    Please click here to see the full Prescribing Information.

    cp-60862v8

    INDICATIONS
  • DARZALEX FASPRO®

    INDICATIONS

    DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

    • In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
    • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
    • In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
    • In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
    • In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
    • In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
    • As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

    DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide, and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    Limitations of Use

    DARZALEX FASPRO® is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    DARZALEX FASPRO® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.

    WARNINGS AND PRECAUTIONS

    Hypersensitivity and Other Administration Reactions

    Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®.

    Systemic Reactions

    In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO® as monotherapy or in combination, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO® administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

    Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.

    Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO®. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

    Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®.

    Local Reactions

    In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO®. Monitor for local reactions and consider symptomatic management.

    Cardiac Toxicity in Patients With AL Amyloidosis

    Serious or fatal cardiac adverse reactions occurred in patients with AL amyloidosis who received DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide, and dexamethasone. Serious cardiac disorders occurred in 16% of patients, and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of AL amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

    Neutropenia

    Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO® until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed.

    Thrombocytopenia

    Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO® until recovery of platelets.

    Embryo-Fetal Toxicity

    Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose.

    The combination of DARZALEX FASPRO® with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy.

    Interference With Serological Testing

    Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.

    Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®. Type and screen patients prior to starting DARZALEX FASPRO®.

    Interference With Determination of Complete Response

    Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO®-treated patients with IgG kappa myeloma protein.

    ADVERSE REACTIONS

    In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO® monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.

    The most common adverse reactions (≥20%) in patients with AL amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

    The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO® are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

    Please click here to see the full Prescribing Information.

    cp-205671v6

    INDICATIONS
  • EDURANT®

    Indication

    Treatment of HIV-1 in Treatment-Naïve Patients

    EDURANT® (rilpivirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35 kg with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.

    Limitations of Use:

    • More EDURANT®-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT®-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL

    Treatment of HIV-1 in Combination With Cabotegravir

    EDURANT® is indicated in combination with VOCABRIA (oral cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as:

    • Oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir, rilpivirine) extended-release injectable suspensions
    • Oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions

    Important Safety Information

    Contraindications

    • Coadministration of EDURANT® with the following drugs is contraindicated because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance and cross-resistance: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, systemic dexamethasone (more than single dose), and products containing St. John’s wort (Hypericum perforatum)
    • Coadministration of rifabutin with cabotegravir [VOCABRIA (cabotegravir) tablets, CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended‑release injectable suspension), co-packaged for intramuscular use] is contraindicated. Consult the Prescribing Information for CABENUVA and VOCABRIA

    Warnings and Precautions

    • Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. EDURANT® should be discontinued immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated
    • Hepatotoxicity: Hepatic adverse events were reported. Patients with underlying hepatic disease, including hepatitis B or C, or marked elevations in transaminases before treatment may be at increased risk for worsening or development of transaminase elevations. Monitor liver function tests (LFTs) before and during treatment. A few hepatotoxicity cases occurred in patients with no pre-existing hepatic disease or other identifiable risk factors; therefore, monitoring of LFTs should be considered in all patients
    • Depressive Disorders: Severe depressive disorders, defined as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation, have been reported with EDURANT®. Immediate medical evaluation is recommended for severe depressive symptoms
    • Immune Reconstitution Syndrome has been reported in patients treated with combination ARV therapy, including EDURANT®. Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barré syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment

    Drug Interactions

    • EDURANT® is primarily metabolized by cytochrome P450 (CYP)3A.
      • Coadministration of EDURANT® and drugs that induce CYP3A may result in decreased plasma concentrations, loss of virologic response and possible resistance to EDURANT® or to the class of NNRTIs
      • Coadministration of EDURANT® and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine
    • Coadministration of EDURANT® with drugs that increase gastric pH may result in decreased plasma concentrations, loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs
    • EDURANT® should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes
    • EDURANT® should not be used in combination with NNRTIs

    This is not a complete list of potential drug interactions.

    Please see full Prescribing Information for more details.

    Use in Specific Populations

    • Hepatic Impairment: No dosage adjustment of EDURANT® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. EDURANT® has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C)
    • Pregnancy: In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period
    • Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission
    • Pediatric Use: Safety and effectiveness in pediatric patients less than 12 years of age or weighing less than 35 kg have not been established
    • Renal Impairment: Use with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. EDURANT® concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. EDURANT® is highly bound to plasma proteins; it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis
    • Geriatric Use: Clinical studies of EDURANT® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT® in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy

    Adverse Reactions

    • The most common adverse drug reactions reported (incidence >2%) of at least moderate intensity (≥ Grade 2) in patients taking EDURANT® through 96 weeks were depressive disorders (5%), headache (3%), insomnia (3%), and rash (3%)

    Please read the full Prescribing Information for EDURANT®.

    cp-51575v8

    INDICATION
  • ERLEADA®

    INDICATIONS

    ERLEADA® (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with:

    • Metastatic castration-sensitive prostate cancer (mCSPC)
    • Non-metastatic castration-resistant prostate cancer (nmCRPC)

    IMPORTANT Safety Information

    WARNINGS AND PRECAUTIONS

    Cerebrovascular and Ischemic Cardiovascular Events In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA® and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA® and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

    In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA® and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA®, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.

    Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events.

    Fractures In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

    Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly. Evaluate patients for fall risk.

    Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

    Severe Cutaneous Adverse Reactions Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens‑Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA®.

    Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA® until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA® [see Dosage and Administration (2.2)].

    Embryo-Fetal Toxicity The safety and efficacy of ERLEADA® have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)].

    ADVERSE REACTIONS

    The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

    Laboratory Abnormalities — All Grades (Grade 3-4)

    • Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (1.8%), placebo 21% (1.6%)
    • Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA® 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA® 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (1.9%), placebo 22% (0.5%)

    Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%).

    The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA®.

    Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA® and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted.

    DRUG INTERACTIONS

    Effect of Other Drugs on ERLEADA® Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)].

    Effect of ERLEADA® on Other Drugs

    CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA® with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA® and evaluate for loss of activity.

    P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA® and evaluate for loss of activity if medication is continued.

    Please see the full Prescribing Information for ERLEADA®.

    cp-50507v6

    INDICATIONS
  • Infliximab

    INDICATIONS

    Crohn’s Disease

    Infliximab is indicated for:

    • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response to conventional therapy.
    • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD.

    Pediatric Crohn’s Disease

    Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy.

    Ulcerative Colitis

    Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy.

    Pediatric Ulcerative Colitis

    Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

    Rheumatoid Arthritis

    Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA).

    Ankylosing Spondylitis

    Infliximab is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).

    Psoriatic Arthritis

    Infliximab is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA).

    Plaque Psoriasis

    Infliximab is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Infliximab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

    IMPORTANT SAFETY INFORMATION FOR Infliximab

    SERIOUS INFECTIONS

    Patients treated with Infliximab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Infliximab if a patient develops a serious infection or sepsis.

    Reported infections include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with Infliximab.1,2 Treatment for latent infection should be initiated prior to treatment with Infliximab.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella, Listeria, and Salmonella.

    The risks and benefits of treatment with Infliximab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Infliximab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with Infliximab included pneumonia, cellulitis, abscess, and skin ulceration.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Infliximab. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    Post-marketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including Infliximab. These cases have had a very aggressive disease course and have been fatal. The majority of reported Infliximab cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with Infliximab at or prior to diagnosis. Carefully assess the risks and benefits of treatment with Infliximab, especially in these patient types.

    In clinical trials of all TNF blockers, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF blockers, including Infliximab, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with Infliximab was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use. As the potential role of TNF blockers in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including Infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    A population-based retrospective cohort study found a 2- to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with Infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between Infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with Infliximab.

    CONTRAINDICATIONS

    The use of Infliximab at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. Infliximab is contraindicated in patients with a previous severe hypersensitivity reaction to Infliximab or any of the inactive ingredients of Infliximab or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

    HEPATITIS B REACTIVATION

    TNF blockers, including Infliximab, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating Infliximab. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing Infliximab for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with Infliximab. Discontinue Infliximab in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of Infliximab and monitor patients closely.

    HEPATOTOXICITY

    Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported in patients receiving Infliximab post-marketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, Infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken.

    HEART FAILURE

    In a randomized, placebo-controlled study in patients with moderate or severe heart failure (NYHA Functional Class III/IV), higher mortality rates and a higher risk of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors. Patients with moderate or severe heart failure taking Infliximab (≤5 mg/kg) or patients with mild heart failure should be closely monitored and treatment should be discontinued if new or worsening symptoms appear.

    HEMATOLOGIC EVENTS

    Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to Infliximab therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of Infliximab in patients who develop significant hematologic abnormalities.

    HYPERSENSITIVITY

    Infliximab has been associated with hypersensitivity reactions that differ in their time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in association with infusions of Infliximab. Medications for the treatment of hypersensitivity reactions should be available.

    CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

    Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of Infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of Infliximab infusion. Monitor patients during infusion and if a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

    NEUROLOGIC EVENTS

    TNF blockers, including Infliximab, have been associated with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering Infliximab in patients with these disorders and consider discontinuation if these disorders develop.

    CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS

    Concurrent use of Infliximab with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as Infliximab is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

    AUTOIMMUNITY

    Treatment with Infliximab may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

    Prior to initiating Infliximab, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with Infliximab due to the possibility of clinical infections, including disseminated infections.

    At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to Infliximab.

    ADVERSE REACTIONS

    In clinical trials, the most common adverse reactions occurring in >10% of Infliximab-treated patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

    For more information, please see the full Prescribing Information, including Boxed Warning, and Medication Guide for Infliximab. Provide the Medication Guide to your patients and encourage discussion.

    References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

    cp-253862v1

    INDICATIONS
  • INTELENCE®

    INDICATION STATEMENT

    INTELENCE® (etravirine), in combination with other antiretroviral (ARV) agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in ARV treatment-experienced adults and pediatric patients ages 2 years and older.

    IMPORTANT SAFETY INFORMATION

    WARNINGS & PRECAUTIONS

    • Severe Skin and Hypersensitivity Reactions:
      • Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking INTELENCE®. In clinical trials, these include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme.
      • Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving INTELENCE® in combination with other HIV-1 ARV agents in an observational study.
      • Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure.

    Discontinue INTELENCE® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema).

      • Monitor clinical status including liver transaminases, and initiate appropriate therapy.
      • Delay in stopping INTELENCE® treatment after the onset of severe rash may result in a life-threatening reaction.
    • Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:
      • The concomitant use of INTELENCE® and other drugs may result in potentially significant drug interactions, some of which may lead to the loss of therapeutic effect of INTELENCE® and possible development of resistance or possible clinically significant adverse reactions from greater exposures of INTELENCE® or concomitant drugs.
      • Consult the full Prescribing Information for potential drug interactions prior to and during INTELENCE® therapy; review concomitant medications during INTELENCE® therapy.
    • Immune Reconstitution Syndrome has been reported in patients treated with ARV therapy, including INTELENCE®. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

    ADVERSE REACTIONS

    • The most common adverse drug reactions (≥2%) of at least moderate intensity (≥Grade 2) reported in adult patients taking INTELENCE® and that occurred at a higher rate compared with placebo were rash (10% vs 3%) and peripheral neuropathy (4% vs 2%). The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea.

    DRUG INTERACTIONS

    • Consult the full Prescribing Information for INTELENCE® for more information on significant drug interactions, including clinical comments.
    • Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P‑glycoprotein (P-gp). Therefore, co‑administration of INTELENCE® and drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp may alter the therapeutic effect or adverse reaction profile of the co‑administered drug(s).

    USE IN SPECIFIC POPULATIONS

    • Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. Patients should not breastfeed if they are receiving INTELENCE®.
    • Hepatic Impairment: INTELENCE® should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics of INTELENCE® have not been evaluated in these patients.
    • Pediatric Use: In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving INTELENCE® have been reported (see Warnings & Precautions).

    Please see full Prescribing Information for INTELENCE®.

    cp-63695v3

    INDICATION
  • INVEGA HAFYERA™

    INDICATION

    INVEGA HAFYERA™, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

    • A once-a-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA SUSTENNA®) for at least four months or
    • An every-three-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA TRINZA®) for at least one three-month cycle.

    IMPORTANT SAFETY INFORMATION

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA HAFYERA™ is not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA HAFYERA™ is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone or INVEGA HAFYERA™ in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse of blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA HAFYERA™ and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA HAFYERA™, drug discontinuation should be considered. However, some patients may require treatment with INVEGA HAFYERA™ despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA HAFYERA™ may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA HAFYERA™ should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA HAFYERA™, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA HAFYERA™. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA HAFYERA™ at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA HAFYERA™ in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA HAFYERA™ elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA HAFYERA™. INVEGA HAFYERA™ has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA HAFYERA™ does not adversely affect them.

    Seizures: INVEGA HAFYERA™ should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For gluteal intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA HAFYERA™ kits. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA HAFYERA™. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA HAFYERA™ may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA HAFYERA™. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA HAFYERA™ during pregnancy. INVEGA HAFYERA™ can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA HAFYERA™ and any potential adverse effect on the breastfed infant from INVEGA HAFYERA™ or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA HAFYERA™: The most common adverse reactions (incidence at least 5% in the double-blind phase) in the INVEGA HAFYERA™ clinical trial were upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA HAFYERA™.

    cp-256050v1

    INDICATION
  • INVEGA SUSTENNA®

    INDICATION

    INVEGA SUSTENNA® (paliperidone palmitate) is indicated for the treatment of:

    • Schizophrenia in adults.
    • Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants in adults.

    IMPORTANT SAFETY INFORMATION FOR INVEGA SUSTENNA® (paliperidone palmitate)

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA SUSTENNA® is not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA SUSTENNA® is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the INVEGA SUSTENNA® formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA SUSTENNA® and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA SUSTENNA® elevates prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA®.

    INVEGA SUSTENNA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA SUSTENNA® does not adversely affect them.

    Seizures: INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA SUSTENNA® kit. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g. carbamazepine, rifampin, St. John’s Wort) during a dosing interval for INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA SUSTENNA® during pregnancy. INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA SUSTENNA® and any potential adverse effects on the breastfed infant from INVEGA SUSTENNA® or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5% and twice placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. No adverse events occurred at a rate of ≥5% and twice placebo during the 15-month double-blind, placebo-controlled study in patients with schizoaffective disorder. The following adverse reactions occurred more frequently (a ≥2% difference vs. placebo) in the long-term study in patients with schizoaffective disorder: weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA®.

    cp-64202v3

    INDICATION
  • INVEGA TRINZA®

    INDICATION

    INVEGA TRINZA® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate) for at least four months.

    INVEGA SUSTENNA® (paliperidone palmitate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

    IMPORTANT SAFETY INFORMATION

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA SUSTENNA® and INVEGA TRINZA® are not approved for use in patients with dementia-related psychosis.

    Contraindications: INVEGA TRINZA® and INVEGA SUSTENNA® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

    Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue INVEGA SUSTENNA® or INVEGA TRINZA® and provide symptomatic treatment and monitoring.

    QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA® or INVEGA TRINZA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA® or INVEGA TRINZA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Orthostatic Hypotension and Syncope: INVEGA TRINZA® and INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA TRINZA® and INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA TRINZA® and INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® and INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA TRINZA® and INVEGA SUSTENNA® elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® and INVEGA SUSTENNA®. INVEGA TRINZA® and INVEGA SUSTENNA® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA TRINZA® and INVEGA SUSTENNA® do not adversely affect them.

    Seizures: INVEGA TRINZA® and INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

    Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA TRINZA® or INVEGA SUSTENNA® kits. Care should be taken to avoid inadvertent injection into a blood vessel.

    Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA TRINZA® or INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

    Pregnancy/Nursing: INVEGA TRINZA® and INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA® or INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA TRINZA® or INVEGA SUSTENNA® during pregnancy. INVEGA TRINZA® and INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® or INVEGA SUSTENNA® and any potential adverse effect on the breastfed infant from INVEGA TRINZA® or INVEGA SUSTENNA® or the mother’s underlying condition.

    Commonly Observed Adverse Reactions for INVEGA TRINZA®: The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism.

    Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA® and click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA®.

    cp-64206v3

    INDICATION
  • INVOKAMET®

    indications

    INVOKAMET® and INVOKAMET® XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

    Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

    Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular death (CV), and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

    Limitations of Use

    INVOKAMET® or INVOKAMET® XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    IMPORTANT SAFETY INFORMATION for INVOKAMET® (canagliflozin/metformin HCl) and INVOKAMET® XR (canagliflozin/metformin HCl extended-release)

    WARNING: LACTIC ACIDOSIS

    • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
    • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
    • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
    • If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET® or INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    CONTRAINDICATIONS

    INVOKAMET® or INVOKAMET® XR is contraindicated in patients with:

    • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
    • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    • Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET® or INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.

    Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET® or INVOKAMET® XR and report these symptoms to their healthcare provider.

    Recommendations to reduce the risk include:

    Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).

    Age 65 or Greater: Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Stop INVOKAMET® or INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET® or INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Discontinue INVOKAMET® or INVOKAMET® XR while patients have restricted food and fluid intake.

    Hypoxic States: Discontinue INVOKAMET® or INVOKAMET® XR in conditions associated with hypoxemia.

    Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    Hepatic Impairment: Avoid use of INVOKAMET® or INVOKAMET® XR in patients with evidence of hepatic disease.

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKAMET® or INVOKAMET® XR.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. INVOKAMET® or INVOKAMET® XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET® or INVOKAMET® XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET® or INVOKAMET® XR; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET® or INVOKAMET® XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET® or INVOKAMET® XR.

    Withhold INVOKAMET® or INVOKAMET® XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET® or INVOKAMET® XR when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET® or INVOKAMET® XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET® or INVOKAMET® XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving canagliflozin. Treatment with INVOKAMET® or INVOKAMET® XR increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use of Sulfonylurea or Insulin: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET® or INVOKAMET® XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET® or INVOKAMET® XR.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET® or INVOKAMET® XR.
    • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET® or INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
    • Vitamin B12 Levels: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2‑ to 3‑year intervals and manage any abnormalities.

    DRUG INTERACTIONS

    Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET® or INVOKAMET® XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

    Drugs That Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, and cimetidine) involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

    Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    UGT Enzyme Inducers: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET® or INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET® or INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg.

    Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET® or INVOKAMET® XR is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

    Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for hypoglycemia.

    Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKAMET® or INVOKAMET® XR with concomitant digoxin for a need to adjust dose of digoxin.

    Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKAMET® or INVOKAMET® XR initiation and dosage changes.

    Drug/Laboratory Test Interference

    Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKAMET® or INVOKAMET® XR is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKAMET® or INVOKAMET® XR is not recommended while breastfeeding.
    • Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
    • Pediatric Use: Safety and effectiveness of INVOKAMET® or INVOKAMET® XR in patients <18 years of age have not been established.
    • Geriatric Use: Frequently monitor renal function after initiating INVOKAMET® or INVOKAMET® XR in elderly patients and adjust dose accordingly.

    Canagliflozin

    Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300‐mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.

    Metformin HCl

    The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.

    Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: Metformin HCl use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET® or INVOKAMET® XR is not recommended in patients with hepatic impairment.

    OVERDOSAGE

    • In the event of an overdose with INVOKAMET® or INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common (≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
    • The most common (≥5%) adverse reactions due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

    Please read full Prescribing Information for INVOKAMET® and INVOKAMET® XR, including Boxed WARNING, and Medication Guide for INVOKAMET® and INVOKAMET® XR.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68815v6

    INDICATIONS
  • INVOKAMET® XR

    indications

    INVOKAMET® and INVOKAMET® XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

    Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

    Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular death (CV), and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

    Limitations of Use

    INVOKAMET® or INVOKAMET® XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    IMPORTANT SAFETY INFORMATION for INVOKAMET® (canagliflozin/metformin HCl) and INVOKAMET® XR (canagliflozin/metformin HCl extended-release)

    WARNING: LACTIC ACIDOSIS

    • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
    • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
    • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
    • If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET® or INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

    CONTRAINDICATIONS

    INVOKAMET® or INVOKAMET® XR is contraindicated in patients with:

    • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
    • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    • Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET® or INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.

    Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET® or INVOKAMET® XR and report these symptoms to their healthcare provider.

    Recommendations to reduce the risk include:

    Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).

    Age 65 or Greater: Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Stop INVOKAMET® or INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET® or INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Discontinue INVOKAMET® or INVOKAMET® XR while patients have restricted food and fluid intake.

    Hypoxic States: Discontinue INVOKAMET® or INVOKAMET® XR in conditions associated with hypoxemia.

    Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    Hepatic Impairment: Avoid use of INVOKAMET® or INVOKAMET® XR in patients with evidence of hepatic disease.

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKAMET® or INVOKAMET® XR.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. INVOKAMET® or INVOKAMET® XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET® or INVOKAMET® XR.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET® or INVOKAMET® XR; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET® or INVOKAMET® XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET® or INVOKAMET® XR.

    Withhold INVOKAMET® or INVOKAMET® XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET® or INVOKAMET® XR when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET® or INVOKAMET® XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET® or INVOKAMET® XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving canagliflozin. Treatment with INVOKAMET® or INVOKAMET® XR increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use of Sulfonylurea or Insulin: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET® or INVOKAMET® XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET® or INVOKAMET® XR.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET® or INVOKAMET® XR.
    • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET® or INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
    • Vitamin B12 Levels: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2‑ to 3‑year intervals and manage any abnormalities.

    DRUG INTERACTIONS

    Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET® or INVOKAMET® XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

    Drugs That Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, and cimetidine) involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

    Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.

    UGT Enzyme Inducers: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET® or INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET® or INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg.

    Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET® or INVOKAMET® XR is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

    Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for hypoglycemia.

    Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKAMET® or INVOKAMET® XR with concomitant digoxin for a need to adjust dose of digoxin.

    Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKAMET® or INVOKAMET® XR initiation and dosage changes.

    Drug/Laboratory Test Interference

    Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKAMET® or INVOKAMET® XR is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKAMET® or INVOKAMET® XR is not recommended while breastfeeding.
    • Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
    • Pediatric Use: Safety and effectiveness of INVOKAMET® or INVOKAMET® XR in patients <18 years of age have not been established.
    • Geriatric Use: Frequently monitor renal function after initiating INVOKAMET® or INVOKAMET® XR in elderly patients and adjust dose accordingly.

    Canagliflozin

    Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300‐mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.

    Metformin HCl

    The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.

    Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: Metformin HCl use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET® or INVOKAMET® XR is not recommended in patients with hepatic impairment.

    OVERDOSAGE

    • In the event of an overdose with INVOKAMET® or INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common (≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
    • The most common (≥5%) adverse reactions due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

    Please read full Prescribing Information for INVOKAMET® and INVOKAMET® XR, including Boxed WARNING, and Medication Guide for INVOKAMET® and INVOKAMET® XR.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68815v6

    INDICATIONS
  • INVOKANA®

    INDICATIONS

    INVOKANA® (canagliflozin) is indicated:

    • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
    • To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD)
    • To reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day

    Limitations of Use

    INVOKANA® is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

    INVOKANA® is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. INVOKANA® is likely to be ineffective in this setting based upon its mechanism of action.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    • Serious hypersensitivity reaction to INVOKANA®, such as anaphylaxis or angioedema

    WARNINGS AND PRECAUTIONS

    • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: In patients with type 1 diabetes mellitus, INVOKANA® significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received SGLT2 inhibitors compared to placebo; this risk may be greater with higher doses of INVOKANA®. INVOKANA® is not indicated for glycemic control in patients with type 1 diabetes mellitus.

    Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA®.

    Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

    Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKANA®; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

    Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKANA®, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA®.

    Withhold INVOKANA®, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA® when the patient is clinically stable and has resumed oral intake.

    • Lower-Limb Amputation: An increased risk of lower-limb amputations associated with INVOKANA® use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.

    Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA® in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA® in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating INVOKANA®, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.

    • Volume Depletion: INVOKANA® can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA® in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
    • Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving INVOKANA®. Treatment with INVOKANA® increases this risk. Evaluate for signs and symptoms and treat promptly.
    • Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA® may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA®.
    • Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
    • Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with INVOKANA®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA®, treat, and monitor until signs and symptoms resolve.
    • Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA®. Prior to initiation, consider factors that contribute to fracture risk.

    DRUG INTERACTIONS

    • UGT Enzyme Inducers: UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) decrease canagliflozin exposure which may reduce the effectiveness of INVOKANA®. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs is administered with INVOKANA®, increase the dosage to 200 mg daily (taken as two 100-mg tablets) in patients currently tolerating INVOKANA® 100 mg daily. The total daily dosage may be increased to 300 mg daily in patients currently tolerating INVOKANA® 200 mg daily who require additional glycemic control.

    For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is administered with INVOKANA®, increase the dose to 200 mg daily (taken as two 100-mg tablets) in patients currently tolerating INVOKANA® 100 mg daily. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

    • Insulin or Insulin Secretagogues: The risk of hypoglycemia is increased when INVOKANA® is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue of insulin to reduce the risk of hypoglycemia.
    • Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKANA® with concomitant digoxin for a need to adjust the dosage of digoxin.
    • Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKANA® initiation and dosage changes.

    Drug/Laboratory Test Interference

    • Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
    • Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: INVOKANA® is not recommended in pregnant women, especially during the second and third trimesters.
    • Lactation: INVOKANA® is not recommended while breastfeeding.
    • Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.
    • Geriatric Use: Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300-mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years.
    • Renal Impairment: The efficacy and safety of INVOKANA® for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using INVOKANA® for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.

    Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.

    • Hepatic Impairment: INVOKANA® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

    OVERDOSAGE

    • In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures.

    ADVERSE REACTIONS

    • The most common adverse reactions (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination.

    Please read full Prescribing Information and Medication Guide for INVOKANA®.

    Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

    cp-68813v8

    INDICATIONS
  • PONVORY®

    INDICATION

    PONVORY® is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

    IMPORTANT SAFETY INFORMATION

    CONTRAINDICATIONS

    PONVORY® is contraindicated in patients who:

    • In the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure.
    • Have presence of Mobitz Type II second-degree, third-degree atrioventricular (AV) block, or sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker.

    WARNINGS AND PRECAUTIONS

    Risk of Infections

    PONVORY® causes a dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. PONVORY® may increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators. Before initiating treatment with PONVORY®, results from a recent complete blood count including lymphocyte count should be reviewed.

    Herpes Viral Infections

    Cases of herpes viral infection have been reported in the development program of PONVORY®; herpes simplex encephalitis and varicella zoster meningitis have been reported with other S1P receptor modulators. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination should be tested for antibodies to VZV prior to initiating PONVORY®.

    Cryptococcal Infections

    Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. PONVORY® treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

    Progressive Multifocal Leukoencephalopathy (PML)

    PML has been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with PONVORY® should be suspended until PML has been excluded.

    If PML is confirmed, treatment with PONVORY® should be discontinued.

    Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

    Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies

    Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects.

    Vaccinations

    Patients without a confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY® treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with PONVORY®, following which initiation of treatment should be postponed for 4 weeks to allow the full effect of vaccination to occur.

    No clinical data are available on the efficacy and safety of vaccinations in patients taking PONVORY®. Vaccinations may be less effective if administered during PONVORY® treatment. If live attenuated vaccines are required, administer at least 1 month prior to initiation of PONVORY®. Avoid the use of live attenuated vaccines during and for 1 to 2 weeks after treatment of PONVORY®.

    Bradyarrhythmia and Atrioventricular Conduction Delays

    Since initiation of PONVORY® treatment results in a transient decrease in heart rate and atrioventricular (AV) conduction delays, an up-titration scheme must be used to reach the maintenance dosage of PONVORY® (20 mg).

    Reduction in Heart Rate

    Initiation of PONVORY® may result in a transient decrease in heart rate. After the first titration dose of PONVORY®, the decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration.

    Atrioventricular Conduction Delays

    Initiation of PONVORY® treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. If treatment with PONVORY® is considered, advice from a cardiologist should be sought for individuals:

    • With significant QT prolongation (QTc greater than 500 msec).
    • With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs.
    • With unstable ischemic heart disease, cardiac decompensated failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension.
    • With a history of Mobitz Type II second degree AV block or higher-grade AV block, sick-sinus syndrome, or sino-atrial heart block.

    Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. For patients taking other drugs that decrease heart rate, treatment with PONVORY® should generally not be initiated without consultation from a cardiologist because of the potential effect on heart rate. In all patients, a dose titration is recommended for initiation of PONVORY® treatment to help reduce cardiac effects.

    Respiratory Effects

    Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide (DLCO) were observed in PONVORY®-treated patients mostly occurring in the first month after treatment initiation. Spirometric evaluation of respiratory function should be performed during therapy with PONVORY® if clinically indicated.

    Liver Injury

    Elevations of transaminases may occur in PONVORY®-treated patients. Obtain transaminase and bilirubin levels, if not recently available (i.e., within last 6 months) before initiation of PONVORY® therapy.

    Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have hepatic enzymes checked. PONVORY® should be discontinued if significant liver injury is confirmed.

    No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). PONVORY® is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C, respectively).

    Increased Blood Pressure

    PONVORY®-treated patients had an average increase of 2.9 mmHg in systolic blood pressure and 2.8 mmHg in diastolic blood pressure. Blood pressure should be monitored during treatment with PONVORY® and managed appropriately.

    Cutaneous Malignancies

    Cases of basal cell carcinoma and other skin malignancies have been reported in patients treated with S1P receptor modulators, including PONVORY®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking PONVORY®.

    Fetal Risk

    Based on animal studies, PONVORY® may cause fetal harm. Because it takes approximately 1 week to eliminate PONVORY® from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 1 week after stopping PONVORY® treatment.

    Macular Edema

    S1P receptor modulators, including PONVORY®, have been associated with an increased risk of macular edema. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and again at any time if a patient reports any change in vision while on PONVORY® therapy. Continuation of therapy in patients with macular edema has not been evaluated.

    Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

    Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during therapy with S1P receptor modulators, including PONVORY®. Therefore, these patients should have regular follow-up examinations of the fundus, including the macula, during treatment with PONVORY®.

    Posterior Reversible Encephalopathy Syndrome

    Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for PONVORY®-treated patients in the development program. However, should a PONVORY®-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, PONVORY® should be discontinued.

    Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies

    When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive effects on the immune system while at the same time minimizing risk of disease reactivation, when initiating PONVORY®. Initiating treatment with PONVORY® after treatment with alemtuzumab is not recommended.

    Severe Increase in Disability After Stopping PONVORY®

    Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping PONVORY® treatment. Patients should be observed for a severe increase in disability upon PONVORY® discontinuation and appropriate treatment should be instituted, as required.

    After stopping PONVORY® in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

    Immune System Effects After Stopping PONVORY®

    After stopping PONVORY® therapy, ponesimod remains in the blood for up to 1 week.

    Starting other therapies during this interval will result in concomitant exposure to ponesimod. Lymphocyte counts returned to the normal range in 90% of patients within 1 week of stopping therapy, however, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for 1 to 2 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 1 to 2 weeks after the last dose of PONVORY®.

    OVERDOSAGE

    In patients with overdosage of PONVORY®, especially upon initiation/re-initiation of treatment, it is important to observe for signs and symptoms of bradycardia as well as AV conduction blocks, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed.

    There is no specific antidote to ponesimod. Neither dialysis nor plasma exchange would result in meaningful removal of ponesimod from the body. The decrease in heart rate induced by PONVORY® can be reversed by atropine.

    In the event of overdose, PONVORY® should be discontinued, and general supportive treatment given until clinical toxicity has been diminished or resolved. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose.

    ADVERSE REACTIONS

    Most common adverse reactions (incidence at least 10%) are upper respiratory tract infection, hepatic transaminase elevation, and hypertension.

    Please see full Prescribing Information and Medication Guide.

    cp-214886v6

    INDICATION
  • PREZCOBIX®

    Indication

    PREZCOBIX® is indicated in combination with other antiretroviral agents for the treatment of Human Immunodeficiency Virus (HIV-1) infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

    Important Safety Information

    Contraindications

    • Darunavir and cobicistat are both inhibitors and substrates of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX® should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). In addition, co-administration of PREZCOBIX® with CYP3A inducers may lead to lower exposures of darunavir and cobicistat, and potential loss of efficacy of darunavir and possible resistance.

    Examples of drugs that are contraindicated for co-administration with PREZCOBIX® are: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, ivabradine, lomitapide, lovastatin, lurasidone, methylergonovine, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

    Warnings and Precautions

    • Hepatotoxicity: Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions. Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported.

    Appropriate laboratory testing should be conducted prior to initiating and during therapy with PREZCOBIX®. Evidence of new or worsening liver dysfunction in patients on PREZCOBIX® should prompt consideration of interruption or discontinuation of treatment.

    • Severe Skin Reactions: Severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported in patients receiving darunavir coadministered with ritonavir. Mild-to-moderate rash was also reported and often occurred and resolved with continued dosing. Discontinue PREZCOBIX® immediately if signs or symptoms of severe skin reaction develop.
    • Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX®.
    • Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. Prior to starting PREZCOBIX®, assess estimated CrCl. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
    • Renal Impairment When Used With Tenofovir Disoproxil Fumarate (DF): Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported with the use of tenofovir DF and cobicistat. Coadministration with tenofovir DF is not recommended in patients who have an estimated CrCl <70 mL/min. In all patients, monitor estimated CrCl, urine glucose, and urine protein prior to initiating and during therapy. Measure serum phosphorus in patients at risk of renal impairment. Coadministration of PREZCOBIX® and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
    • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Initiation of PREZCOBIX®, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX® may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX®. These interactions may lead to clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications; clinically significant adverse reactions from higher exposures of PREZCOBIX®; loss of therapeutic effect of concomitant medications from lower exposures of active metabolite(s); or loss of therapeutic effect of PREZCOBIX® and possible development of resistance from lower exposures of PREZCOBIX®.
    • Antiretrovirals Not Recommended: Do not use PREZCOBIX® in combination with other antiretroviral drugs that require pharmacokinetic boosting or which contain the individual components of PREZCOBIX® (darunavir and cobicistat) or with ritonavir.
    • Diabetes Mellitus/Hyperglycemia and Hemophilia: New onset or exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. Increased bleeding in hemophiliacs has been reported in patients receiving protease inhibitors.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.
    • Immune Reconstitution Syndrome including the occurrence of autoimmune disorders with variable time to onset has been reported.

    Adverse Reactions

    • The most common clinical adverse reactions (incidence ≥5%) of at least moderate intensity (≥Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting during the darunavir clinical development program, where darunavir was coadministered with ritonavir.

    This is not a complete list of all adverse drug reactions reported with the use of PREZCOBIX®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

    Drug Interactions

    • Consult the full Prescribing Information for PREZCOBIX® for information on potentially significant drug interactions, including clinical comments.

    Use in Specific Populations

    • PREZCOBIX® is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.
    • PREZCOBIX® should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with PREZCOBIX®.

    Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

    • The safety and effectiveness of PREZCOBIX® have not been established and is not recommended in pediatric patients weighing less than 40 kg.
    • Consult the full Prescribing Information for PREZCOBIX® for additional information on the Uses in Specific Populations.

    Please see full Prescribing Information for more details.

    cp-08641v12

    INDICATION
  • PREZISTA®

    Indication

    PREZISTA® (darunavir), coadministered with ritonavir (PREZISTA®/r), in combination with other antiretroviral agents (ARVs), is indicated for the treatment of Human Immunodeficiency Virus (HIV-1) infection in adult patients.

    Important Safety Information

    Contraindications

    • Co-administration of PREZISTA®/ritonavir (PREZISTA®/r) is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below. Due to the need for co-administration of PREZISTA® with ritonavir, please refer to ritonavir Prescribing Information for a description of ritonavir contraindications.
      • alfuzosin, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, ivabradine, lomitapide, lovastatin, lurasidone, methylergonovine, oral midazolam, naloxegol, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil (for the treatment of pulmonary arterial hypertension), simvastatin, and triazolam.

    Warnings & Precautions

    • PREZISTA® must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA® with ritonavir and food may result in a loss of efficacy of darunavir.
    • Hepatotoxicity: Drug-induced hepatitis has been reported with PREZISTA®/r. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA®/r. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

    Post-marketing cases of liver injury, including some fatalities, have been reported. A causal relationship with PREZISTA®/r therapy has not been established.

    Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA®/r and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA®/r treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA®/r should prompt consideration of interruption or discontinuation of treatment.

    • Severe Skin Reactions: Severe skin reactions (0.4%), accompanied by fever and/or elevations of transaminases in some cases, and Stevens-Johnson Syndrome (<0.1%) have been reported in patients receiving PREZISTA®/r. During post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported in patients receiving PREZISTA®/r. Discontinue PREZISTA®/r immediately if signs or symptoms of severe skin reactions develop (including, but not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).

    In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of patients receiving PREZISTA®/r. Discontinuation due to rash was 0.5%.

    Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA®/r + raltegravir compared to subjects receiving either drug regimen alone. However, rash that was considered drug-related occurred at similar rates. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

    • Sulfa Allergy: PREZISTA® should be used with caution in patients with known sulfonamide allergy.
    • Risk of Serious Adverse Reactions Due to Drug Interactions: Initiation of PREZISTA®/r, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA®/r, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZISTA®/r, respectively. These interactions may lead to:
      • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
      • Clinically significant adverse reactions from greater exposures of PREZISTA®/r.
      • Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).
      • Loss of therapeutic effect of PREZISTA®/r and possible development of resistance from lower exposures of PREZISTA®/r.

    Consider the potential for drug interactions prior to and during PREZISTA®/r therapy, review concomitant medications during PREZISTA®/r therapy, and monitor for the adverse reactions associated with the concomitant drugs.

    • Diabetes Mellitus/Hyperglycemia and Hemophilia: New-onset or exacerbations of preexisting diabetes mellitus, hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. A causal relationship between protease inhibitors and these events has not been established.
    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
    • Immune Reconstitution Syndrome: Patients receiving PREZISTA®/r may develop new onset or exacerbations of immune reconstitution syndrome.

    Adverse Reactions

    • In treatment-naïve adult patients, the most common adverse drug reactions (≥5%) reported of at least moderate intensity (≥Grade 2) in the PREZISTA®/r arm through 192 weeks were diarrhea (9%), headache (7%), abdominal pain (6%), and rash (6%).
    • In treatment-experienced adult patients, the most common adverse drug reactions (≥5%) reported of at least moderate intensity (≥Grade 2) in the PREZISTA®/r arm through 96 weeks were diarrhea (14%), nausea (7%), rash (7%), abdominal pain (6%), and vomiting (5%).

    This is not a complete list of all adverse drug reactions reported with the use of PREZISTA®/r.

    Drug Interactions

    • Consult the full Prescribing Information for PREZISTA® for information on potentially significant drug interactions, including clinical comments.

    Use in Specific Populations

    • Hepatic Impairment: PREZISTA®/r is not recommended for use in patients with severe hepatic impairment. There are no pharmacokinetic or safety data available in patients with severe hepatic impairment.

    This list of uses in specific populations is not complete.

    Please refer to the ritonavir Prescribing Information for additional safety information.

    Please see full Prescribing Information for more details.

    cp-07779v7

    INDICATION
  • REMICADE®

    INDICATIONS

    Crohn's Disease

    REMICADE® is indicated for:

    • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy.
    • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD.

    Pediatric Crohn's Disease

    REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy.

    Ulcerative Colitis

    REMICADE® is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy.

    Pediatric Ulcerative Colitis

    REMICADE® is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

    Rheumatoid Arthritis

    REMICADE®, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA).

    Ankylosing Spondylitis

    REMICADE® is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).

    Psoriatic Arthritis

    REMICADE® is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA).

    Plaque Psoriasis

    REMICADE® is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

    IMPORTANT SAFETY INFORMATION FOR REMICADE® (infliximab)

    SERIOUS INFECTIONS

    Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.

    Reported infections include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®.1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella, Listeria, and Salmonella.

    The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including REMICADE®. These cases have had a very aggressive disease course and have been fatal. The majority of reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.

    In clinical trials of all TNF blockers, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF blockers, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF blockers in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    A population-based retrospective cohort study found a 2- to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with REMICADE® compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between REMICADE® and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMICADE®.

    CONTRAINDICATIONS

    The use of REMICADE® at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. REMICADE® is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab or any of the inactive ingredients of REMICADE® or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

    HEPATITIS B REACTIVATION

    TNF blockers, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.

    HEPATOTOXICITY

    Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.

    HEART FAILURE

    In a randomized, placebo-controlled study in patients with moderate or severe heart failure (NYHA Functional Class III/IV), higher mortality rates and a higher risk of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been postmarketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors. Patients with moderate or severe heart failure taking REMICADE® (≤5 mg/kg) or patients with mild heart failure should be closely monitored and treatment should be discontinued if new or worsening symptoms appear.

    HEMATOLOGIC EVENTS

    Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.

    HYPERSENSITIVITY

    REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Medications for the treatment of hypersensitivity reactions should be available.

    CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

    Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of REMICADE® infusion. Cases of transient visual loss have been reported during or within 2 hours of REMICADE® infusion. Monitor patients during infusion and if a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

    NEUROLOGIC EVENTS

    TNF blockers, including REMICADE®, have been associated with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE® in patients with these disorders and consider discontinuation if these disorders develop.

    CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS

    Concurrent use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as REMICADE® is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

    AUTOIMMUNITY

    Treatment with REMICADE® may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

    Prior to initiating REMICADE®, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with REMICADE® due to the possibility of clinical infections, including disseminated infections.

    At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to REMICADE®.

    ADVERSE REACTIONS

    In clinical trials, the most common adverse reactions occurring in >10% of REMICADE®-treated patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

    For more information, please see the full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.

    References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

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    INDICATIONS
  • RISPERDAL CONSTA®

    INDICATION

    RISPERDAL CONSTA® (risperidone) long-acting injection is indicated for the treatment of schizophrenia.

    IMPORTANT SAFETY INFORMATION FOR RISPERDAL CONSTA® (risperidone)

    WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

    See full prescribing information for complete Boxed Warning.

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL CONSTA® is not approved for use in patients with dementia-related psychosis.

    Contraindications: RISPERDAL CONSTA® is contraindicated in patients with a known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL CONSTA®.

    Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL CONSTA® is not approved for the treatment of patients with dementia-related psychosis.

    Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs.

    Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

    If NMS is suspected, immediately discontinue RISPERDAL CONSTA® and provide symptomatic treatment and monitoring.

    Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

    The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possible masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

    If signs and symptoms of TD appear in a patient on RISPERDAL CONSTA®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL CONSTA® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

    Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

    Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL CONSTA®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Monitor glucose regularly in patients with diabetes or at risk for diabetes. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

    Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

    Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

    Orthostatic Hypotension and Syncope: RISPERDAL CONSTA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. RISPERDAL CONSTA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

    Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL CONSTA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

    Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL CONSTA®. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL CONSTA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL CONSTA® and have their WBC followed until recovery.

    Potential for Cognitive and Motor Impairment: Somnolence was reported in multiple trials in subjects treated with RISPERDAL CONSTA®. Since RISPERDAL CONSTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL CONSTA® does not adversely affect them.

    Seizures: RISPERDAL CONSTA® should be used cautiously in patients with a history of seizures.

    Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Use cautiously in patients at risk for aspiration pneumonia.

    Priapism has been reported. Severe priapism may require surgical intervention.

    Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with RISPERDAL CONSTA® use.

    Thrombotic Thrombocytopenic Purpura (TTP) has been reported.

    Administration: For intramuscular injection only. Care should be taken to avoid inadvertent injection into a blood vessel.

    Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS.

    Use RISPERDAL CONSTA® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g., recent myocardial infarction or unstable cardiac disease).

    Pregnancy/Nursing: RISPERDAL CONSTA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with RISPERDAL CONSTA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to RISPERDAL CONSTA® during pregnancy. RISPERDAL CONSTA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for RISPERDAL CONSTA® and any potential adverse effect on the breastfed infant from RISPERDAL CONSTA® or the mother’s underlying condition.

    Fertility: RISPERDAL CONSTA® may cause a reversible reduction in fertility in females.

    Commonly Observed Adverse Reactions for RISPERDAL CONSTA®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5%) were headache, Parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities, and dry mouth.

    Please click here to read the full Prescribing Information, including Boxed WARNING, for RISPERDAL CONSTA®.

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    INDICATIONS
  • RYBREVANT®

    INDICATION

    RYBREVANT® (amivantamab-vmjw) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

    This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Infusion-Related Reactions

    RYBREVANT® can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

    Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT®. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT® due to IRR.

    Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT® based on severity.

    Interstitial Lung Disease/Pneumonitis

    RYBREVANT® can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT®, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT® due to ILD/pneumonitis.

    Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

    Dermatologic Adverse Reactions

    RYBREVANT® can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT®, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT® was permanently discontinued due to rash in 0.7% of patients.

    Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT®.

    Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT®. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol‑free emollient cream is recommended for dry skin.

    If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

    Ocular Toxicity

    RYBREVANT® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

    Embryo-Fetal Toxicity

    Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT®.

    Adverse Reactions

    The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

    Please read full Prescribing Information for RYBREVANT®.

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    INDICATION
  • SIMPONI®

    INDICATIONS

    SIMPONI® is a tumor necrosis factor (TNF) blocker indicated for the treatment of adult patients with:

    • Moderately to severely active rheumatoid arthritis (RA), in combination with methotrexate (MTX)
    • Active psoriatic arthritis (PsA) alone, or in combination with MTX
    • Active ankylosing spondylitis (AS)
    • Moderately to severely active ulcerative colitis (UC) who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine for:
      • Inducing and maintaining clinical response
      • Improving endoscopic appearance of the mucosa during induction
      • Inducing clinical remission
      • Achieving and sustaining clinical remission in induction responders

    IMPORTANT SAFETY INFORMATION

    SERIOUS INFECTIONS

    Patients treated with SIMPONI® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI® if a patient develops a serious infection.

    Reported infections with TNF blockers, of which SIMPONI® is a member, include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI® use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI® use.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

    The risks and benefits of treatment with SIMPONI® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI® included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.

    MALIGNANCIES

    Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI® is a member.

    Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI®, more cases of lymphoma have been observed among patients receiving TNF-blocking treatment compared with control patients. In the Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), and Ankylosing Spondylitis (AS) clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI® group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI® and was similar to what would be expected in the general population. In controlled and uncontrolled portions of the Phase 2/3 studies in ulcerative colitis (UC) with a mean follow-up of approximately 1 year, there were no cases of lymphoma with SIMPONI®. Short follow-up periods, such as those of 1 year or less in the studies above, may not adequately reflect the true incidence of malignancies. Cases of acute and chronic leukemia have been reported with TNF-blocker use, including SIMPONI®. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

    Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or UC, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for HSTCL in patients treated with TNF blockers cannot be excluded.

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocking agents, including SIMPONI®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    HEPATITIS B REACTIVATION

    The use of TNF-blocking agents including SIMPONI® has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

    All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI®. Discontinue SIMPONI® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI®, and monitor patients closely.

    HEART FAILURE

    Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers, including SIMPONI®. Some cases had a fatal outcome. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI® if new or worsening symptoms of heart failure appear.

    DEMYELINATING DISORDERS

    TNF-blocking agents, of which SIMPONI® is a member, have been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported with SIMPONI®. Exercise caution in considering the use of SIMPONI® in patients with these disorders. Consider discontinuation if these disorders develop.

    AUTOIMMUNITY

    Treatment with TNF blockers, including SIMPONI®, may result in the formation of antinuclear antibodies and, rarely, in the development of a lupus-like syndrome. Discontinue treatment if symptoms suggestive of a lupus-like syndrome develop.

    HEMATOLOGIC CYTOPENIAS

    There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia in patients receiving SIMPONI®. Exercise caution when using SIMPONI® in patients who have or had significant cytopenias.

    USE WITH OTHER DRUGS

    The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the use of SIMPONI® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI® with biologics approved to treat RA, PsA, or AS is not recommended because of the possibility of an increased risk of infection.

    VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS

    People receiving SIMPONI® can receive vaccinations, except for live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. Administration of live vaccines to infants exposed to SIMPONI® in utero is not recommended for 6 months following the mother’s last SIMPONI® injection during pregnancy due to an increased risk of infection. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI® due to the possibility of clinical infections, including disseminated infections.

    HYPERSENSITIVITY REACTIONS

    Serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported with SIMPONI®, some occurring after the first dose. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI® immediately and institute appropriate therapy.

    ADVERSE REACTIONS

    The most serious adverse reactions were serious infections and malignancies.

    Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI® as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI® compared with 2% of patients in the control group.

    In the Phase 2/3 trials in UC evaluating SIMPONI®-treated patients, no new adverse drug reactions were identified, and the frequency of adverse drug reactions was similar to the safety profile observed in patients with RA, PsA, and AS.

    Please see the full Prescribing Information and Medication Guide for SIMPONI®. Provide the Medication Guide to your patients and encourage discussion.

    cp-51205v1

    INDICATIONS
  • SIMPONI ARIA®

    INDICATIONS

    SIMPONI ARIA® (golimumab) is a tumor necrosis factor (TNF) blocker indicated for the treatment of:

    • Adult patients with moderately to severely active Rheumatoid Arthritis (RA) in combination with methotrexate
    • Active Psoriatic Arthritis (PsA) in patients 2 years of age and older
    • Adult patients with active Ankylosing Spondylitis (AS)
    • Active polyarticular Juvenile Idiopathic Arthritis (pJIA) in patients 2 years of age and older

    IMPORTANT SAFETY INFORMATION

    SERIOUS INFECTIONS

    Patients treated with SIMPONI ARIA® (golimumab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI ARIA® if a patient develops a serious infection.

    Reported infections with TNF blockers, of which SIMPONI ARIA® is a member, include:

    • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before SIMPONI ARIA® use and during therapy. Initiate treatment for latent infection prior to SIMPONI ARIA® use.
    • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
    • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

    Consider the risks and benefits of treatment with SIMPONI ARIA® prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI ARIA® in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

    Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients treated with SIMPONI ARIA® included sepsis, pneumonia, cellulitis, and abscess.

    MALIGNANCIES

    Malignancies, some fatal, have been reported in children, adolescents, and young adult patients treated with golimumab. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

    In the controlled portions of clinical trials of TNF blockers including the subcutaneous formulation of golimumab, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. In clinical trials, the incidence of malignancies other than lymphoma and non-melanoma skin cancer per 100 patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA® group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group. Cases of acute and chronic leukemia have been reported with TNF-blocker use, including SIMPONI ARIA®. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

    Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or ulcerative colitis, and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for HSTCL in patients treated with TNF blockers cannot be excluded.

    Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocking agents, including SIMPONI ARIA®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

    HEPATITIS B REACTIVATION

    The use of TNF blockers, of which SIMPONI ARIA® is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

    All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI ARIA® for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI ARIA®. Discontinue SIMPONI ARIA® in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI ARIA®, and monitor patients closely.

    CONGESTIVE HEART FAILURE

    Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers, including SIMPONI ARIA®. Some cases had a fatal outcome. Exercise caution in CHF patients receiving SIMPONI ARIA® and monitor them closely during therapy. Discontinue SIMPONI ARIA® if new or worsening symptoms of heart failure appear.

    DEMYELINATING DISORDERS

    Use of TNF blockers, including SIMPONI ARIA®, has been associated with rare cases of new-onset or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with golimumab. Exercise caution in considering the use of SIMPONI ARIA® in patients with these disorders. Consider discontinuation if these disorders develop.

    AUTOIMMUNITY

    Treatment with TNF blockers, including SIMPONI ARIA®, may result in the formation of antinuclear antibodies. Rarely, treatment with TNF blockers may result in a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

    USE WITH OTHER DRUGS

    The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI ARIA® in combination with these products is not recommended. Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI ARIA® with biologics approved to treat RA is not recommended because of the possibility of an increased risk of infection.

    HEMATOLOGIC CYTOPENIAS

    There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia in patients receiving SIMPONI ARIA®. Exercise caution when using SIMPONI ARIA® in patients who have or had significant cytopenias.

    VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS

    Live vaccines or therapeutic infectious agents should not be given with SIMPONI ARIA® due to the possibility of clinical infections, including disseminated infections.

    Update vaccinations prior to initiation of treatment in accordance with current vaccination guidelines. Advise patients to discuss with the physician before seeking any immunizations. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to SIMPONI ARIA®.

    HYPERSENSITIVITY REACTIONS

    Serious systemic hypersensitivity reactions (including anaphylaxis) have been reported following administration of the subcutaneous formulation of golimumab and SIMPONI ARIA®, some occurring after the first dose. Hypersensitivity reactions including hives, pruritus, dyspnea, and nausea, were reported in association with infusions of SIMPONI ARIA®. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI ARIA® immediately and institute appropriate therapy.

    ADVERSE REACTIONS

    The most serious adverse reactions were serious infections and malignancies.

    The most common adverse reactions (incidence ≥ 3%) reported in clinical trials were: upper respiratory tract infection, alanine aminotransferase increase, viral infection, aspartate aminotransferase increase, neutrophil count decrease, bronchitis, hypertension, and rash. In the controlled phase of Trial RA, the rate of infusions associated with an infusion reaction was reported in 1.1% of SIMPONI ARIA® infusions compared with 0.2% of infusions in the control group.

    The adverse reactions observed in pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA) were consistent with the established safety profile of SIMPONI ARIA® in adult patients with RA and PsA.

    Please see the full Prescribing Information and Medication Guide for SIMPONI ARIA®. Provide the Medication Guide to your patients and encourage discussion.

    cp-51207v3

    INDICATIONS
  • SPRAVATO®

    Indications and Limitations of Use:

    SPRAVATO® (esketamine) CIII Nasal Spray is indicated, in conjunction with an oral antidepressant, for the treatment of:

    • Treatment-resistant depression (TRD) in adults.
    • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

    Limitations of Use:

    • The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO® does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO®.
    • SPRAVATO® is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO® as an anesthetic agent have not been established.

    Important Safety Information

    WARNING: SEDATION, DISSOCIATION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS

    See full prescribing information for complete boxed warning

    • Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration (5.1, 5.2).
    • Potential for abuse and misuse. Consider the risks and benefits of using SPRAVATO® prior to use in patients at higher risk of abuse. Monitor for signs and symptoms of abuse and misuse (5.3).
    • SPRAVATO® is only available through a restricted program called the SPRAVATO® REMS (5.4).
    • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO® is not approved for use in pediatric patients (5.5).

    CONTRAINDICATIONS

    SPRAVATO® is contraindicated in patients with:

    • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
    • History of intracerebral hemorrhage.
    • Hypersensitivity to esketamine, ketamine, or any of the excipients.

    WARNINGS AND PRECAUTIONS

    Sedation: In clinical trials, 48% to 61% of SPRAVATO®-treated patients developed sedation and 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness.

    Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

    Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants (e.g., benzodiazepines, opioids, alcohol).

    Dissociation: The most common psychological effects of SPRAVATO® were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO®-treated patients developed dissociative or perceptual changes). Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.

    Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

    Abuse and Misuse: SPRAVATO® contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient’s risk for abuse or misuse prior to prescribing and monitor all patients for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and monitor for signs of abuse or dependence.

    SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS): SPRAVATO® is available only through a restricted program called the SPRAVATO® REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.

    Important requirements of the SPRAVATO® REMS include the following:

    • Healthcare settings must be certified in the program and ensure that SPRAVATO® is:
      • Only dispensed and administered in healthcare settings.
      • Patients treated in outpatient settings (e.g., medical offices and clinics) must be enrolled in the program.
      • Administered by patients under the direct observation of a healthcare provider and that patients are monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO®.
    • Pharmacies must be certified in the REMS and must only dispense SPRAVATO® to healthcare settings that are certified in the program.

    Further information, including a list of certified pharmacies, is available at www.SPRAVATOrems.com/ or 1-855-382-6022.

    Suicidal Thoughts and Behaviors in Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included adult and pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater than in placebo-treated patients. SPRAVATO® is not approved in pediatric (<18 years of age) patients.

    There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

    Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO® and/or the concomitant oral antidepressant, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

    Increase in Blood Pressure: SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO® administration and last approximately 4 hours.

    Approximately 8% to 19% of SPRAVATO®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risk.

    Assess BP prior to administration of SPRAVATO®. In patients whose BP is elevated prior to SPRAVATO® administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO® therapy should take into account the balance of benefit and risk in individual patients.

    BP should be monitored for at least 2 hours after SPRAVATO® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.

    Closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) or monoamine oxidase inhibitors (MAOIs).

    In patients with a history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.

    Cognitive Impairment

    Short-Term Cognitive Impairment: In a study in healthy volunteers, a single dose of SPRAVATO® caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO®-treated subjects required a greater effort to complete the cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO® and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.

    Long-Term Cognitive Impairment: Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. No adverse effects of SPRAVATO® nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO® have not been evaluated beyond one year.

    Impaired Ability to Drive and Operate Machinery: Before SPRAVATO® administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep. Patients will need to arrange transportation home following treatment with SPRAVATO®.

    Ulcerative or Interstitial Cystitis: Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine. In clinical studies with SPRAVATO® nasal spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in SPRAVATO®-treated patients than in placebo-treated patients. No cases of esketamine-related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year.

    Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO® and refer to an appropriate healthcare provider as clinically warranted.

    PREGNANCY, EMBRYO-FETAL TOXICITY, AND LACTATION

    SPRAVATO® is not recommended during pregnancy. SPRAVATO® may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to an infant exposed to SPRAVATO® in utero. Advise women of reproductive potential to consider pregnancy planning and prevention.

    There are risks to the mother associated with untreated depression in pregnancy. If a woman becomes pregnant while being treated with SPRAVATO®, treatment with SPRAVATO® should be discontinued and the patient should be counseled about the potential risk to the fetus.

    Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

    SPRAVATO® is present in human milk. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with SPRAVATO®.

    SELECT USE IN SPECIFIC POPULATIONS

    Geriatric Use: No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age. At the end of a 4-week, randomized, double-blind study, there was no statistically significant difference between groups on the primary efficacy endpoint.

    Hepatic Impairment: SPRAVATO®-treated patients with moderate hepatic impairment may need to be monitored for adverse reactions for a longer period of time.

    SPRAVATO® has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.

    ADVERSE REACTIONS

    The most common adverse reactions with SPRAVATO® plus oral antidepressant (incidence ≥5% and at least twice that of placebo nasal spray plus oral antidepressant) were:

    TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

    Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo.

    Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for SPRAVATO®.

    cp-361448v1

    INDICATIONS AND LIMITATIONS OF USE:
  • STELARA®

    INDICATIONS

    STELARA® (ustekinumab) is indicated for the treatment of patients 6 years and older with active psoriatic arthritis.

    STELARA® (ustekinumab) is indicated for the treatment of patients 6 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

    STELARA® (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.

    STELARA® (ustekinumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

    IMPORTANT SAFETY INFORMATION

    STELARA® (ustekinumab) is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients.

    Infections

    STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections requiring hospitalization or otherwise clinically significant infections were reported. In patients with psoriasis, these included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. In patients with psoriatic arthritis, this included cholecystitis. In patients with Crohn’s disease, these included anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and Listeria meningitis. In patients with ulcerative colitis, these included gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.

    Treatment with STELARA® should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STELARA® in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA® and consider discontinuing STELARA® for serious or clinically significant infections until the infection resolves or is adequately treated.

    Theoretical Risk for Vulnerability to Particular Infections

    Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® may be susceptible to these types of infections. Appropriate diagnostic testing should be considered (eg, tissue culture, stool culture) as dictated by clinical circumstances.

    Pre-Treatment Evaluation of Tuberculosis (TB)

    Evaluate patients for TB prior to initiating treatment with STELARA®. Do not administer STELARA® to patients with active tuberculosis infection. Initiate treatment of latent TB before administering STELARA®. Closely monitor patients receiving STELARA® for signs and symptoms of active TB during and after treatment.

    Malignancies

    STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had risk factors for developing non-melanoma skin cancer (NMSC). All patients receiving STELARA®, especially those >60 years or those with a history of PUVA or prolonged immunosuppressant treatment, should be monitored for the appearance of NMSC.

    Hypersensitivity Reactions

    Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA®. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®.

    Posterior Reversible Encephalopathy Syndrome (PRES)

    Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.

    Monitor all patients treated with STELARA® for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA®.

    Immunizations

    Prior to initiating therapy with STELARA®, patients should receive all age-appropriate immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.

    Concomitant Therapies

    The safety of STELARA® in combination with other biologic immunosuppressive agents or phototherapy was not evaluated in clinical studies of psoriasis. Ultraviolet-induced skin cancers developed earlier and more frequently in mice. In psoriasis studies, the relevance of findings in mouse models for malignancy risk in humans is unknown. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease and ulcerative colitis induction studies, concomitant use of 6-mercaptopurine, azathioprine, methotrexate, and corticosteroids did not appear to influence the overall safety or efficacy of STELARA®.

    Noninfectious Pneumonia

    Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and, in certain cases, administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment.

    Allergen Immunotherapy

    STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.

    Most Common Adverse Reactions

    The most common adverse reactions (≥3% and higher than that with placebo) in adults from psoriasis clinical studies for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively. The safety profile in pediatric patients with plaque psoriasis was similar to that of adults with plaque psoriasis. In psoriatic arthritis (PsA) studies, a higher incidence of arthralgia and nausea was observed in patients treated with STELARA® when compared with placebo (3% vs 1% for both). In Crohn’s disease induction studies, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 8 for STELARA® 6 mg/kg intravenous single infusion or placebo included: vomiting (4% vs 3%). In the Crohn’s disease maintenance study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 44 for STELARA® 90 mg subcutaneous injection or placebo were: nasopharyngitis (11% vs 8%), injection site erythema (5% vs 0%), vulvovaginal candidiasis/mycotic infection (5% vs 1%), bronchitis (5% vs 3%), pruritus (4% vs 2%), urinary tract infection (4% vs 2%) and sinusitis (3% vs 2%). In the ulcerative colitis induction study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 8 for STELARA® 6 mg/kg intravenous single infusion or placebo included: nasopharyngitis (7% vs 4%). In the ulcerative colitis maintenance study, common adverse reactions (3% or more of patients treated with STELARA® and higher than placebo) reported through Week 44 for STELARA® 90 mg subcutaneous injection or placebo included: nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

    Please click to see the full Prescribing Information and Medication Guide for STELARA®. Provide the Medication Guide to your patients and encourage discussion.

    cp-124933v5

    INDICATIONS
  • SYMTUZA®

    INDICATION

    SYMTUZA® is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg:

    • who have no prior antiretroviral treatment history or
    • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

    IMPORTANT SAFETY INFORMATION

    BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

    • Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of SYMTUZA®.

    Action: Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA®. If appropriate, anti-hepatitis B therapy may be warranted.

    CONTRAINDICATIONS

    • Darunavir and cobicistat are both inhibitors and substrates of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA® should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events. In addition, co-administration of SYMTUZA® with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance.

    Action: Examples of drugs that are contraindicated for co-administration with SYMTUZA® due to the potential for serious and/or life-threatening events or loss of therapeutic effect are listed below: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

    WARNINGS AND PRECAUTIONS

    • Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA®. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

    Action: Monitor liver function prior to initiating and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases. Patients with evidence of new or worsening liver function should consider discontinuing SYMTUZA®. SYMTUZA® is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

    • Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA®, severe skin reactions may occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These include conditions accompanied by fever and/or elevations of transaminases.

    Action: Discontinue SYMTUZA® immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

    • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
    • Immune Reconstitution Syndrome: Patients receiving SYMTUZA® may develop new onset or exacerbations of immune reconstitution syndrome.
    • New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events. SYMTUZA® is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

    Action: Prior to initiating or during treatment, on a clinically appropriate schedule, monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA® in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

    • Sulfa Allergy: Darunavir contains a sulfonamide moiety. The incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

    Action: Monitor patients with a known sulfonamide allergy.

    • Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA®, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals.

    Action: Discontinue SYMTUZA® in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

    • Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors.

    Action: Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

    • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.
    • Hemophilia: Patients with hemophilia may develop an increase in bleeding events.

    ADVERSE REACTIONS

    • The most common clinical adverse reactions (all grades) occurring in at least 2% of treatment-naïve patients were diarrhea, rash,* nausea, fatigue, headache, abdominal discomfort, and flatulence.

    *Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.

    Grade 2-4 laboratory abnormalities have been reported in patients receiving SYMTUZA®, including elevations in serum creatinine, liver function tests, triglycerides, total cholesterol, low-density lipoproteins, and glucose levels. This is not a complete list of all adverse reactions reported with the use of SYMTUZA®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: SYMTUZA® is not recommended for use during pregnancy and should not be initiated in pregnant individuals because of substantially lower exposures of darunavir and cobicistat during pregnancy.

    Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

    • Pediatric Use: The safety and effectiveness of SYMTUZA® have not been established and is not recommended in pediatric patients weighing less than 40 kg.
    • Consult the full Prescribing Information for SYMTUZA® for additional information on the Uses in Specific Populations.

    Please see full Prescribing Information, including Boxed WARNING for SYMTUZA®.

    cp-62076v10

    INDICATION
  • TALVEY™

    INDICATION AND USAGE

    TALVEY™ (talquetamab-tgvs) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

    This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    IMPORTANT SAFETY INFORMATION

    WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

    Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY™. Initiate TALVEY™ treatment with step-up dosing to reduce the risk of CRS. Withhold TALVEY™ until CRS resolves or permanently discontinue based on severity.

    Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and serious and life-threatening or fatal reactions, can occur with TALVEY™. Monitor patients for signs and symptoms of neurologic toxicity including ICANS during treatment. Withhold or discontinue TALVEY™ based on severity.

    Because of the risk of CRS and neurologic toxicity, including ICANS, TALVEY™ is available only through a restricted program called the TECVAYLI® and TALVEY™ Risk Evaluation and Mitigation Strategy (REMS).

    CONTRAINDICATIONS: None.

    WARNINGS AND PRECAUTIONS

    Cytokine Release Syndrome (CRS): TALVEY™ can cause cytokine release syndrome, including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 76% of patients who received TALVEY™ at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

    Initiate therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY™ in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next TALVEY™ dose.

    Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity, and consider further management per current practice guidelines. Withhold TALVEY™ until CRS resolves or permanently discontinue based on severity.

    Neurologic Toxicity including ICANS: TALVEY™ can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including fatal reactions. In the clinical trial, neurologic toxicity occurred in 55% of patients who received the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).

    ICANS was reported in 9% of 265 patients where ICANS was collected and who received the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

    Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue TALVEY™ based on severity and consider further management per current practice guidelines. [see Dosage and Administration (2.5)].

    Due to the potential for neurologic toxicity, patients receiving TALVEY™ are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule, and in the event of new onset of any neurological symptoms, until symptoms resolve.

    TECVAYLI® and TALVEY™ REMS: TALVEY™ is available only through a restricted program under a REMS, called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.

    Further information about the TECVAYLI® and TALVEY™ REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.

    Oral Toxicity and Weight Loss: TALVEY™ can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis. In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.

    TALVEY™ can cause weight loss. In the clinical trial, 62% of patients experienced weight loss of 5% or greater, regardless of having an oral toxicity, including 28% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported weight loss.

    Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice, including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold TALVEY™ or permanently discontinue based on severity.

    Infections: TALVEY™ can cause infections, including life-threatening or fatal infections. Serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis and COVID-19 (2.7%).

    Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY™ and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or permanently discontinue TALVEY™ as recommended, based on severity.

    Cytopenias: TALVEY™ can cause cytopenias, including neutropenia and thrombocytopenia. In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received TALVEY™. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold TALVEY™ as recommended, based on severity.

    Skin Toxicity: TALVEY™ can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash. In the clinical trial, skin reactions occurred in 62% of patients, with grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to grade 1 or less was 33 days.

    Monitor for skin toxicity, including rash progression. Consider early intervention and treatment to manage skin toxicity. In the clinical trial, supportive care included topical steroids (15%). Oral steroid tapers (4.4%) were typically administered for Grade 3 skin reactions. Withhold or permanently discontinue TALVEY™, based on severity.

    Hepatotoxicity: TALVEY™ can cause hepatotoxicity. Elevated ALT occurred in 33% of patients, with grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.

    Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TALVEY™ or consider permanent discontinuation of TALVEY™, based on severity [see Dosage and Administration (2.5)].

    Embryo-Fetal Toxicity: Based on its mechanism of action, TALVEY™ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TALVEY™ and for 3 months after the last dose.

    Adverse Reactions: The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.

    The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased.

    Please read full Prescribing Information, including Boxed WARNING, for TALVEY™.

    cp-394174v2

    INDICATION
  • TECVAYLI®

    INDICATION AND USAGE

    TECVAYLI® (teclistamab-cqyv) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

    This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

    IMPORTANT SAFETY INFORMATION

    WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

    Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI®. Initiate treatment with TECVAYLI® step-up dosing schedule to reduce risk of CRS. Withhold TECVAYLI® until CRS resolves or permanently discontinue based on severity.

    Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI®. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment. Withhold TECVAYLI® until neurologic toxicity resolves or permanently discontinue based on severity.

    TECVAYLI® is available only through a restricted program called the TECVAYLI® and TALVEY™ Risk Evaluation and Mitigation Strategy (REMS).

    WARNINGS AND PRECAUTIONS

    Cytokine Release Syndrome - TECVAYLI® can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI® at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI®. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).

    Initiate therapy according to TECVAYLI® step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI® accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization. Administer supportive care based on severity and consider further management per current practice guidelines. Withhold or permanently discontinue TECVAYLI® based on severity.

    TECVAYLI® is available only through a restricted program under a REMS.

    Neurologic Toxicity including ICANS - TECVAYLI® can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

    In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI® at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI®.

    In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI® at the recommended dose. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI®. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

    Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or permanently discontinue TECVAYLI® based on severity per recommendations and consider further management per current practice guidelines.

    Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI® step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.

    TECVAYLI® is available only through a restricted program under a REMS.

    TECVAYLI® and TALVEY™ REMS - TECVAYLI® is available only through a restricted program under a REMS called the TECVAYLI® and TALVEY™ REMS because of the risks of CRS and neurologic toxicity, including ICANS.

    Hepatotoxicity - TECVAYLI® can cause hepatotoxicity, including fatalities. In patients who received TECVAYLI® at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.

    Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Infections - TECVAYLI® can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI® at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI® and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Monitor immunoglobulin levels during treatment with TECVAYLI® and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

    Neutropenia - TECVAYLI® can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI® at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.

    Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines. Monitor patients with neutropenia for signs of infection. Withhold TECVAYLI® based on severity.

    Hypersensitivity and Other Administration Reactions - TECVAYLI® can cause both systemic administration-related and local injection-site reactions. Systemic Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions - In patients who received TECVAYLI® at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients, with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI® or consider permanent discontinuation of TECVAYLI® based on severity.

    Embryo-Fetal Toxicity - Based on its mechanism of action, TECVAYLI® may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI® and for 5 months after the last dose.

    ADVERSE REACTIONS

    The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

    Please read full Prescribing Information, including Boxed WARNING, for TECVAYLI®.

    cp-322928v3

    INDICATION
  • TREMFYA®

    INDICATIONS

    TREMFYA® (guselkumab) is indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

    TREMFYA® is indicated for the treatment of adults with active psoriatic arthritis.

    IMPORTANT SAFETY INFORMATION