Indication and Important Safety Information

Darzalex® ( daratumumab )

Indication

DARZALEX® is a CD38-directed cytolytic antibody indicated:

  • in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy
  • in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
  • as monotherapy, for the treatment of patients with multiple myeloma 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 - None

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX® can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. 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 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.

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 are 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 – DARZALEX® 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. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human 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.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%). DARZALEX® in combination with lenalidomide and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were neutropenia (36%) and lymphopenia (42%).

In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). DARZALEX® in combination with bortezomib and dexamethasone: treatment-emergent Grade 3-4 hematology laboratory abnormalities20% were lymphopenia (41%) and thrombocytopenia (28%).

In patients who received DARZALEX® as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). DARZALEX® as monotherapy: treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% was lymphopenia (30%).

In patients who received DARZALEX® in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). DARZALEX® in combination with pomalidomide and dexamethasone: treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were anemia (30%), neutropenia (36%, 46%), and lymphopenia (45%, 26%).

DRUG INTERACTIONS
Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX® did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX® with bortezomib did not affect the pharmacokinetics of bortezomib.

074829-170616

Please see full Prescribing Information.

Doxil® ( doxorubicin HCl liposome injection )

INDICATIONS

DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

DOXIL® is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

DOXIL® in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

Important Safety Information

CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

DOXIL® (doxorubicin HCl liposome injection) can cause myocardial damage, including congestive heart failure, as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study of 250 patients with advanced cancer who were treated with DOXIL®, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450-550 mg/m2. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation. See additional information on Cardiomyopathy in Warnings and Precautions below.

Acute infusion-related reactions consisting of, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension occurred in 11% of patients with solid tumors treated with DOXIL®. Serious, life-threatening and fatal infusion reactions have been reported. Medications/emergency equipment to treat such reactions should be available for immediate use. See additional information on Infusion-Related Reactions in Warnings and Precautions below.

Contraindications

DOXIL® is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin HCl.

Warnings and Precautions

Cardiomyopathy: Doxorubicin HCl can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin HCl is generally proportional to the cumulative exposure. The relationship between cumulative DOXIL® dose and the risk of cardiac toxicity has not been determined. Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of DOXIL®, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Administer DOXIL® to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

Infusion-Related Reactions: Serious and sometimes life-threatening infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL®: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. The majority of infusion-related events occurred during the first infusion. Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment is available for immediate use prior to initiation of DOXIL®. Initiate DOXIL® infusions at a rate of 1 mg/min and increase rate as tolerated. In the event of an infusion-related reaction, temporarily stop the drug until resolution then resume at a reduced infusion rate. Discontinue DOXIL® infusion for serious or life-threatening infusion-related reactions.

Hand-foot syndrome (HFS): HFS may occur during therapy with DOXIL®. Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required.

  • HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier
  • Delay DOXIL® for the first episode of Grade 2 or greater HFS
  • Discontinue DOXIL® if HFS is severe and debilitating

Secondary Oral Neoplasms: Cases of secondary oral cancer have been reported in patients with more than one year's exposure to DOXIL®. Cases were diagnosed both during treatment and up to 6 years after the last dose. Patients should be examined at regular intervals for the presence of oral ulceration or any oral discomfort that may be indicative of secondary oral cancer.

Embryofetal Toxicity: Based on animal data, DOXIL® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL®.

Adverse Reactions

Most common adverse reactions observed with DOXIL® (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia.

Use in Specific Populations

Lactation: Because of the potential for serious adverse reactions in nursing infants, discontinue nursing during treatment with DOXIL®.

Click here to read full Prescribing Information including BOXED WARNINGS.

020669-150414

Edurant® ( rilpivirine )

Indication

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

The following points should be considered when initiating therapy with EDURANT®:

  • 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
  • Regardless of HIV-1 RNA at the start of therapy, more EDURANT®-treated subjects with CD4+ cell count less than 200 cells/mm3 experienced virologic failure compared to EDURANT®-treated subjects with CD4+ cell count greater than or equal to 200 cells/mm3
  • The observed virologic failure rate in EDURANT®-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
  • More subjects treated with EDURANT® developed tenofovir and lamivudine/emtricitabine-associated resistance compared to efavirenz

EDURANT® is not recommended for patients less than 12 years of age.

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)

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.
  • 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
  • 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
  • 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 has been reported in patients treated with combination ARV therapy, including EDURANT®. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) 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® should be used with caution when coadministered with drugs that may reduce the exposure of rilpivirine, such as antacids and H2-receptor antagonists
  • Concomitant use of EDURANT® with rifabutin may cause a decrease in the plasma concentrations of rilpivirine. Please read the Dosage and Administration Section of the Prescribing Information for more details regarding the concomitant use of EDURANT® and rifabutin
  • 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: EDURANT® should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics of EDURANT® have not been evaluated in these patients
  • Pregnancy Category B: EDURANT® should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women

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 see full Prescribing Information for more details.

034144-151202

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 patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other ARV agents.

The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class ARV (NNRTI, N[t]RTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single arm, Phase 2 trial in ARV treatment-experienced pediatric subjects 6 years to less than 18 years of age.

In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with INTELENCE®:

  • Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance
  • In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs
  • The use of other active ARV agents with INTELENCE® is associated with an increased likelihood of treatment response
  • The safety and efficacy of INTELENCE® have not been established in pediatric patients less than 6 years of age or in treatment-naïve adult or pediatric patients

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®. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme
    • 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

    In the DUET studies, Grade 3 and 4 rashes were reported in 1.3% of patients receiving INTELENCE® compared to 0.2% of patients in the placebo arm. Discontinuation rate due to rash was 2.2% in patients taking INTELENCE®. In clinical trials of patients on INTELENCE®, the incidence of rash was higher in women compared to men. Rash occurred most commonly during the first 6 weeks of therapy. In the PIANO study of children ages 6 to ≤17 years of age, rash was seen more commonly than in adults and occurred in 15% (≥Grade 2) of pediatric subjects

    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
  • 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 has been reported in patients treated with ARV therapy, including INTELENCE®. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) 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

Use in Specific Populations

  • 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
  • Pregnancy Category B: INTELENCE® should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women

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

  • INTELENCE® should not be coadministered with the following ARVs: fosamprenavir/ritonavir, tipranavir/ritonavir, full-dose ritonavir (600 mg bid), PIs administered without low-dose ritonavir, and other NNRTIs
  • INTELENCE® should only be used with dolutegravir when coadministered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. INTELENCE® should not be coadministered with dolutegravir in the absence of a boosted PI. INTELENCE® significantly reduces plasma concentrations of dolutegravir
  • INTELENCE® should not be coadministered with carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin (when part of a regimen containing PI/ritonavir), or products containing St. John’s wort (Hypericum perforatum)
  • Caution should be used when prescribing agents such as substrates, inhibitors, or inducers of CYP3A, CYP2C9, CYP2C19, and/or P-glycoprotein in patients receiving INTELENCE® as it may alter the therapeutic effect or adverse reaction profile of INTELENCE® or the coadministered drug(s)

This is not a complete list of potential drug interactions.

Please see full Prescribing Information for more details.

028189-150121

Invokamet® (canagliflozin/metformin HCl)

INVOKAMET® and INVOKAMET® XR Professional Indication Statement & ISI

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

INVOKAMET® and INVOKAMET® XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate.

INVOKAMET® and INVOKAMET® XR are not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for INVOKAMET® and INVOKAMET® XR

WARNING: LACTIC ACIDOSIS AND LOWER-LIMB AMPUTATION

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®/ INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower-Limb Amputation

  • An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
  • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
  • Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
  • Monitor patients receiving INVOKAMET®/INVOKAMET® XR for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
     

CONTRAINDICATIONS

  • Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • History of a serious hypersensitivity reaction to canagliflozin or metformin, 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. Metformin-associated lactic acidosis was characterized by 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. Metformin decreases liver uptake of lactate, increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation. In INVOKAMET®/INVOKAMET® XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin. Hemodialysis has often resulted in reversal of symptoms and recovery.

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

    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

    Renal Impairment:  Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: The concomitant use of INVOKAMET®/INVOKAMET® XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs). Consider more frequent monitoring of patients.

    Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age due to a greater likelihood of hepatic, renal, or cardiac impairment. Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET®/INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of 45 to 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®/INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.

    INVOKAMET®/INVOKAMET® XR should be temporarily discontinued while patients have restricted food and fluid intake.

    Hypoxic States: Several postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure. Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET®/INVOKAMET® XR.

    Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.

    Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid use of INVOKAMET®/INVOKAMET® XR in patients with clinical or laboratory evidence of hepatic disease.

  • Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In CANVAS, canagliflozin-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, canagliflozin-treated patients and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. 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.

  • Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET®/INVOKAMET® XR, particularly in patients with an eGFR <60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating INVOKAMET®/INVOKAMET® XR in patients with ≥1 of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
  • Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Before initiating INVOKAMET®/INVOKAMET® XR, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKAMET®/INVOKAMET® XR, consider monitoring for ketoacidosis and temporarily discontinuing in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or surgery).
  • Acute Kidney Injury and Impairment in Renal Function: Canagliflozin causes intravascular volume contraction and can cause renal impairment. Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, were reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications. Consider temporarily discontinuing INVOKAMET®/INVOKAMET® XR in any setting of reduced oral intake or fluid losses; monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue promptly and institute treatment.

    Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. Renal function should be evaluated prior to initiation and periodically thereafter. Dose adjustment and more frequent renal function monitoring are recommended in patients with an eGFR <60 mL/min/1.73 m2.

  • Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia.

    Monitor serum potassium levels periodically after initiating INVOKAMET®/INVOKAMET® XR in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

  • Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms and treat promptly.
  • Use With Medications Known to Cause Hypoglycemia

    Canagliflozin
    Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET®/INVOKAMET® XR.
    Metformin
    Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Monitor for a need to lower the dose of INVOKAMET®/INVOKAMET® XR to minimize the risk of hypoglycemia in these patients.

  • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections. Patients with a history of these infections and uncircumcised males were more likely to develop these 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®/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. Consider factors that contribute to fracture risk prior to initiating INVOKAMET®/INVOKAMET® XR.
  • Vitamin B12 Levels: In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET®/INVOKAMET® XR and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to develop subnormal vitamin B12 levels.
  • Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. Monitor LDL-C and treat if appropriate after initiating INVOKAMET®/INVOKAMET® XR.
  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with canagliflozin or metformin.

DRUG INTERACTIONS

  • Drug Interactions With Metformin
    Carbonic Anhydrase Inhibitors
    Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.
    Drugs That Reduce Metformin Clearance
    Drugs that are eliminated by renal tubular secretion (eg, cationic drugs such as cimetidine) may increase accumulation of metformin and risk for lactic acidosis.
    Alcohol
    Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
    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®/INVOKAMET® XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be observed closely for hypoglycemia.
  • Drug Interactions With Canagliflozin
    UGT Enzyme Inducers
    Rifampin: Rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET®/INVOKAMET® XR. If an inducer of UGT enzymes must be co-administered with INVOKAMET®/INVOKAMET® XR, consider increasing the total daily dose of canagliflozin to 300 mg if patients are currently tolerating a total daily dose of 100 mg canagliflozin, have an eGFR >60 mL/min/1.73 m2, and require additional glycemic control.
    Digoxin
    Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET®/INVOKAMET® XR with concomitant digoxin for a need to adjust dose of either drug.
  • Drug/Laboratory Test Interference
    Positive Urine Glucose Test
    Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.
    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay
    Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data showing adverse renal effects, INVOKAMET®/INVOKAMET® XR is not recommended during the second and third trimesters of pregnancy. A clear association of major birth defect or miscarriage risk with metformin or canagliflozin use during pregnancy has not been determined. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
  • Nursing Mothers: There is no information regarding the presence of INVOKAMET®/INVOKAMET® XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. There is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, INVOKAMET®/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 may result in ovulation in some anovulatory women.
  • Pediatric Use: Safety and effectiveness of INVOKAMET®/INVOKAMET® XR in patients <18 years of age have not been established.
  • Geriatric Use: Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, frequently monitor renal function after initiating INVOKAMET®/INVOKAMET® XR in elderly patients and adjust dose based on renal function.
    Canagliflozin
    2034 patients ≥65 years and 345 patients ≥75 years were exposed to canagliflozin in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; 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 (-0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg).
    Metformin
    Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function.
  • Renal Impairment: INVOKAMET®/INVOKAMET® XR should not be used in patients with severe renal impairment (eGFR <45 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
  • Hepatic Impairment: Metformin use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET®/INVOKAMET® XR is not recommended in patients with hepatic impairment.

OVERDOSAGE

  • In the event of an overdose with INVOKAMET®/INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures (eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as needed.
    Canagliflozin
    There were no reports of overdose during the clinical development program of canagliflozin.
    Metformin
    Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

ADVERSE REACTIONS

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

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET® XR.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET®.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for INVOKANA®.

 

076193-170713

Invokamet® XR ( canagliflozin/metformin HCl extended-release tablets )

INVOKAMET® and INVOKAMET® XR Professional Indication Statement & ISI

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

INVOKAMET® and INVOKAMET® XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate.

INVOKAMET® and INVOKAMET® XR are not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for INVOKAMET® and INVOKAMET® XR

WARNING: LACTIC ACIDOSIS AND LOWER-LIMB AMPUTATION

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®/ INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Risk of Lower-Limb Amputation

  • An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
  • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
  • Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
  • Monitor patients receiving INVOKAMET®/INVOKAMET® XR for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
     

CONTRAINDICATIONS

  • Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • History of a serious hypersensitivity reaction to canagliflozin or metformin, 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. Metformin-associated lactic acidosis was characterized by 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. Metformin decreases liver uptake of lactate, increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

    If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation. In INVOKAMET®/INVOKAMET® XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin. Hemodialysis has often resulted in reversal of symptoms and recovery.

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

    For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

    Renal Impairment:  Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.

    Drug Interactions: The concomitant use of INVOKAMET®/INVOKAMET® XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs). Consider more frequent monitoring of patients.

    Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age due to a greater likelihood of hepatic, renal, or cardiac impairment. Assess renal function more frequently in elderly patients.

    Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET®/INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of 45 to 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®/INVOKAMET® XR if renal function is stable.

    Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.

    INVOKAMET®/INVOKAMET® XR should be temporarily discontinued while patients have restricted food and fluid intake.

    Hypoxic States: Several postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure. Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET®/INVOKAMET® XR.

    Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.

    Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid use of INVOKAMET®/INVOKAMET® XR in patients with clinical or laboratory evidence of hepatic disease.

  • Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In CANVAS, canagliflozin-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, canagliflozin-treated patients and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. 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.

  • Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET®/INVOKAMET® XR, particularly in patients with an eGFR <60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating INVOKAMET®/INVOKAMET® XR in patients with ≥1 of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
  • Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Before initiating INVOKAMET®/INVOKAMET® XR, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKAMET®/INVOKAMET® XR, consider monitoring for ketoacidosis and temporarily discontinuing in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or surgery).
  • Acute Kidney Injury and Impairment in Renal Function: Canagliflozin causes intravascular volume contraction and can cause renal impairment. Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, were reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications. Consider temporarily discontinuing INVOKAMET®/INVOKAMET® XR in any setting of reduced oral intake or fluid losses; monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue promptly and institute treatment.

    Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. Renal function should be evaluated prior to initiation and periodically thereafter. Dose adjustment and more frequent renal function monitoring are recommended in patients with an eGFR <60 mL/min/1.73 m2.

  • Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia.

    Monitor serum potassium levels periodically after initiating INVOKAMET®/INVOKAMET® XR in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

  • Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms and treat promptly.
  • Use With Medications Known to Cause Hypoglycemia

    Canagliflozin
    Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET®/INVOKAMET® XR.
    Metformin
    Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Monitor for a need to lower the dose of INVOKAMET®/INVOKAMET® XR to minimize the risk of hypoglycemia in these patients.

  • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections. Patients with a history of these infections and uncircumcised males were more likely to develop these 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®/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. Consider factors that contribute to fracture risk prior to initiating INVOKAMET®/INVOKAMET® XR.
  • Vitamin B12 Levels: In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET®/INVOKAMET® XR and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to develop subnormal vitamin B12 levels.
  • Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. Monitor LDL-C and treat if appropriate after initiating INVOKAMET®/INVOKAMET® XR.
  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with canagliflozin or metformin.

DRUG INTERACTIONS

  • Drug Interactions With Metformin
    Carbonic Anhydrase Inhibitors
    Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.
    Drugs That Reduce Metformin Clearance
    Drugs that are eliminated by renal tubular secretion (eg, cationic drugs such as cimetidine) may increase accumulation of metformin and risk for lactic acidosis.
    Alcohol
    Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
    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®/INVOKAMET® XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be observed closely for hypoglycemia.
  • Drug Interactions With Canagliflozin
    UGT Enzyme Inducers
    Rifampin: Rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET®/INVOKAMET® XR. If an inducer of UGT enzymes must be co-administered with INVOKAMET®/INVOKAMET® XR, consider increasing the total daily dose of canagliflozin to 300 mg if patients are currently tolerating a total daily dose of 100 mg canagliflozin, have an eGFR >60 mL/min/1.73 m2, and require additional glycemic control.
    Digoxin
    Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET®/INVOKAMET® XR with concomitant digoxin for a need to adjust dose of either drug.
  • Drug/Laboratory Test Interference
    Positive Urine Glucose Test
    Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.
    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay
    Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data showing adverse renal effects, INVOKAMET®/INVOKAMET® XR is not recommended during the second and third trimesters of pregnancy. A clear association of major birth defect or miscarriage risk with metformin or canagliflozin use during pregnancy has not been determined. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
  • Nursing Mothers: There is no information regarding the presence of INVOKAMET®/INVOKAMET® XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. There is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, INVOKAMET®/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 may result in ovulation in some anovulatory women.
  • Pediatric Use: Safety and effectiveness of INVOKAMET®/INVOKAMET® XR in patients <18 years of age have not been established.
  • Geriatric Use: Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, frequently monitor renal function after initiating INVOKAMET®/INVOKAMET® XR in elderly patients and adjust dose based on renal function.
    Canagliflozin
    2034 patients ≥65 years and 345 patients ≥75 years were exposed to canagliflozin in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; 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 (-0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg).
    Metformin
    Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function.
  • Renal Impairment: INVOKAMET®/INVOKAMET® XR should not be used in patients with severe renal impairment (eGFR <45 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
  • Hepatic Impairment: Metformin use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET®/INVOKAMET® XR is not recommended in patients with hepatic impairment.

OVERDOSAGE

  • In the event of an overdose with INVOKAMET®/INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures (eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as needed.
    Canagliflozin
    There were no reports of overdose during the clinical development program of canagliflozin.
    Metformin
    Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

ADVERSE REACTIONS

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

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET® XR.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET®.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for INVOKANA®.

 

076193-170713

Invokana® ( canagliflozin )

INDICATION AND USAGE

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information

IMPORTANT SAFETY INFORMATION

WARNING: LOWER-LIMB AMPUTATION

  • An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA® use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD. 
  • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
  • Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
  • Monitor patients receiving INVOKANA® for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.


CONTRAINDICATIONS

  • History of a serious hypersensitivity reaction to INVOKANA®, such as anaphylaxis or angioedema
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis

WARNINGS and PRECAUTIONS

  • Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA® use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In CANVAS, INVOKANA®-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, INVOKANA®-treated patients and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. 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, 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. 

  • Hypotension: INVOKANA® causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA®, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating in patients with ≥1 of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating.
  • Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA®. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA®. Before initiating INVOKANA®, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKANA®, consider monitoring for ketoacidosis and temporarily discontinuing in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or surgery).
  • Acute Kidney Injury and Impairment in Renal Function: INVOKANA® causes intravascular volume contraction and can cause renal impairment. Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, were reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications. Consider temporarily discontinuing INVOKANA® in any setting of reduced oral intake or fluid losses; monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue promptly and institute treatment.

    INVOKANA® increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. Renal function should be evaluated prior to initiation and periodically thereafter. Dose adjustment and more frequent renal function monitoring are recommended in patients with an eGFR <60 mL/min/1.73 m2.

  • Hyperkalemia: INVOKANA® can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
  • Urosepsis and Pyelonephritis: There have been reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA®. Treatment with SGLT2 inhibitors increases this risk. Evaluate patients for signs and symptoms and treat promptly.
  • Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: INVOKANA® can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.
  • Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections. Patients with history of these infections and uncircumcised males were more likely to develop these 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 per standard of care, 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®. Consider factors that contribute to fracture risk prior to initiating INVOKANA®.
  • Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with INVOKANA®. Monitor LDL-C and treat per standard of care after initiating.
  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA®.

DRUG INTERACTIONS

  • UGT Enzyme Inducers: Rifampin: Co-administration of INVOKANA® with rifampin decreased INVOKANA® area under the curve (AUC) by 51% and therefore may decrease efficacy. If an inducer of UGT enzymes must be co-administered with INVOKANA®, consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA® 100 mg once daily, have an eGFR ≥60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR <60 mL/min/1.73 m2 who require additional glycemic control.
  • Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin (20% and 36%, respectively) when co-administered with INVOKANA® 300 mg. Monitor appropriately.
  • Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.
  • Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data showing adverse renal effects, INVOKANA® is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKANA® in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to mother and fetus associated with poorly controlled diabetes in pregnancy.
  • Nursing Mothers: There is no information regarding the presence of INVOKANA® in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA® is not recommended while breastfeeding.
  • Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.
  • Geriatric Use: 2034 patients ≥65 years and 345 patients ≥75 years were exposed to INVOKANA® in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; 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 (-0.61% with INVOKANA® 100 mg and -0.74% with INVOKANA® 300 mg) compared to younger patients (-0.72% with INVOKANA® 100 mg and -0.87% with INVOKANA® 300 mg).
  • Renal Impairment: Efficacy and safety were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with 300 mg were more likely to experience increases in potassium. INVOKANA® is not recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
  • 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, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as needed.

ADVERSE REACTIONS

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

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide.

076189-170713

Olysio® ( simeprevir )

Indications

OLYSIO® is indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection  

  • in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis;
  • in combination with peginterferon alfa (Peg‐IFN‐alfa) and ribavirin (RBV) in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis.

Limitations of Use:

  • Efficacy of OLYSIO® in combination with Peg‐IFN‐alfa and RBV is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with HCV genotype 1a without the Q80K polymorphism.
  • OLYSIO® is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO® or other HCV protease inhibitors.

Important Safety Information

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with OLYSIO®. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and posttreatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

 

Contraindications:

  • Because OLYSIO® is used only in combination with other antiviral drugs (including Peg‐IFN‐alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. Refer to the respective prescribing information for a list of contraindications.

 

Warnings and Precautions:

  • Risk of Hepatitis B Virus Reactivation in Patients Coinfected With HCV and HBV: HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

    HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis; i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

    Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with OLYSIO®. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with OLYSIO® and during posttreatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

  • Serious Symptomatic Bradycardia When Coadministered With Sofosbuvir and Amiodarone: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered with a sofosbuvir containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.
     
    Coadministration of amiodarone with OLYSIO® in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be coadministered OLYSIO® and sofosbuvir:
    • Counsel patients about the risk of serious symptomatic bradycardia. 
    • Cardiac monitoring in an in‐patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self‐monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

    Patients who are taking sofosbuvir in combination with OLYSIO® who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

    Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO® should also undergo similar cardiac monitoring as outlined above.

    Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems.

  • Hepatic Decompensation and Hepatic Failure: Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO® in combination with Peg‐IFN‐alfa and RBV or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made, and a causal relationship between treatment with OLYSIO® and these events have not been established.
     
    OLYSIO® is not recommended for patients with moderate or severe hepatic impairment (Child‐Pugh B or C).
     
    In clinical trials of OLYSIO®, modest increases in bilirubin levels were observed without impacting hepatic function. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO® combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:
    • Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces.
    • Discontinue OLYSIO® if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.
  • Risk of Serious Adverse Reactions Associated With Combination Treatment: Because OLYSIO® is used in combination with other antiviral drugs for the treatment of chronic HCV infection, consult the prescribing information for these drugs before starting therapy with OLYSIO®. Warnings and precautions related to these drugs also apply to their use in OLYSIO® combination treatment.
     
  • Photosensitivity: Photosensitivity reactions have been observed with OLYSIO® combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO® in combination with Peg‐IFN‐alfa and RBV. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.
     
    Use sun protective measures and limit sun exposure during treatment with OLYSIO®. Avoid use of tanning devices during treatment with OLYSIO®. Discontinuation of OLYSIO® should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO® in the setting of a photosensitivity reaction, expert consultation is advised.
     
  • Rash: Rash has been observed with OLYSIO® combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO® have been reported in subjects receiving OLYSIO® in combination with Peg‐IFN‐alfa and RBV. Most of the rash events in OLYSIO®‐treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO® should be discontinued. Patients should be monitored until the rash has resolved.
     
  • Sulfa Allergy: OLYSIO® contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO®.
     
  • Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: Coadministration of OLYSIO® with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions. The potential for drug-drug interactions must be considered prior to and during treatment.

Adverse Reactions:

  • Use With Sofosbuvir: The most common (all grades, ≥10%) adverse events reported during 12 or 24 weeks of treatment with OLYSIO® in combination with sofosbuvir were headache (17% and 23%), fatigue (16% and 32%), nausea (14% and 13%), rash (including photosensitivity)(12% and 16%), diarrhea (6% and 16%), and dizziness (3% and 16%), respectively.
  • Use With Peg‐IFN‐alfa and RBV: Adverse reactions (all grades, ≥3% higher frequency) for OLYSIO® with Peg‐IFN‐alfa and RBV vs. Peg‐IFN‐alfa and RBV alone during the first 12 weeks of treatment were rash (including photosensitivity) (28% vs. 20%), pruritus (22% vs. 15%), nausea (22% vs. 18%), myalgia (16% vs. 13%), and dyspnea (12% vs. 8%).

Use in Specific Populations:

  • Pregnancy: If OLYSIO® is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to prescribing information for RBV and for other drugs used in combination with OLYSIO® for information on use in pregnancy. No adequate human data are available to establish whether or not OLYSIO® poses a risk to pregnancy outcomes. Pregnant women should be advised of potential risk to the fetus.
     
  • Race: Patients of East Asian ancestry exhibit higher plasma simeprevir exposures, but no dosage adjustment is required based on race. 
     
  • Renal Impairment: No dosage adjustment of OLYSIO® is required in patients with mild, moderate, or severe renal impairment. The safety and efficacy of OLYSIO® have not been studied in HCV‐infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end‐stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.
     
  • Hepatic Impairment: No dosage adjustment of OLYSIO® is required in patients with mild hepatic impairment (Child‐Pugh A). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C). In clinical trials of OLYSIO® in combination with Peg-IFN-alfa and RBV, higher simeprevir exposures were associated with increased frequency of adverse reactions, including increased bilirubin, rash, and photosensitivity. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO® combination therapy.
     
    The safety and efficacy of OLYSIO® have not been studied in liver transplant patients.

 

Not a complete list of Uses in Specific Populations. 

Consult the PI for Peg‐IFN‐alfa and RBV or sofosbuvir before starting your patients on therapy with OLYSIO®. Safety information related to these drugs also applies to their use in OLYSIO® combination treatment.

Please see full Prescribing Information, including Boxed Warning, and Patient Information for more details.

041676-170517

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 with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

Important Safety Information

Contraindications

  • Do not coadminister PREZCOBIX® and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, cisapride, colchicine, dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, lovastatin, lurasidone, methylergonovine, oral midazolam, 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: 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: PREZCOBIX® is a CYP3A inhibitor. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZCOBIX® or the concomitant medications. This may lead to clinically significant adverse reactions (potentially leading to severe, life threatening, or fatal events) from higher exposures of the concomitant medications or adverse reactions from higher exposures of PREZCOBIX®. Decreased concentrations of PREZCOBIX® may result in loss of therapeutic effect and possible development of resistance.

  • 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

  • Consult the full Prescribing Information for PREZCOBIX® for information on the Uses in Specific Populations.

Please see full Prescribing Information for more details.

061036-161020

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 patients.

Important Safety Information

Contraindications

  • Coadministration of 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. Coadministration is also contraindicated with drugs that may result in reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance.
    • Drugs that are contraindicated with PREZISTA®/r are: alfuzosin, cisapride, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, lovastatin, lurasidone, methylergonovine, oral midazolam, pimozide, ranolazine, rifampin, sildenafil (for the treatment of pulmonary arterial hypertension), simvastatin, St. John’s Wort (Hypericum perforatum) 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. 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 PREZISTA®/r and possible development of resistance

    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 has been reported in patients treated with combination ARV therapy, including PREZISTA®. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time of onset is more variable and can occur many months after the initiation of treatment.

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

  • Coadministration is not recommended with apixaban, avanafil, boceprevir, dabigatran etexilate (in specific renal impairment groups), everolimus, indinavir, lopinavir/ritonavir, rivaroxaban, rifapentine, saquinavir, salmeterol, simeprevir, telaprevir, or voriconazole.
  • Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A, CYP2D6, or P-gp in patients receiving PREZISTA®/r.

This list of potential drug interactions is not complete.

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 read the full Prescribing Information for more details.

055991-170628

Procrit® ( epoetin alfa )

INDICATIONS

Anemia Due to Chronic Kidney Disease

PROCRIT® is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusion.

Anemia Due to Zidovudine in HIV-infected Patients

PROCRIT® is indicated for the treatment of anemia due to zidovudine administered at ≤ 4200 mg/week in HIV-infected patients with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.

Anemia Due to Chemotherapy in Patients With Cancer

PROCRIT® is indicated for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery

PROCRIT® is indicated to reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin > 10 to ≤ 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery. PROCRIT® is not indicated for patients who are willing to donate autologous blood preoperatively.

PROCRIT® has not been shown to improve quality of life, fatigue, or patient well-being.

PROCRIT® is not indicated for use:

  • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure or in whom the anemia can be managed by transfusion.
  • In patients scheduled for surgery who are willing to donate autologous blood.
  • In patients undergoing cardiac or vascular surgery.
  • As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Important Safety Information

WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

Chronic Kidney Disease:

  • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL.
  • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
  • Use the lowest PROCRIT® dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Cancer:

  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
  • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
  • Use ESAs only for anemia from myelosuppressive chemotherapy.
  • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • Discontinue following the completion of a chemotherapy course.

Perisurgery:
Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

(See WARNINGS AND PRECAUTIONS: Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism, and WARNINGS AND PRECAUTIONS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION.)

Contraindications

PROCRIT® is contraindicated in patients with:

  • Uncontrolled hypertension
  • Pure red cell aplasia (PRCA) that begins after treatment with PROCRIT® or other erythropoietin protein drugs
  • Serious allergic reactions to PROCRIT®

PROCRIT® from multiple-dose vials contains benzyl alcohol and is contraindicated in:

  • Neonates, infants, pregnant women, and lactating women. When therapy with PROCRIT® is needed in these patient populations, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol.

Additional Important Safety Information

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

  • In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL), PROCRIT® and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
  • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
  • In controlled clinical trials of patients with cancer, PROCRIT® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
  • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer

  • ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS). Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer, lymphoid malignancy, and cervical cancer; in patients with advanced head and neck cancer receiving radiation therapy; and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy.

Hypertension

  • PROCRIT® is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of PROCRIT®, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving PROCRIT®.
  • Appropriately control hypertension prior to initiation of and during treatment with PROCRIT®. Reduce or withhold PROCRIT® if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Seizures

  • PROCRIT® increases the risk of seizures in patients with CKD. During the first several months following initiation of PROCRIT®, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.

Lack or Loss of Hemoglobin Response to PROCRIT®

  • For lack or loss of hemoglobin response to PROCRIT®, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to PROCRIT® therapy.

Pure Red Cell Aplasia

  • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which PROCRIT® is not approved).

  • If severe anemia and low reticulocyte count develop during treatment with PROCRIT®, withhold PROCRIT® and evaluate patients for neutralizing antibodies to erythropoietin. Contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) to perform assays for binding and neutralizing antibodies. Permanently discontinue PROCRIT® in patients who develop PRCA following treatment with PROCRIT® or other erythropoietin protein drugs. Do not switch patients to other ESAs.

Serious Allergic Reactions

  • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with PROCRIT®. Immediately and permanently discontinue PROCRIT® and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

Severe Cutaneous Reactions

  • Blistering and skin exfoliation reactions, including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including PROCRIT® ) in the postmarketing setting. Discontinue PROCRIT® therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative

  • PROCRIT® from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women. In addition, do not mix PROCRIT® with bacteriostatic saline (which also contains benzyl alcohol) when administering PROCRIT® to these patient populations.

  • Serious and fatal reactions, including “gasping syndrome,” can occur in neonates and infants treated with benzyl alcohol–preserved drugs, including PROCRIT® multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. PROCRIT® multiple-dose vials contain 11 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Risk of Infectious Diseases Due to Albumin (Human) Content

  • PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Dialysis Management

  • Patients may require adjustments in their dialysis prescriptions after initiation of PROCRIT®. Patients receiving PROCRIT® may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Anemia in Patients with Chronic Kidney Disease

  • In adult patients not on dialysis:
    • Consider initiating PROCRIT® treatment only when the hemoglobin level is less than 10 g/dL and:
      • The patient’s rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and
      • Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
    • If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of PROCRIT®, and use the lowest dose of PROCRIT® sufficient to reduce the need for RBC transfusions.
  • In adult patients on dialysis:
    • Initiate PROCRIT® treatment when the hemoglobin level is less than 10 g/dL.
    • If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of PROCRIT®.
  • In pediatric patients:
    • Initiate PROCRIT® treatment only when the hemoglobin level is less than 10 g/dL.
    • If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of PROCRIT®.
  • When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
    • Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
    • If the hemoglobin rises rapidly (e.g. more than 1 g/dL in any 2-week period), reduce the dose of PROCRIT® by 25% or more as needed to reduce rapid responses.
    • For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
    • For patients who do not respond adequately over a 12-week escalation period, increasing the PROCRIT® dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue PROCRIT® if responsiveness does not improve.
  • Adverse reactions in ≥5% of PROCRIT®-treated adult patients not on dialysis in clinical studies were hypertension and arthralgia.
  • Adverse reactions in ≥5% of PROCRIT®-treated patients on dialysis were hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion and upper respiratory tract infection.

Anemia Due to Chemotherapy in Patients with Cancer

  • PROCRIT® is not indicated for use in patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • PROCRIT® is not indicated for use in patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • PROCRIT® is not indicated for use in patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • Initiate PROCRIT® in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
  • Use the lowest dose of PROCRIT® necessary to avoid RBC transfusions.
  • Reduce dose by 25% if:
    • Hemoglobin increases greater than 1 g/dL in any 2-week period or
    • Hemoglobin reaches a level needed to avoid RBC transfusion.
  • Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
  • Adverse reactions in ≥5% of PROCRIT®-treated patients in clinical studies were nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis.

Surgery/Perisurgery

  • PROCRIT® is not indicated for use in patients scheduled for surgery who are willing to donate autologous blood.
  • PROCRIT® is not indicated for use in patients undergoing cardiac or vascular surgery.
  • Deep venous thrombosis prophylaxis is recommended during PROCRIT® therapy.
  • Adverse reactions in ≥5% of PROCRIT®-treated patients in clinical studies were nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension.

Anemia Due to Zidovudine in Patients with HIV infection

  • Withhold PROCRIT® if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
  • Discontinue PROCRIT® if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
  • Adverse reactions in ≥5% of PROCRIT®-treated patients in clinical studies were pyrexia, cough, rash, and injection site irritation.

Please see full Prescribing Information, including Boxed WARNINGS.

080071-171019

Remicade® ( infliximab )

INDICATIONS

REMICADE® is indicated for:

Crohn's Disease

  • 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

  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age or older with moderately to severely active CD who have had an inadequate response to conventional therapy

Ulcerative Colitis

  • 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

  • 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

  • Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate (MTX)

Psoriatic Arthritis

  • Reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis (PsA)

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis (AS)

Plaque Psoriasis

  • The treatment of adult patients with chronic severe (ie, extensive and/or disabling) plaque psoriasis 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

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 and pneumocystosis. 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 and Listeria.

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 inhibitors, 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 inhibitors, 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 inhibitors 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.

CONTRAINDICATIONS

REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.

HEPATITIS B REACTIVATION

TNF inhibitors, 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 rarely 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.

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. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.

NEUROLOGIC EVENTS

TNF inhibitors, including REMICADE®, have been associated in rare cases 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.

AUTOIMMUNITY

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

ADVERSE REACTIONS

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

USE WITH OTHER DRUGS

Concomitant 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.

LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

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

Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE®. 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®.

For more information, please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion. (Requires Adobe® Reader®. Click here to download.)

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.

039670-150902

Simponi® ( golimumab )

What is SIMPONI® (golimumab)?

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
  • Active psoriatic arthritis (PsA) alone, or in combination with methotrexate
  • Active ankylosing spondylitis (AS)
  • Moderately to severely active ulcerative colitis (UC) for inducing and maintaining clinical response, improving endoscopic appearance of the mucosa during induction, inducing clinical remission, and achieving and sustaining clinical remission in induction responders 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

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, and thrombocytopenia in patients receiving SIMPONI® in clinical trials. Additionally, aplastic anemia has been reported in patients receiving TNF-blocking agents, of which SIMPONI® is a member. 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 read the full Prescribing Information and Medication Guide for SIMPONI®. Provide the Medication Guide to your patients and encourage discussion.

066808-170206

Simponi Aria® ( golimumab )

INDICATION

SIMPONI ARIA® 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), and active ankylosing spondylitis (AS).

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

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

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, of which SIMPONI ARIA® is a member, 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 the subcutaneous formulation of 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, and thrombocytopenia in patients receiving SIMPONI ARIA® in clinical trials. Additionally, aplastic anemia has been reported in patients receiving TNF blockers. Exercise caution when using SIMPONI ARIA® in patients who have or had significant cytopenias.

VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS

People receiving SIMPONI ARIA® 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 ARIA® in utero is not recommended for 6 months following the mother’s last SIMPONI ARIA® infusion during pregnancy due to an increased risk of infection. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI ARIA® due to the possibility of clinical infections, including disseminated infections.

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.

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

082223-171013

Stelara® ( ustekinumab )

Indications

STELARA® (ustekinumab) is indicated for the treatment of adult patients with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX).

STELARA® (ustekinumab) is indicated for the treatment of patients 12 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 who:

  • have failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) blocker, or
  • failed or were intolerant to treatment with one or more TNF blockers.

For psoriatic arthritis:

STELARA®, available as 45 mg and 90 mg, is a subcutaneous injection intended for use under the guidance and supervision of a physician with patients who will be closely monitored and have regular follow-up visits with a physician. If a physician determines that it is appropriate, a patient may self-inject or a caregiver may inject STELARA® after proper training in subcutaneous injection technique. Patients should be instructed to follow the directions provided in the Medication Guide.

For plaque psoriasis:

STELARA®, available as 45 mg and 90 mg, is a subcutaneous injection intended for use under the guidance and supervision of a physician with patients who will be closely monitored and have regular follow-up visits with a physician. In adolescent patients, it is recommended that STELARA® be administered by a healthcare provider. If a physician determines that it is appropriate, a patient may self-inject or a caregiver may inject STELARA® after proper training in subcutaneous injection technique. Patients should be instructed to follow the directions provided in the Medication Guide.

For Crohn’s disease:

STELARA® for intravenous infusion is available as a 130 mg/26 mL (5 mg/mL) single-dose vial. It must be diluted, prepared, and infused by a healthcare professional for Crohn’s disease.

STELARA®, available as 90 mg, is a subcutaneous injection intended for use under the guidance and supervision of a physician with patients who will be closely monitored and have regular follow-up. If a physician determines that it is appropriate, a patient may self-inject or a caregiver may inject STELARA® after proper training in subcutaneous injection technique. Patients should be instructed to follow the directions provided in the Medication Guide.

Important Safety Information

Infections

STELARA® (ustekinumab) may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections, some requiring hospitalization, were reported. In patients with psoriasis, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In patients with psoriatic arthritis, serious infections included cholecystitis. In patients with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, ophthalmic herpes, pneumonia, and Listeria meningitis.

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, e.g., 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

STELARA® is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or excipients. 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®.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis. No cases of RPLS were observed in clinical studies of Crohn’s disease. If RPLS is suspected, administer appropriate treatment and discontinue STELARA®. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.

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 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 MTX use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease studies, concomitant use of 6-mercaptopurine, azathioprine, methotrexate and corticosteroids did not appear to influence the overall safety or efficacy of STELARA®.

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 adolescents with plaque psoriasis through Week 60 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 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%).

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

081646-171004

Sylvant® ( siltuximab )

Indication

SYLVANT® (siltuximab) is indicated for the treatment of patients with Multicentric Castleman's Disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Limitation of Use. SYLVANT® was not studied in patients with MCD who are HIV-positive or HHV-8 positive because SYLVANT® did not bind to virally produced IL-6 in a nonclinical study.

Important Safety Information

CONTRAINDICATIONS – Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT®.

Concurrent Active Severe Infections – Do not administer to patients with severe infections until the infection resolves. SYLVANT® may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Monitor patients closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT® until the infection resolves.

Vaccinations – Do not administer live vaccines to patients receiving SYLVANT® because interleukin-6 (IL-6) inhibition may interfere with the normal immune response to new antigens.

Infusion Related Reactions and Hypersensitivity – Stop the infusion if the patient develops signs of anaphylaxis. Discontinue further therapy.

Stop the infusion if the patient develops mild to moderate infusion reactions. If the reaction resolves, the infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT® if the patient does not tolerate the infusion following these interventions.

Administer SYLVANT® in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.

Gastrointestinal (GI) Perforation – Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated with or suggestive of GI perforation.

Adverse Reactions – The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

Drug Interactions Cytochrome P450 (CYP450) Substrates – Upon initiation or discontinuation of SYLVANT®, in patients being treated with CYP450 substrates with narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. Exercise caution when SYLVANT® is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).

Please click here to read full Prescribing Information for SYLVANT®.

011215-160609

TREMFYA ( guselkumab )

Indication

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

TREMFYA™ is administered as a 100 mg subcutaneous injection once every 8 weeks, after starter doses at weeks 0 and 4. TREMFYA™ is intended for use under the guidance and supervision of a physician. Patients may self-inject with TREMFYA™ after physician approval and proper training.

Important Safety Information

Important Safety Information

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, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections.

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

067010-170208

 

Xarelto® ( rivaroxaban )

Indications

XARELTO® is indicated to reduce the risk of stroke and systemic embolism in 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 of PE following initial 6 months treatment for DVT and/or PE.

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

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 XARELTO® in patients with active pathological hemorrhage.
    • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.
    • Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).
  • 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 the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban 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 XARELTO® 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. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any 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 if they experience 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 of XARELTO® in patients who develop acute renal failure while on XARELTO®.
    • Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
    • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue the treatment.
  • Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO® 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.
  • Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A4 inhibitors. Avoid concomitant use of XARELTO® with drugs that are known combined P-gp and strong CYP3A4 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 and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
  • Patients With Prosthetic Heart Valves: The safety and efficacy of XARELTO® have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO® is not recommended in these patients.
  • 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.

DRUG INTERACTIONS

  • Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.
  • Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the 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 CYP3A4 inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.
  • Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase the risk of bleeding.
  • Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

USE IN SPECIFIC POPULATIONS

  • Pregnancy Category C: XARELTO® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing.
  • Labor and Delivery: Safety and effectiveness of XARELTO® during labor and delivery have not been studied in clinical trials.
  • Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.
  • Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
  • Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

OVERDOSAGE

  • Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

  • The most common adverse reactions with XARELTO® were bleeding complications.

Please see full Prescribing Information, including Boxed WARNINGS.

070439-170404

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® (trabectedin) is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.   

WARNINGS AND PRECAUTIONS

Neutropenic sepsis, including fatal cases, can occur. In Trial 1, 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%). 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 YONDELIS® for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS® for life-threatening or prolonged, severe neutropenia in the preceding cycle.

Rhabdomyolysis — YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients. 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 YONDELIS® for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS® for rhabdomyolysis.

Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 × ULN were not enrolled in Trial 1. In Trial 1, 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). 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 1, 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). ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients. 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 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, 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). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2- to 3-month intervals thereafter until YONDELIS® is discontinued. Withhold YONDELIS® for LVEF below lower limit of normal. Permanently discontinue YONDELIS® for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks.

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.

Embryofetal 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 see full Prescribing Information for YONDELIS®.

072957-170515

Zytiga® ( abiraterone acetate )

Indication

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

Important Safety Information

Contraindications - ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, 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. 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.

Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

Adverse Reactions - The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions - 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 (2.3)]. 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.

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, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 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®.

Use in Specific Populations - Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

051320-160413