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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.
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 (incidence ≥20%) 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 abnormalities ≥20% 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%).
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.
Please see full Prescribing Information.
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.
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.
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®.
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®.
ERLEADA™ (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.
Pregnancy — ERLEADA™ (apalutamide) can cause fetal harm and potential loss of pregnancy.
WARNINGS AND PRECAUTIONS
Falls and Fractures — In a randomized study (SPARTAN), falls and fractures occurred in 16% and 12% of patients treated with ERLEADA™ compared to 9% and 7% treated with placebo, respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.
Seizure — In a randomized study (SPARTAN), 2 patients (0.2%) treated with ERLEADA™ experienced a seizure. Permanently discontinue ERLEADA™ in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA™. Advise patients of the risk of developing a seizure while receiving ERLEADA™ and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
Adverse Reactions — The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.
Laboratory Abnormalities — All Grades (Grade 3-4)
- Hematology — anemia ERLEADA™ 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA™ 41% (2%), placebo 21% (2%)
- Chemistry — hypercholesterolemia ERLEADA™ 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA™ 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA™ 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA™ 32% (2%), placebo 22% (0.5%)
Rash — Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA™ versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA™ treatment (5%) versus placebo (0.3%).
The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four percent of patients treated with ERLEADA™ received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA™.
Hypothyroidism was reported for 8% of patients treated with ERLEADA™ and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA™ and 7% of patients treated with placebo. The median onset was day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.
Effect of Other Drugs on ERLEADA™ — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA™ dose based on tolerability [see Dosage and Administration (2.2)].
Effect of ERLEADA™ on Other Drugs — ERLEADA™ is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA™ with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA™ with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA™ and evaluate for loss of activity.
P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA™ with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA™ and evaluate for loss of activity if medication is continued.
Please see the full Prescribing Information for ERLEADA™.
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.
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.
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.
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.
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.
- 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.
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.)
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.
- 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.
- 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.
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.
- Consider initiating PROCRIT® treatment only when the hemoglobin level is less than 10 g/dL and:
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.
- 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.
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.
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®.
YONDELIS® (trabectedin) is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
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%).
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®.
ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients
- with metastatic castration-resistant prostate cancer (mCRPC)
- with metastatic high-risk castration-sensitive prostate cancer (CSPC)
Contraindications - ZYTIGA® (abiraterone acetate) can cause fetal harm and potential loss of pregnancy.
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment.
Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. The safety of ZYTIGA® in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)].
Adrenocortical Insufficiency (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. Measure serum transaminases alanine aminotransferase (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA® dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Re-treatment with ZYTIGA® at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [See Dosage and Administration (2.4)].
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.
The safety of ZYTIGA® re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
Adverse Reactions - The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory tract infection, cough, and headache.
The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia 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
- Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception.
- Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).