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Kyprolis

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Kyprolis

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia

Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see DOSAGE AND ADMINISTRATION]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications.

Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see DOSAGE AND ADMINISTRATION].

Pulmonary Complications

Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Infusion Reactions

Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see DOSAGE AND ADMINISTRATION]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see PATIENT INFORMATION].

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see DOSAGE AND ADMINISTRATION]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see DOSAGE AND ADMINISTRATION].

Thrombocytopenia

KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see DOSAGE AND ADMINISTRATION].

Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported ( < 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.

Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS AND PRECAUTIONS].

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m² based on body surface area.

Nursing Mothers

It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of KYPROLIS in pediatric patients have not been established.

Geriatric Use

In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older.

Renal Impairment

The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m² on Cycle 1, 20 mg/m² on Cycle 2, and 27 mg/m² on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 upper limit of normal (ULN) and bilirubin ≥ 2 ULN [see CLINICAL PHARMACOLOGY].

Cardiac Impairment

Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated.

Last reviewed on RxList: 7/25/2012
This monograph has been modified to include the generic and brand name in many instances.

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