May 25, 2016
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Kyprolis

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Kyprolis

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. In clinical studies with Kyprolis, these events typically occurred early in the course of Kyprolis therapy ( < 5 cycles). Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see DOSAGE AND ADMINISTRATION].

While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see DOSAGE AND ADMINISTRATION].

In patients ≥ 75 years of age, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction , and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications [see Use in Specific Populations].

Acute Renal Failure

Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred with an incidence of approximately 8% in a randomized controlled trial. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see DOSAGE AND ADMINISTRATION].

Tumor Lysis Syndrome

Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed [see DOSAGE AND ADMINISTRATION]. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly including interruption of Kyprolis until TLS is resolved [see DOSAGE AND ADMINISTRATION].

Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in less than 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis [see DOSAGE AND ADMINISTRATION].

Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in approximately 1% 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].

Dyspnea

Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4 % of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONSCardiac Toxicities, Pulmonary Toxicity, and ADVERSE REACTIONS].

Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment [see DOSAGE AND ADMINISTRATION].

Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In the combination study, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the Kyprolis combination arm versus 6 % in the control arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%. Thromboprophylaxis is recommended and should be based on an assessment of the patient's underlying risks, treatment regimen, and clinical status.

Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include 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 infusion reactions [see DOSAGE AND ADMINISTRATION]. Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur [see Patient Counseling Information].

Thrombocytopenia

Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle with recovery to baseline platelet count usually by the start of the next cycle [see ADVERSE REACTIONS]. Thrombocytopenia was reported in approximately 40% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see DOSAGE AND ADMINISTRATION].

Hepatic Toxicity And Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported ( < 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome

Cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) including fatal outcome have been reported in patients who received Kyprolis. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have been reported in patients receiving Kyprolis. Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate.

The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

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, 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

Risk Summary

Kyprolis, a proteasome inhibitor, may cause fetal harm based on findings from animal studies [see Data] and the drug's mechanism of action [see CLINICAL PHARMACOLOGY]. There are no adequate and well-controlled studies in pregnant women using Kyprolis.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis. Consider the benefits and risks of Kyprolis and possible risks to the fetus when prescribing Kyprolis to a pregnant woman. If Kyprolis is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data

Animal Data

Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats 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.

Lactation

Risk Summary

There is no information regarding the presence of Kyprolis in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Kyprolis and any potential adverse effects on the breastfed infant from Kyprolis or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Contraception

Kyprolis can cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception measures to prevent pregnancy during treatment with Kyprolis and for at least 2 weeks following completion of therapy.

Pediatric Use

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

Geriatric Use

Of 598 patients treated with Kyprolis monotherapy, 293 patients (49%) were ≥ 65 years of age and 96 patients (16%) were ≥ 75 years of age. The median age was 64 years. The incidence of serious adverse events was 44% in patients < 65 years of age, 55% in patients 65 to 74 years of age, and 56% in patients ≥ 75 years of age [see WARNINGS AND PRECAUTIONS - Cardiac Toxicities]. In Study 2 (n = 266), no overall differences in effectiveness were observed between these and younger patients.

Of 392 patients treated with Kyprolis in combination with lenalidomide and dexamethasone, 185 patients (47%) were ≥ 65 years of age and 43 patients (11%) were ≥ 75 years of age. The median age was 64 years. No overall differences in effectiveness were observed between these and younger patients. The incidence of serious adverse events was 50% in patients < 65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥ 75 years of age [see WARNINGS AND PRECAUTIONS - Cardiac Toxicities].

Renal Impairment

No starting dose adjustment is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. 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. In this study, the pharmacokinetics of Kyprolis was 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 or recent myocardial infarction (within 3 to 6 months in different protocols) were not eligible for the clinical trials. Safety in this population has not been evaluated.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 9/14/2015

Warnings
Precautions

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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