CONTRAINDICATIONS / PRECAUTIONS
Angina, cardiac arrest, cardiac arrhythmias, cardiomyopathy, edema, heart failure, myocardial infarction, pulmonary edema
Serious cardiac toxicity (e.g., cardiac arrest, new or worsening congestive heart failure (CHF) with decreased left ventricular function/ejection fraction and pulmonary edema, myocardial infarction (MI)/ischemia, and restrictive cardiomyopathy) has been reported with carfilzomib use; fatal cardiac arrest has occurred within a day of carfilzomib administration. Some events occurred in patients with normal baseline ventricular function. Monitor patients for signs or symptoms of cardiac failure or cardiac ischemia and fluid/volume overload (edema); adjust total IV fluids and manage symptoms promptly. Withhold therapy until recovery for grade 3 or 4 cardiac adverse events. Restart carfilzomib at a reduced dose if therapy is resumed following a benefit/risk assessment. Patients aged 75 years or older may have a higher risk of heart failure compared with younger patients. Patients with NYHA class III and IV CHF, recent MI, angina, and conduction abnormalities (i.e., cardiac arrhythmias not controlled with medication) were not included in clinical studies and may be at increased risk for cardiac complications. These patients should have a comprehensive medical assessment (e.g., blood pressure and fluid status) prior to starting and during treatment.[51306]
Infusion-related reactions
Infusion-related reactions may occur immediately following or up to 24 hours after carfilzomib administration. Premedication with dexamethasone is recommended to attenuate infusion-related events. Advise patients to promptly report infusion-related signs and symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina.
Tumor lysis syndrome (TLS)
Tumor lysis syndrome (TLS) has been reported rarely with carfilzomib use; some cases were fatal. Patients with multiple myeloma and a high tumor burden may be at increased risk for TLS; consider prophylactic uric acid lowering agents in these patients. Hydrate patients well prior to administering carfilzomib. Monitor patients for evidence of TLS (e.g., hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) during treatment. If TLS occurs, hold therapy until signs or symptoms resolve; manage symptoms promptly.
Neutropenia, thrombocytopenia
Hematologic toxicity including neutropenia and thrombocytopenia has been reported with carfilzomib therapy. Platelet nadirs typically occur around day 8 and 15 of each 28-day treatment cycle; counts usually return to baseline prior to the start of the next cycle. Monitor blood and platelet counts frequently during therapy. Interruption of therapy and/or a dose reduction may be necessary in patients who develop severe neutropenia or thrombocytopenia or febrile neutropenia.
Hepatic disease, hepatotoxicity
Hepatotoxicity (e.g., elevated hepatic enzymes and fatal hepatic failure) has been reported with carfilzomib use. Use carfilzomib with caution in patients with pre-existing hepatic disease; adverse events occurred more often in patients with hepatic impairment (63%) compared with patients with normal hepatic function (27%) in a study. Reduce the initial dose of carfilzomib in patients with mild or moderate hepatic impairment. Monitor liver function tests prior to starting carfilzomib and frequently during therapy. Interruption of therapy and a dose reduction may be necessary in patients who develop grade 3 or 4 hepatotoxicity.
Bleeding, GI bleeding, intracranial bleeding, pulmonary bleeding
Serious and potentially fatal bleeding (e.g., GI bleeding, pulmonary bleeding, and intracranial bleeding) has been reported with carfilzomib use. Bleeding has occurred in patients with low or normal platelet counts and in patients who were not receiving antiplatelet/anticoagulant therapy; additionally, intracranial bleeding has occurred without trauma. Promptly evaluate patients with blood loss. Interruption of therapy and/or a dose reduction may be necessary in patients who develop severe bleeding or any bleeding with thrombocytopenia.
Hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura (TTP)
Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura (TTP)/hemolytic-uremic syndrome (HUS)) has been reported in patients with multiple myeloma who received carfilzomib; some cases were fatal. Monitor patients for signs and symptoms of TTP (e.g., petechiae, bleeding, low platelet counts) or HUS (e.g., increased serum creatinine/BUN levels, anemia, hematuria). Discontinue therapy if TTP/HUS is suspected or diagnosed. Therapy may be restarted if TTP/HUS is excluded. The safety of restarting carfilzomib in patients who developed TTP/HUS on therapy is unknown.
Renal failure, renal impairment
Renal toxicity including renal failure has been reported in patients with advanced multiple myeloma who received carfilzomib; some cases were fatal. Acute renal failure occurred more often with single-agent carfilzomib therapy. Monitor renal function (e.g., serum creatinine, creatinine clearance) prior to starting carfilzomib and during therapy. Interruption of therapy or a dose reduction may be necessary in patient who develop renal toxicity. Patients with renal impairment at baseline may have a higher risk of developing fatal renal failure.
Pneumonitis, pulmonary disease, respiratory distress syndrome
Acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease (e.g., pneumonitis and interstitial lung disease) have been reported with carfilzomib use; some cases were fatal. Discontinue therapy if drug-induced pulmonary toxicity occurs. Severe dyspnea has also occurred with carfilzomib use. Exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes in patients who develop dyspnea. Hold carfilzomib until symptoms resolve or return to baseline in patients who experience grade 3 or 4 dyspnea. Resume therapy only after a benefit/risk assessment.
Hypertension
Severe hypertension (e.g., hypertensive crisis, hypertensive emergency) has been reported with carfilzomib use; some cases were fatal. Ensure patients have good blood pressure control prior to starting carfilzomib therapy. Monitor blood pressure regularly during therapy. Hold therapy in patients with uncontrolled hypertension. Resume therapy only after a benefit/risk assessment.
Pulmonary hypertension
Pulmonary arterial hypertension (PAH) has been reported with carfilzomib use. If PAH is suspected, evaluate with cardiac imaging and/or other tests as indicated. Hold carfilzomib until symptoms resolve or return to baseline in patients who develop pulmonary hypertension. Resume therapy only after a benefit/risk assessment.
Thromboembolic disease
Venous thromboembolic disease (e.g., deep venous thrombosis and pulmonary embolism) has been reported in patients who received carfilzomib in combination with dexamethasone or lenalidomide plus dexamethasone and in patients who received single-agent carfilzomib in clinical studies. The use of carfilzomib as part of combination therapy increases the risk of venous thromboembolic events (VTE). Therefore, thromboprophylaxis is recommended in patients who receive combination therapy; the choice of agent should be based on an assessment of the patient’s underlying risks. The use of oral contraceptives or a hormonal method of contraception may increase the risk of VTE; consider an alternative method of effective contraception in patients receiving carfilzomib as part of combination therapy.
Encephalopathy
Posterior reversible encephalopathy syndrome (PRES) has been reported with carfilzomib use. Symptoms of PRES include hypertension, seizures, headache, lethargy, confusion, blindness, altered consciousness, and/or other visual or neurological disturbances. Discontinue therapy if PRES is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. PRES may be reversible if detected and treated early. The safety of restarting carfilzomib in patients who developed PRES on therapy is unknown.
Immunosuppression, progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) has been reported in patients who received carfilzomib. Immunosuppression due to prior or concurrent immunosuppressive therapy may increase a patient's risk of developing PML. Evaluate patients who develop new-onset or changes in neurologic symptoms. Stop carfilzomib therapy if PML is suspected and initiate further evaluation including a neurology consult; discontinue carfilzomib if a PML diagnosis is confirmed.
Geriatric
In clinical studies evaluating carfilzomib therapy (n = 2,387), serious adverse events occurred more often in geriatric patients aged 65 to 74 years (58%) or 75 years or older (63%) who received carfilzomib compared with younger patients (49%). In one randomized clinical trial (n = 308), fatal adverse reactions were reported in 14% of patients aged 65 to 74 years or 75 years or older who received carfilzomib, daratumumab, and dexamethasone compared with 6% of patients aged less than 65 years.
Pregnancy
Carfilzomib may cause fetal harm when administered to a pregnant woman, based on the mechanism of action and animal studies. Advise females of reproductive potential to avoid becoming pregnant while taking carfilzomib. Discuss the potential hazard to the fetus if carfilzomib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicity including pre-implantation loss, early resorption and post implantation loss, and a decrease in fetal weight was observed in pregnant rabbits who received carfilzomib doses approximately 20% and 40% of the recommended human dose of 27 mg/m2.[51306]
Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk
Counsel patients about the reproductive risk and contraception requirements during carfilzomib treatment. Pregnancy testing should be performed prior to starting carfilzomib in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception (or abstain from sexual activity) during and for 6 months after the last carfilzomib dose. Due to male-mediated teratogenicity, men with female partners should avoid fathering a child and use effective contraception during and for 3 months after the last carfilzomib dose.
Breast-feeding
It is not known if carfilzomib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during carfilzomib therapy and for 2 weeks after the last dose.[51306]