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Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia) [see Clinical Trials Experience under Adverse Reactions].
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold Kyprolis for Grade 3 or 4 cardiac adverse reactions until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients 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 Administration Precautions under Dosage & Administration].
In patients ≥75 years of age, the risk of cardiac failure is increased compared to younger patients. The risk of cardiac failure is also increased in Asian patients. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications; for these patients, complete a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Elderly as follows].
Acute Renal Failure: Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 9% of patients who received Kyprolis. The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft-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 Modifications for Adverse Reactions under Dosage & Administration].
Tumor Lysis Syndrome: Cases of 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.Administer oral and intravenous fluids before administration of Kyprolis in Cycle 1 and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for TLS during treatment and manage promptly including interruption of Kyprolis until TLS is resolved [see Administration Precautions under Dosage & Administration].
Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis. Some events were fatal.
In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.
Pulmonary Hypertension: Pulmonary arterial hypertension was reported in approximately 2% of patients who received Kyprolis, with Grade 3 or greater in less than 1%.
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.
Dyspnea: Dyspnea was reported in 25% of patients treated with Kyprolis, with Grade 3 or greater in 4%.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 Cardiac Toxicities and Pulmonary Toxicity as previously mentioned and Clinical Trials Experience under Adverse Reactions).
Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 28% in the Kd arm. Some of these events have been fatal.
Optimize blood pressure prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.
Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, with thromboprophylaxis used in both arms, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In ENDEAVOR, the incidence of venous thromboembolic events in months 1-6 was 9% in the Kd arm versus 2% in the Vd arm.
Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone, with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patient's underlying risks.
For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination [see Females and Males of Reproductive Potential under Use of Pregnancy & Lactation].
Infusion-Related Reactions: Infusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal 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-related reactions [see Administration Precautions and Recommended Dosage under Dosage & Administration, Clinical Trials Experience under Adverse Reactions].
Haemorrhage: Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis [see Clinical Trials Experience under Adverse Reactions]. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation.
Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse under Dosage & Administration].
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 Clinical Trials Experience under Adverse Reactions]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur [see Clinical Trials Experience under Adverse Reactions, Haemorrhage as previously mentioned].
Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases [see Clinical Trials Experience under Adverse Reactions].
Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Thrombotic Microangiopathy: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have been fatal.
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: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. 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.
Progressive Multifocal Leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributary factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression.
Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients: In CLARION, a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six- week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant- ineligible patients with newly diagnosed multiple myeloma.
Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and a decrease in fetal weight.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [see Use Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation), Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
Hepatic Impairment: Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin > 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. A recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Dosage Modifications for Hepatic Impairment under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
The incidence of serious adverse reactions was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [see Hepatic Toxicity and Hepatic Failure under Precautions, Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of Kyprolis in pediatric patients have not been established.
Use in Elderly: Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients < 65 years of age, 58% in patients 65 to 74 years of age, and 63% in patients ≥ 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients ≥ 75 years of age [see Clinical Trials Experience under Adverse Reactions]. No overall differences ineffectiveness were observed between older and younger patients.
