Carfilzomib

Kyprolis is a proteasome inhibitor that is indicated: for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone. ( 1 , 14 ) as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. ( 1 , 14 )

1.1 Relapsed or Refractory Multiple Myeloma Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with: Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone. Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

For injection: 10 mg, 30 mg and 60 mg as a white to off-white lyophilized cake or powder in single-dose vial for reconstitution. For injection: 10 mg, 30 mg or 60 mg lyophilized powder in single-dose vial for reconstitution. ( 3 )

None. None. ( 4 )

Cardiac Toxicities : Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. ( 5.1 ) Acute Renal Failure : Monitor serum creatinine regularly. ( 5.2 ) Tumor Lysis Syndrome (TLS) : Administer pre-treatment hydration. (2.1 ) Monitor for TLS, including uric acid levels and treat promptly. ( 5.3 ) Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease : Withhold Kyprolis and evaluate promptly. ( 5.4 ) Pulmonary Hypertension : Withhold Kyprolis and evaluate. ( 5.5 ) Dyspnea : For severe or life-threatening dyspnea, withhold Kyprolis and evaluate. ( 5.6 ) Hypertension, including Hypertensive Crisis : Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis. ( 5.7 ) Venous Thrombosis : Thromboprophylaxis is recommended. ( 5.8 ) Infusion-related Reactions : Premedicate with dexamethasone. ( 2.1 , 5.9 ) Hemorrhage : Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. ( 5.10 ) Thrombocytopenia : Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. ( 2.3 , 5.11 ) Hepatic Toxicity and Hepatic Failure : Monitor liver enzymes regularly. Withhold Kyprolis if suspected. ( 5.12 ) Thrombotic Microangiopathy : Monitor for signs and symptoms. Discontinue Kyprolis if suspected. ( 5.13 ) Posterior Reversible Encephalopathy Syndrome (PRES) : Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. ( 5.14 ) Progressive Multifocal Leukoencephalopathy : Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. ( 5.15 ) Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients ( 5.16 ) Embryo-Fetal Toxicity : Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.17 , 8.1 )

5.1 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 Adverse Reactions (6.1) ]. 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 and Administration (2.3) ] . 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 Dosage and Administration (2.1) ] . In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to younger 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 Specific Populations (8.5) ] .

5.2 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. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. 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 and Administration (2.3) ] .

5.3 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 Dosage and Administration (2.1) ] .

5.4 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.

5.5 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.

5.6 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 Warnings and Precautions (5.1 , 5.4) and Adverse Reactions (6.1) ] .

5.7 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.

5.8 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. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiac Toxicities [see Warnings and Precautions (5.1) ] Acute Renal Failure [see Warnings and Precautions (5.2) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.3) ] Pulmonary Toxicity [see Warnings and Precautions (5.4) ] Pulmonary Hypertension [see Warnings and Precautions (5.5) ] Dyspnea [see Warnings and Precautions (5.6) ] Hypertension [see Warnings and Precautions (5.7) ] Venous Thrombosis [see Warnings and Precautions (5.8) ] Infusion-Related Reactions [see Warnings and Precautions (5.9) ] Hemorrhage [see Warnings and Precautions (5.10) ] Thrombocytopenia [see Warnings and Precautions (5.11) ] Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions (5.12) ] Thrombotic Microangiopathy [see Warnings and Precautions (5.13) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.14) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.15) ] The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral. ( 6 ) The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 2,239 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., CANDOR, IKEMA, EQUULEUS, and PLEIADES. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia. Kyprolis in Combination with Lenalidomide and Dexamethasone The safety of Kyprolis 20/27 mg/m 2 twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [see Clinical Studies (14.1) ] . The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm. Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in 45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse reactions within 30 days of the last dose of any Rd therapy. The most frequent cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus 9 (2%), and other adverse reactions 23 (6%) versus 22 (6%). Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most frequent serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%). Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm. Table 8 summarizes the adverse reactions in the first 12 cycles in ASPIRE. Table 8: Adverse Reactions (≥ 10%) Occurring in Cycles 1–12 in Patients Who Received KRd (20/27 mg/m 2 Regimen) in ASPIRE Adverse Reactions KRd (N = 392) n (%) Rd (N = 389) n (%) Any Grade ≥ Grade 3 Any Grade ≥ Grade 3 KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone Blood and Lymphatic System Disorders Anemia 138 (35) 53 (14) 127 (33) 47 (12) Neutropenia 124 (32) 104 (27) 115 (30) 89 (23) Thrombocytopenia 100 (26) 58 (15) 75 (19) 39 (10) Gastrointestinal Disorders Diarrhea 119 (30) 8 (2) 106 (27) 12 (3) Constipation 68 (17) 0 (0) 55 (14) 1 (0) Nausea 63 (16) 1 (0) 43 (11) 3 (1) General Disorders and Administration Site Conditions Fatigue 113 (29) 23 (6) 107 (28) 20 (5) Pyrexia 93 (24) 5 (1) 64 (17) 1 (0) Edema peripheral 59 (15) 3 (1) 48 (12) 2 (1) Asthenia 54 (14) 11 (3) 49 (13) 7 (2) Infections Upper respiratory tract infection 87 (22) 7 (2) 54 (14) 4 (1) Bronchitis 55 (14) 5 (1) 40 (10) 2 (1) Viral upper respiratory tract infection 55 (14) 0 (0) 44 (11) 0 (0) Pneumonia Pneumonia includes pneumonia and bronchopneumonia. 54 (14) 35 (9) 43 (11) 27 (7) Metabolism and Nutrition Disorders Hypokalemia 78 (20) 22 (6) 35 (9) 12 (3) Hypocalcemia 55 (14) 10 (3) 39 (10) 5 (1) Hyperglycemia 43 (11) 18 (5) 33 (9) 15 (4) Musculoskeletal and Connective Tissue Disorders Muscle spasms 92 (24) 3 (1) 75 (19) 3 (1) Back pain 41 (11) 4 (1) 54 (14) 6 (2) Nervous System Disorders Peripheral neuropathies Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. 43 (11) 7 (2) 39 (10) 4 (1) Psychiatric Disorders Insomnia 64 (16) 6 (2) 51 (13) 8 (2) Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes cough and productive cough. 93 (24) 2 (1) 54 (14) 0 (0) Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 71 (18) 8 (2) 61 (16) 6 (2) Skin and Subcutaneous Tissue Disorders Rash 45 (12) 5 (1) 54 (14) 5 (1) Vascular Disorders Embolic and thrombotic events Embolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. 49 (13) 16 (4) 23 (6) 9 (2) Hypertension Hypertension includes hypertension, hypertensive crisis. 41 (11) 12 (3) 15 (4) 4 (1) There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles. […]

Geriatric Use : In the Kyprolis clinical trials, the incidence of adverse reactions was greater in patients ≥ 75 years of age. ( 8.5 ) Hepatic Impairment : Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. ( 2.4 ) Patients on Hemodialysis : Administer Kyprolis after the hemodialysis procedure. ( 2.1 ) Lactation : Advise women not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] . There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data ) . Advise pregnant women of the potential risk 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. 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/m 2 based on BSA.

8.2 Lactation Risk Summary There are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.

8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose. Infertility Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] . There are no data on the effect of Kyprolis on human fertility.

8.4 Pediatric Use The safety and effectiveness of Kyprolis in pediatric patients have not been established. The safety and effectiveness of Kyprolis in combination with chemotherapy was evaluated, but not established in an open label trial (Study 20140106; NCT02303821) in 124 patients aged 1 to younger than 17 years with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who have received prior targeted B-cell immune therapy or relapsed or refractory T-cell ALL. No new safety signals were observed in these pediatric patients. The systemic exposure of carfilzomib in these pediatric patients was within range of that observed in adults given the same dose based on body surface area.

8.5 Geriatric Use Of the 2,837 patients with relapsed or refractory multiple myeloma exposed to Kyprolis in monotherapy and combination therapy studies [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 , 14.5) ] , 50% were 65 years and older, while 13% were 75 years and older. The incidence of serious adverse reactions was 50% in patients < 65 years of age, 60% 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 Adverse Reactions (6.1) ] . No overall differences in effectiveness were observed between older and younger patients.

8.6 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 and Administration (2.4) , Clinical Pharmacology (12.3) ] . 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 Warnings and Precautions (5.12) , Clinical Pharmacology (12.3) ] .

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.