KYPROLIS

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Hydrate prior to and following Kyprolis as needed. ( 2.1 ) Premedicate prior to all Cycle 1 doses and if infusion-related reactions develop or reappear. ( 2.1 ) The recommended dosing regimens are as follows. See Full Prescribing Information for additional dosage information. ( 2.2 ) Regimen Dosage Infusion Time Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) 20/70 mg/m 2 once weekly 30 minutes Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) or Kyprolis, Isatuximab and Dexamethasone (Isa-Kd) or Kyprolis Monotherapy 20/56 mg/m 2 twice weekly 30 minutes Kyprolis, Lenalidomide and Dexamethasone (KRd) or Kyprolis Monotherapy 20/27 mg/m 2 twice weekly 10 minutes 2.1 Administration Precautions Hydration Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles. Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure [see Warnings and Precautions (5.1 , 5.3) ] . Electrolyte Monitoring Monitor serum potassium levels regularly during treatment with Kyprolis [see Adverse Reactions (6.1) ] . Premedications and Concomitant Medications Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy [see Dosage and Administration (2.2) ] . Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions [see Warnings and Precautions (5.9) ] . Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles. Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [see Warnings and Precautions (5.8) ] . Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1) ] . Dose Calculation For patients with body surface area (BSA) of 2.2 m 2 or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less. For patients with a BSA greater than 2.2 m 2 , calculate the Kyprolis dose using a BSA of 2.2 m 2 . 2.2 Recommended Dosage Once Weekly 20/70 mg/m 2 (30-minute infusion) Kyprolis once weekly 20/70 mg/m 2 administered in combination with dexamethasone (Kd), daratumumab plus dexamethasone (DKd), or daratumumab and hyaluronidase-fihj plus dexamethasone (DKd). The recommended starting dosage of Kyprolis is 20 mg/m 2 on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m 2 on Cycle 1, Day 8. Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity as shown in Table 1 [see Clinical Studies (14.2) ] . Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before daratumumab or daratumumab and hyaluronidase-fihj. For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.2 (Kd) and 14.3 (DKd) . Refer to the Prescribing Information for dexamethasone, intravenous daratumumab, and subcutaneous daratumumab and hyaluronidase-fihj for additional dosage information. Table 1: Kyprolis 20/70 mg/m 2 Once Weekly (30-Minute In …

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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 …

8 USE IN SPECIFIC POPULATIONS 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 ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. A reco …

12.1 Mechanism of Action 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.

11 DESCRIPTION Carfilzomib is a proteasome inhibitor. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure: Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C 40 H 57 N 5 O 7 . Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions. Kyprolis for injection, for intravenous use is a sterile, white to off-white lyophilized powder in a single-dose vial. Each 10 mg vial contains 10 mg of carfilzomib, 500 mg sulfobutylether beta-cyclodextrin, and 9.6 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 30 mg vial contains 30 mg of carfilzomib, 1500 mg sulfobutylether beta-cyclodextrin, and 28.8 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5). Chemical Structure

10 OVERDOSAGE Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error. There is no known specific antidote for Kyprolis overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Kyprolis (carfilzomib) for Injection is supplied as: An individually packaged single-dose vial containing 10 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-103-01, NDC 76075-103-21. An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-102-01, NDC 76075-102-21. An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-101-01, NDC 76075-101-21. Storage and Handling Unopened vials should be stored refrigerated 2°C to 8°C (36°F to 46°F). Retain in original package to protect from light.