HIGHLIGHTS OF PRESCRIBING INFORMATION -----------------------WARNINGS AND PRECAUTIONS----------------------- These highlights do not include all the information needed to use Cardiac Adverse Reactions including heart failure and ischemia: Monitor for KYPROLIS safely and effectively. See full prescribing information for cardiac complications. Treat promptly and withhold KYPROLIS. (2.4, 5.1) KYPROLIS. Pulmonary Hypertension: Withhold dosing if suspected. (2.4, 5.2) Pulmonary Complications: Monitor for and manage dyspnea immediately; KYPROLIS™ (carfilzomib) for Injection, for intravenous use interrupt KYPROLIS until symptoms have resolved or returned to baseline. Initial U.S. Approval: 2012 (2.4, 5.3) Infusion Reactions: Pre-medicate with dexamethasone to prevent. (2.3) ---------------------------INDICATIONS AND USAGE--------------------------- Advise patients to seek immediate medical attention if symptoms KYPROLIS is a proteasome inhibitor indicated for the treatment of patients with develop. (5.4) multiple myeloma who have received at least two prior therapies including Tumor Lysis Syndrome (TLS): Hydrate patients to prevent. (2.2) Monitor for bortezomib and an immunomodulatory agent and have demonstrated disease TLS and treat promptly. (5.5) progression on or within 60 days of completion of the last therapy. Approval is Thrombocytopenia: Monitor platelet counts; reduce or interrupt dosing as based on response rate. Clinical benefit, such as improvement in survival or clinically indicated. (2.4, 5.6) symptoms, has not been verified. (1, 14) Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes and withhold dosing if suspected. (2.4, 5.7) -----------------------DOSAGE AND ADMINISTRATION----------------------- Embryo-fetal Toxicity: KYPROLIS can cause fetal harm. Females of Administer intravenously over 2 to 10 minutes, on two consecutive days each reproductive potential should avoid becoming pregnant while being treated. week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest (5.8, 8.1) period (Days 17 to 28). (2.1) 2 Recommended Cycle 1 dose is 20 mg/m /day and if tolerated increase Cycle 2 ------------------------------ADVERSE REACTIONS------------------------------ 2 dose and subsequent cycles doses to 27 mg/m /day. (2.1) Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, Hydrate patients prior to and following administration. (2.2) anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. (6) Pre-medicate with dexamethasone prior to all Cycle 1 doses, during the first cycle of dose escalation, and if infusion reaction symptoms develop or To report SUSPECTED ADVERSE REACTIONS, contact Onyx reappear. (2.3) Pharmaceuticals, Inc. at 1-877-669-9121 or FDA at 1-800-FDA-1088 or Modify dosing based on toxicity. (2.4) www.fda.gov/medwatch. ---------------------DOSAGE FORMS AND STRENGTHS--------------------- -----------------------USE IN SPECIFIC POPULATIONS----------------------- Single-use vial: 60 mg sterile lyophilized powder (3) Patients on dialysis: Administer KYPROLIS after the dialysis procedure. (8.6) ------------------------------CONTRAINDICATIONS------------------------------ None (4) See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2012 FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers 2.1 Dosing Guidelines 8.4 Pediatric Use 2.2 Hydration and Fluid Monitoring 8.5 Geriatric Use 2.3 Dexamethasone Premedication 8.6 Renal Impairment 2.4 Dose Modifications based on Toxicities 8.7 Hepatic Impairment 2.5 Administration Precautions 8.8 Cardiac Impairment 2.6 Reconstitution and Preparation for Intravenous Administration 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia 12.2 Pharmacodynamics 5.2 Pulmonary Hypertension 12.3 Pharmacokinetics 5.3 Pulmonary Complications 13 NONCLINICAL TOXICOLOGY 5.4 Infusion Reactions 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 5.5 Tumor Lysis Syndrome 13.2 Animal Toxicology and/or Pharmacology 5.6 Thrombocytopenia 14 CLINICAL STUDIES 5.7 Hepatic Toxicity and Hepatic Failure 14.1 Relapsed Multiple Myeloma 5.8 Embryo-fetal Toxicity 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 16.1 How Supplied 6.1 Clinical Trials Safety Experience 16.2 Storage and Handling 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the Full Prescribing Information are not listed. Reference ID: 3161927 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Guidelines KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration (2.4)]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. 2 Reference ID: 3161927 Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 1 2 3–7 8 9 10–14 15 16 17–21 22–28 KYPROLIS 20 20 No 20 20 No 20 20 No No (20 mg/m2): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 1 2 3–7 8 9 10–14 15 16 17–21 22–28 KYPROLIS 27 27 No 27 27 No 27 27 No No (27 mg/m2): Dosing Dosing Dosing Dosing a If previous cycle dosage is tolerated. 2.2 Hydration and Fluid Monitoring Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions (5.5)]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions (5.1)]. 2.3 Dexamethasone Premedication Pre-medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions (5.4)]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. 2.4 Dose Modifications based on Toxicities Recommended actions and dose modifications are presented in Table 2. 3 Reference ID: 3161927 Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity Recommended Action Grade 3a or 4 Neutropenia Withhold dose. Grade 4 Thrombocytopenia If fully recovered before next scheduled dose, continue at same [see Warnings and Precautions (5.6)] dose level. If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Non-Hematologic Toxicity Recommended Action Cardiac Toxicity Withhold until resolved or returned to baseline. Grade 3 or 4, new onset or worsening of: After resolution, consider if restarting KYPROLIS at a reduced 2 2 congestive heart failure; dose is appropriate (from 27 mg/m to 20 mg/m , OR from 2 2 decreased left ventricular function; 20 mg/m to 15 mg/m ). If tolerated, the reduced dose may be escalated to the previous or myocardial ischemia dose at the discretion of the physician. [see Warnings and Precautions (5.1)] Pulmonary Hypertension Withhold until resolved or returned to baseline. [see Warnings and Precautions (5.2)] Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Pulmonary Complications Withhold until resolved or returned to baseline. Grade 3 or 4 Consider restarting at the next scheduled treatment with one dose 2 2 2 [see Warnings and Precautions (5.3)] level reduction (from 27 mg/m to 20 mg/m , OR from 20 mg/m to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Hepatic Toxicity Withhold until resolved or returned to baseline. Grade 3 or 4 elevation of After resolution, consider if restarting KYPROLIS is appropriate; transaminases, bilirubin or other liver may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, abnormalities OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of [see Warnings and Precautions (5.7)] liver function.