HIGHLIGHTS OF PRESCRIBING INFORMATION Hypotension: Use caution when treating patients taking These highlights do not include all the information needed to antihypertensives, with a history of syncope, or with dehydration. use VELCADE safely and effectively. See full prescribing (5.2) information for VELCADE. Cardiac Toxicity: Worsening of and development of cardiac VELCADE® (bortezomib) for injection, for subcutaneous or failure has occurred. Closely monitor patients with existing heart intravenous use disease or risk factors for heart disease. (5.3) Initial U.S. Approval: 2003 Pulmonary Toxicity: Acute respiratory syndromes have ------------------------RECENT MAJOR CHANGES-------------------------- occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. (5.4) Warnings and Precautions, Posterior Reversible Encephalopathy Syndrome: Consider MRI Thrombotic Microangiopathy (5.10) 04/2019 imaging for onset of visual or neurological symptoms; ------------------------INDICATIONS AND USAGE-------------------------- discontinue VELCADE if suspected. (5.5) VELCADE is a proteasome inhibitor indicated for: Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and treatment of adult patients with multiple myeloma (1.1) vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (5.6) treatment of adult patients with mantle cell lymphoma (1.2) Thrombocytopenia and Neutropenia: Monitor complete blood ----------------------DOSAGE AND ADMINISTRATION--------------------- counts regularly throughout treatment. (5.7) For subcutaneous or intravenous use only. Each route of Tumor Lysis Syndrome: Closely monitor patients with high tumor administration has a different reconstituted concentration; burden. (5.8) Exercise caution when calculating the volume to be Hepatic Toxicity: Monitor hepatic enzymes during treatment. administered. (2.1, 2.10) Interrupt VELCADE therapy to assess reversibility. (5.9) 2 The recommended starting dose of VELCADE is 1.3 mg/m Thrombotic Microangiopathy: Monitor for signs and symptoms. administered either as a 3 to 5 second bolus intravenous Discontinue VELCADE if suspected. (5.10) injection or subcutaneous injection. (2.2, 2.4, 2.6) Embryo-fetal Toxicity: VELCADE can cause fetal harm. Advise Retreatment for multiple myeloma: May retreat starting at the females of reproductive potential of the potential risk to a fetus last tolerated dose. (2.6) and to avoid pregnancy. (5.11) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (2.8) --------------------------ADVERSE REACTIONS--------------------------------- Most commonly reported adverse reactions (incidence ≥20%) in Dose must be individualized to prevent overdose. (2.10) clinical studies include nausea, diarrhea, thrombocytopenia, --------------------DOSAGE FORMS AND STRENGTHS-------------------- neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, For injection: Single-dose vial contains 3.5 mg of bortezomib as leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and lyophilized powder for reconstitution and withdrawal of the anorexia. (6.1) appropriate individual patient dose. (3) To report SUSPECTED ADVERSE REACTIONS, contact --------------------------CONTRAINDICATIONS--------------------------------- Millennium Pharmaceuticals at 1-866-VELCADE or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. --------------------------DRUG INTERACTIONS--------------------------------- (4) Strong CYP3A4 Inhibitors: Closely monitor patients with Contraindicated for intrathecal administration. (4) concomitant use. (7.1) Strong CYP3A4 Inducers: Avoid concomitant use. (7.3) -----------------------WARNINGS AND PRECAUTIONS---------------------- ---------------------USE IN SPECIFIC POPULATIONS------------------------ Peripheral Neuropathy: Manage with dose modification or Patients with diabetes may require close monitoring of blood glucose discontinuation. (2.7) Patients with preexisting severe and adjustment of antidiabetic medication. (8.8) neuropathy should be treated with VELCADE only after careful risk-benefit assessment. (2.7, 5.1) See 17 for PATIENT COUNSELING INFORMATION Revised: 04/2019 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 5.1 Peripheral Neuropathy 1.1 Multiple Myeloma 5.2 Hypotension 1.2 Mantle Cell Lymphoma 5.3 Cardiac Toxicity 2 DOSAGE AND ADMINISTRATION 5.4 Pulmonary Toxicity 2.1 Important Dosing Guidelines 5.5 Posterior Reversible Encephalopathy Syndrome (PRES) 2.2 Dosage in Previously Untreated Multiple Myeloma 5.6 Gastrointestinal Toxicity 2.3 Dose Modification Guidelines for VELCADE When Given in 5.7 Thrombocytopenia/Neutropenia Combination with Melphalan and Prednisone 5.8 Tumor Lysis Syndrome 2.4 Dosage in Previously Untreated Mantle Cell Lymphoma 5.9 Hepatic Toxicity 2.5 Dose Modification Guidelines for VELCADE When Given in 5.10 Thrombotic Microangiopathy Combination with Rituximab, Cyclophosphamide, 5.11 Embryo-fetal Toxicity Doxorubicin and Prednisone 6 ADVERSE REACTIONS 2.6 Dosage and Dose Modifications for Relapsed Multiple 6.1 Clinical Trials Safety Experience Myeloma and Relapsed Mantle Cell Lymphoma 6.2 Postmarketing Experience 2.7 Dose Modifications for Peripheral Neuropathy 7 DRUG INTERACTIONS 2.8 Dosage in Patients with Hepatic Impairment 7.1 Effects of Other Drugs on VELCADE 2.9 Administration Precautions 7.2 Drugs Without Clinically Significant Interactions with 2.10 Reconstitution/Preparation for Intravenous and VELCADE Subcutaneous Administration 8 USE IN SPECIFIC POPULATIONS 3 DOSAGE FORMS AND STRENGTHS 8.1 Pregnancy 4 CONTRAINDICATIONS 8.2 Lactation 5 WARNINGS AND PRECAUTIONS 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use Page 2 of 44 8.5 Geriatric Use 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 8.6 Renal Impairment 13.2 Animal Toxicology and/or Pharmacology 8.7 Hepatic Impairment 14 CLINICAL STUDIES 8.8 Patients with Diabetes 14.1 Multiple Myeloma 10 OVERDOSAGE 14.2 Mantle Cell Lymphoma 11 DESCRIPTION 15 REFERENCES 12 CLINICAL PHARMACOLOGY 16 HOW SUPPLIED/STORAGE AND HANDLING 12.1 Mechanism of Action 17 PATIENT COUNSELING INFORMATION 12.2 Pharmacodynamics * Sections or subsections omitted from the full prescribing information 12.3 Pharmacokinetics are not listed. 13 NONCLINICAL TOXICOLOGY Page 3 of 44 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma VELCADE is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma VELCADE is indicated for the treatment of adult patients with mantle cell lymphoma. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing Guidelines VELCADE is for intravenous or subcutaneous use only. Do not administer VELCADE by any other route. Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered. The recommended starting dose of VELCADE is 1.3 mg/m2. VELCADE is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL [see Dosage and Administration (2.10)]. VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least six months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6)]. When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma VELCADE is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1. In Cycles 1 to 4, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly VELCADE (Cycles 1 to 4) Week 1 2 3 4 5 6 VELCADE Day Day Day Day rest Day Day Day Day rest -- -- (1.3 mg/m2) 1 4 8 11 period 22 25 29 32 period Melphalan (9 mg/m2) Day Day Day Day rest rest -- -- -- -- -- -- Prednisone (60 mg/m2) 1 2 3 4 period period Once Weekly VELCADE (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 VELCADE Day Day rest Day Day rest -- -- (1.3 mg/m2) 1 8 period 22 29 period Melphalan (9 mg/m2) Day Day Day Day rest rest -- -- -- -- -- -- Prednisone (60 mg/m2) 1 2 3 4 period period Page 4 of 44 2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone: Platelet count should be at least 70 x 109/L and the absolute neutrophil count (ANC) should be at least 1 x 109/L Nonhematological toxicities should have resolved to Grade 1 or baseline Table 2: Dose Modifications During Cycles of Combination VELCADE, Melphalan and Prednisone Therapy Toxicity Dose modification or delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or Consider reduction of the melphalan dose by thrombocytopenia, or thrombocytopenia with 25% in the next cycle bleeding is observed in the previous cycle If platelet count is not above 30