Reference ID: 4110010 - VELCADE

1 1/38 HIGHLIGHTS OF prescribing information These highlights do not include all the information needed to use VELCADE safely and effectively. See full prescribing information for VELCADE . VELCADE ( bortezomib ) for injection, for subcutaneous or intravenous use Initial Approval: 2003 ------------------------RECENT MAJOR CHANGES------------------------- Warnings and Precautions ( ) 6/2017 ------------------------INDICATIONS AND USAGE-------------------------- VELCADE is a proteasome inhibitor indicated for: treatment of patients with multiple myeloma ( ) treatment of patients with mantle cell lymphoma ( ) ----------------------DOSAGE AND ADMINISTRATION--------------------- For subcutaneous or intravenous use only.

2 Each route of administration has a different reconstituted concentration; Exercise caution when calculating the volume to be administered. ( , ) The recommended starting dose of VELCADE is mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. ( , , ) Retreatment for multiple myeloma: May retreat starting at the last tolerated dose. ( ) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. ( ) Dose must be individualized to prevent overdose ( ) --------------------DOSAGE FORMS AND STRENGTHS-------------------- For injection: Single-use vial contains mg of bortezomib as lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose.

3 (3) --------------------------CONTRAINDICATI ONS--------------------------------- Patients with hypersensitivity (not including local reactions) to bortezomib , boron, or mannitol, including anaphylactic reactions. (4) Contraindicated for intrathecal administration. (4) -----------------------WARNINGS AND PRECAUTIONS---------------------- Peripheral Neuropathy: Manage with dose modification or discontinuation. ( ) Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ( , ) Hypotension: Use caution when treating patients taking anti-hypertensives, with a history of syncope, or with dehydration.

4 ( ) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ( ) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ( ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ( ) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.

5 ( ) Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ( ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden ( ) Hepatic Toxicity: Monitor hepatic enzymes during treatment. ( ) Embryo-fetal Toxicity: VELCADE can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy. ( ) --------------------------ADVERSE REACTIONS------------------------------- -- Most commonly reported adverse reactions (incidence 20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

6 ( ) To report SUSPECTED ADVERSE REACTIONS, contact Millennium Pharmaceuticals at 1-866 VELCADE or FDA at 1-800-FDA-1088 or --------------------------DRUG INTERACTIONS---------------------------- ----- Co-administration with strong CYP3A4 inhibitors can increase VELCADE exposure. Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. ( ) Co-administration with strong CYP3A4 inducers can decrease VELCADE exposure. Avoid concomitant use of strong CYP3A4 inducers. ( ) ---------------------USE IN SPECIFIC POPULATIONS------------------------ Patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication.

7 ( ) See 17 for PATIENT COUNSELING information Revised: 6/2017 FULL prescribing information : CONTENTS* 1 INDICATIONS AND USAGE Multiple Myeloma Mantle Cell Lymphoma 2 DOSAGE AND ADMINISTRATION General Dosing Guidelines Dosage in Previously Untreated Multiple Myeloma Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone Dosage in Previously Untreated Mantle Cell Lymphoma Dose Modification Guidelines for VELCADE When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Dose Modifications for Peripheral Neuropathy Dosage in Patients with Hepatic Impairment Administration Precautions Reconstitution/Preparation for Intravenous and Subcutaneous Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy Hypotension Cardiac Toxicity Pulmonary Toxicity Posterior Reversible Encephalopathy Syndrome (PRES)

8 Gastrointestinal Toxicity Thrombocytopenia/Neutropenia Tumor Lysis Syndrome Hepatic Toxicity Embryo-fetal Toxicity 6 ADVERSE REACTIONS Clinical Trials Safety Experience Postmarketing Experience 7 DRUG INTERACTIONS CYP3A4 inhibitors CYP2C19 inhibitors CYP3A4 inducers Dexamethasone Melphalan-Prednisone 8 USE IN SPECIFIC POPULATIONS Pregnancy Lactation Females and Males of Reproductive Potential Pediatric Use Geriatric Use Patients with Renal Impairment Patients with Hepatic Impairment Patients with Diabetes 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY Mechanism of Action Pharmacodynamics Pharmacokinetics 13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Reference ID: 4110010 2/38 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES Multiple Myeloma Mantle Cell Lymphoma 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING information *Sections or subsections omitted from the full prescribing information are not listedReference ID.

9 4110010 3/38 FULL prescribing information 1 INDICATIONS AND USAGE Multiple Myeloma VELCADE ( bortezomib ) is indicated for the treatment of patients with multiple myeloma. Mantle Cell Lymphoma VELCADE is indicated for the treatment of patients with mantle cell lymphoma. 2 DOSAGE AND ADMINISTRATION Important Dosing Guidelines VELCADE is for intravenous or subcutaneous use only. VELCADE should not be administered by any other route. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. The recommended starting dose of VELCADE is mg/m2.

10 VELCADE may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of mg/mL [see Dosage and Administration ( )]. VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least 6 months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration ( )]. When administered intravenously, VELCADE is administered as a 3 to 5 second bolus intravenous injection. Dosage in Previously Untreated Multiple Myeloma VELCADE is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1.