Bortezomib

1 INDICATIONS AND USAGE Bortezomib for Injection is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma. ( 1.1 ) treatment of adult patients with mantle cell lymphoma. ( 1.2 ) 1.1 Multiple Myeloma Bortezomib for Injection is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma Bortezomib for Injection is indicated for the treatment of adult patients with mantle cell lymphoma.

2 DOSAGE AND ADMINISTRATION For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. ( 2.1 , 2.10 ) The recommended starting dose of Bortezomib for Injection is 1.3 mg/m 2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. ( 2.2 , 2.4 , 2.6 ) Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. ( 2.6 ) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. ( 2.8 ) Dose must be individualized to prevent overdose. ( 2.10 ) 2.1 Important Dosing Guidelines Bortezomib for Injection is for intravenous or subcutaneous use only. Do not administer Bortezomib for Injection 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 Bortezomib for Injection is 1.3 mg/m 2 . Bortezomib for Injection 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 )] . Bortezomib for Injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezomib for Injection and who have relapsed at least six months after completing prior Bortezomib for Injection treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration ( 2.6 )] . When administered intravenously, administer Bortezomib for Injection as a 3 to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma Bortezomib for Injection 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, Bortezomib for Injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib for Injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib for Injection. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib for Injection (Cycles 1 to 4) Week 1 2 3 4 5 6 Bortezomib for Injection (1.3 mg/m 2 ) Day 1 -- -- Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period Once Weekly Bortezomib for Injection (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 Bortezomib for Injection (1.3 mg/m 2 ) Day 1 -- -- Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period 2.3 Dose Modification Guidelines for Bortezomib for Injection When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with Bortezomib for Injection in combination with melphalan and prednisone: Platelet count should be at least 70 x 10 9 /L and the absolute neutrophil count (ANC) should be at least 1 x 10 9 /L Nonhematological toxicities should have resolved to Grade 1 or baseline Table 2: Dose Modifications During Cycles of Combination Bortezomib for Injection, Melphalan and Prednisone Therapy Toxicity Dose Modification or Delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle If platelet count is not above 30 x 10 9 /L or ANC is not above 0.75 x 10 9 /L on a Bortezomib for Injection dosing day (other than Day 1) Withhold Bortezomib for Injection dose If several Bortezomib for Injection doses in consecutive cycles are withheld due to toxicity Reduce B…

5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with pre-existing severe neuropathy should be treated with Bortezomib for Injection only after careful risk-benefit assessment. ( 2.7 , 5.1 ) Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ( 5.2 ) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ( 5.3 ) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting Bortezomib for Injection therapy. ( 5.4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for Injection if suspected. ( 5.5 ) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ( 5.6 ) Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. ( 5.7 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. ( 5.8 ) Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt Bortezomib for Injection therapy to assess reversibility. ( 5.9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib for Injection if suspected. ( 5.10 ) Embryo-Fetal Toxicity: Bortezomib for Injection can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 ) 5.1 Peripheral Neuropathy Bortezomib for Injection treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with Bortezomib for Injection. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing Bortezomib for Injection subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group [see Adverse Reactions ( 6.1 )] . Starting Bortezomib for Injection subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during Bortezomib for Injection therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration ( 2.7 )] . In the Bortezomib for Injection vs dexamethasone Phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the Phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. 5.2 Hypotension The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% [see Adverse Reactions ( 6.1 )] . These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are d…

4 CONTRAINDICATIONS Bortezomib for Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions ( 6.1 )] . Bortezomib for Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib for Injection. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. ( 7.1 ) Strong CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) 7.1 Effects of Other Drugs on Bortezomib for Injection Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology ( 12.3 )] which may decrease Bortezomib for Injection efficacy. Avoid coadministration with strong CYP3A4 inducers. Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [see Clinical Pharmacology ( 12.3 )] which may increase the risk of bortezomib toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors. 7.2 Drugs Without Clinically Significant Interactions with Bortezomib for Injection No clinically significant drug interactions have been observed when Bortezomib for Injection was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology ( 12.1 )] and findings in animals, Bortezomib for Injection can cause fetal harm when administered to a pregnant woman. There are no studies with the use of Bortezomib for Injection in pregnant women to inform drug-associated risks. Bortezomib 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. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m 2 in the rat and 0.05 mg/kg; 0.6 mg/m 2 in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m 2 ) experienced significant postimplantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Peripheral Neuropathy [see Warnings and Precautions ( 5.1 )] Hypotension [see Warnings and Precautions ( 5.2 )] Cardiac Toxicity [see Warnings and Precautions ( 5.3 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.4 )] Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.5 )] Gastrointestinal Toxicity [see Warnings and Precautions ( 5.6 )] Thrombocytopenia/Neutropenia [see Warnings and Precautions ( 5.7 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.8 )] Hepatic Toxicity [see Warnings and Precautions ( 5.9 )] Thrombotic Microangiopathy [see Warnings and Precautions ( 5.10 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avenacy at 1-855-283-6229 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma Table 9 describes safety data from 340 patients with previously untreated multiple myeloma who received Bortezomib for Injection (1.3 mg/m 2 ) administered intravenously in combination with melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) in a prospective randomized study. The safety profile of Bortezomib for Injection in combination with melphalan/prednisone is consistent with the known safety profiles of both Bortezomib for Injection and melphalan/prednisone. Table 9: Most Commonly Reported Adverse Reactions (≥10% in the Bortezomib for Injection, Melphalan and Prednisone Arm) with Grades 3 and ≥4 Intensity in the Previously Untreated Multiple Myeloma Study Bortezomib for Injection, Melphalan and Prednisone Melphalan and Prednisone (n=340) (n=337) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 * Represents High Level Term Peripheral Neuropathies NEC Blood and Lymphatic System Disorders Thrombocytopenia 164 (48) 60 (18) 57 (17) 140 (42) 48 (14) 39 (12) Neutropenia 160 (47) 101 (30) 33 (10) 143 (42) 77 (23) 42 (12) Anemia 109 (32) 41 (12) 4 (1) 156 (46) 61 (18) 18 (5) Leukopenia 108 (32) 64 (19) 8 (2) 93 (28) 53 (16) 11 (3) Lymphopenia 78 (23) 46 (14) 17 (5) 51 (15) 26 (8) 7 (2) Gastrointestinal Disorders Nausea 134 (39) 10 (3) 0 70 (21) 1 (<1) 0 Diarrhea 119 (35) 19 (6) 2 (1) 20 (6) 1 (<1) 0 Vomiting 87 (26) 13 (4) 0 41 (12) 2 (1) 0 Constipation 77 (23) 2 (1) 0 14 (4) 0 0 Abdominal pain upper 34 (10) 1 (<1) 0 20 (6) 0 0 Nervous System Disorders Peripheral neuropathy * 156 (46) 42 (12) 2 (1) 4 (1) 0 0 Neuralgia 117 (34) 27 (8) 2 (1) 1 (<1) 0 0 Paresthesia 42 (12) 6 (2) 0 4 (1) 0 0 General Disorders and Administration Site Conditions Fatigue 85 (25) 19 (6) 2 (1) 48 (14) 4 (1) 0 Asthenia 54 (16) 18 (5) 0 23 (7) 3 (1) 0 Pyrexia 53 (16) 4 (1) 0 19 (6) 1 (<1) 1 (<1) Infections and Infestations Herpes zoster 39 (11) 11 (3) 0 9 (3) 4 (1) 0 Metabolism and Nutrition Disorders Anorexia 64 (19) 6 (2) 0 19 (6) 0 0 Skin and Subcutaneous Tissue Disorders Rash 38 (11) 2 (1) 0 7 (2) 0 0 Psychiatric Disorders Insomnia 35 (10) 1 (<1) 0 21 (6) 0 0 Relapsed Multiple Myeloma Randomized Study of Bortezomib for Injection vs Dexamethasone The safety data described below and in Table 10 reflect exposure to either Bortezomib for Injection (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib for Injection was administered intravenously …