bortezomib

1 INDICATIONS AND USAGE Bortezomib 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 Injection is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma Bortezomib 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 final concentration. Exercise caution when calculating the volume to be administered . (2.1 , 2.10 ) The recommended starting dose of Bortezomib 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 ) See Full Prescribing Information for preparation and administration instructions. ( 2.10 ) 2.1 Important Dosing Guidelines Bortezomib Injection is for intravenous or subcutaneous use only. Do not administer Bortezomib Injection by any other route. Because each route of administration has a different final concentration, use caution when calculating the volume to be administered. The recommended starting dose of Bortezomib Injection is 1.3 mg/m 2 . Bortezomib 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 retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib and who have relapsed at least six months after completing prior bortezomib treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6)]. When administered intravenously, administer Bortezomib Injection as a 3 to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma Bortezomib 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 Injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib Injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib Injection. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib Injection (Cycles 1 to 4) Week 1 2 3 4 5 6 Bortezomib 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 Injection (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 Bortezomib 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 Dosage Modification Guidelines for Bortezomib Injection When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with Bortezomib 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 1x 10 9 /L Non-hematological toxicities should have resolved to Grade 1 or baseline Table 2: Dosage Modifications During Cycles of Combination Bortezomib 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 × 10 9 /L or ANC is not above 0.75 x 10 9 /L on a Bortezomib Injection dosing day (other than Day 1) Withhold Bortezomib Injection dose If several Bortezomib Injection doses in consecutive cycles are withheld due to toxicity Reduce Bortezomib Injection dose by one dose level (from 1 …

3 DOSAGE FORMS AND STRENGTHS Injection: Bortezomib Injection is a clear, colorless to slightly yellow sterile solution available as: 3.5 mg/3.5 mL (1 mg/mL) in a ready-to-use single-dose vial 3.5 mg/1.4 mL (2.5 mg/mL) in a ready-to-use single-dose vial Injection 3.5 mg/3.5 mL (1 mg/mL) in a single-dose vial 3.5 mg/1.4 mL (2.5 mg/mL) in a single-dose vial

4 CONTRAINDICATIONS Bortezomib 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 Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration. ( 4 )

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 MAIA Pharmaceuticals, Inc. at 1-888-877-9064 or FDA at 1-800-FDA-1088 or www.fda.g ov/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 8 describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (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 Injection in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 9 reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m 2 twice weekly for two out of three weeks (21 day cycle). After eight 21 day cycles patients continued therapy for three 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (>20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients …

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 Injection Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may decrease Bortezomib 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 Injection toxicities. Monitor patients for signs of bortezomib toxicity and consider a Bortezomib Injection dose reduction if Bortezomib Injection must be given in combination with strong CYP3A4 inhibitors. 7.2 Drugs Without Clinically Significant Interactions with Bortezomib Injection No clinically significant drug interactions have been observed when bortezomib was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. ( 8.8 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action [ see Clinical Pharmacology (12.1) ] and findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman. There are no studies with the use of bortezomib 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 post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. 8.2 Lactation Risk Summary There are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from bortezomib is unknown, advise nursing women not to breastfeed during treatment with Bortezomib Injection and for two months after treatment. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations (8.1) ]. Pregnancy Testing Conduct pregnancy testing in females of reproductive potential prior to initiating Bortezomib Injection treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Bortezomib Injection and for seven months after the last dose. Males Males with female partners of reproductive potential should use effective contraception during treatment with Bortezomib Injection and for four months after the last dose. Infertility Based on the mechanism of action and findings in animals, bortezomib may have an effect on either male or female fertility [ see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness of Bortezomib Injection have not been established in pediatric patients. The activity and safety of bortezomib in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, nonrandomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in three blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; Block 2 included cyclophosphamide, etoposide and methotrexate; Block 3 included high-dose cytosine arabinoside and asparaginase. bortezomib was administered at a dose …

12.1 Mechanism of Action Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro . Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

11 DESCRIPTION Bortezomib Injection contains bortezomib which is a proteasome inhibitor. Bortezomib is a modified dipeptidyl boronic acid. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. Bortezomib has the following chemical structure: The molecular weight is 384.24. The molecular formula is C 19 H 25 BN 4 O 4 . The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5. Bortezomib Injection is available as a ready-to-use sterile solution for intravenous injection: Each mL of the 3.5 mg/3.5 mL (1 mg/mL) strength contains 1 mg of bortezomib, 10 mg mannitol, 0.82 mg sodium acetate, 20 mg dimethyl sulfoxide, in water for injection in a 5 mL single-dose vial. The pH may have been adjusted with hydrochloric acid or sodium hydroxide. Each mL of the 3.5 mg/1.4 mg/mL (2.5 mg/mL) strength contains 2.5 mg of bortezomib, 25 mg mannitol, 0.82 mg sodium acetate, 22 mg dimethyl sulfoxide, in water for injection in a 2 mL single-dose vial. The pH may have been adjusted with hydrochloric acid or sodium hydroxide. bortezomib-structure

10 OVERDOSAGE There is no known specific antidote for Bortezomib Injection overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given. Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m 2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m 2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour postadministration, with progression to death in 12 to 14 hours following drug administration.

16 HOW SUPPLIED/STORAGE AND HANDLING Bortezomib Injection is a clear, colorless to slightly yellow ready-to-use, sterile solution supplied as individually cartoned 5 mL vials containing 3.5 mg/3.5 mL (1 mg/mL) or 2 mL vials containing 3.5 mg/1.4 mL (2.5 mg/mL) of Bortezomib Injection. 3.5 mg/3.5 mL (1mg/mL) in a single-dose 5 mL vial NDC 70511-161-05 3.5 mg/1.4 mL (2.5 mg/mL) in a single-dose 2 mL vial NDC 70511-162-02 Store Bortezomib Injection in a refrigerator at 2o to 8°C (36° to 46°F) in the original package to protect from light. Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1 .