Bortezomib

Indications and Usage, Mantle Cell Lymphoma ( 1.2 ), Removed phrase “who have received at least 1 prior therapy” 12/2022 Dosage and Administration ( 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 , 2.10 ) 12/2022 Warnings and Precautions, Thrombocytopenia/Neutropenia ( 5.7 ) 12/2022

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 , 3.5 mg/vial 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 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 is for intravenous or subcutaneous use only. Do not administer bortezomib 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 is 1.3 mg/m 2 . Bortezomib 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 as a 3 to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma Bortezomib 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 is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, bortezomib is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of bortezomib. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib (Cycles 1 to 4) Week 1 2 3 4 5 6 Bortezomib (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 (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 Bortezomib (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 When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with bortezomib 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, 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 dosing day (other than Day 1) Withhold bortezomib dose If several bortezomib doses in consecutive cycles are withheld due to toxicity Reduce bortezomib dose by one dose level (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ) Grade 3 or higher nonhematological toxicities Withhold bortezomib therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg …

3 DOSAGE FORMS AND STRENGTHS For injection: Each single-dose vial of bortezomib for injection contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white cake or powder for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration ( 2.10) ] . For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized white to off-white cake or powder for reconstitution and withdrawal of the appropriate individual patient dose. ( 3 )

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 )

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 Hainan Shuangcheng Pharmaceuticals Co., Ltd. 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 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 (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 for Injection-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 for Injection 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 from the Bortezomib for Injection treatment arm experie …

7 DRUG INTERACTIONS Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration with strong CYP3A4 inhibitors can increase Bortezomib for Injection exposure. Closely monitor patients receiving Bortezomib for Injection in combination with strong CYP3A4 inhibitors. ( 7.1 ) Co-administration with strong CYP3A4 inducers can decrease Bortezomib for Injection exposure. Avoid concomitant use of strong CYP3A4 inducers. ( 7.3 ) 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 for Injection 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 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 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 Error! Hyperlink reference not valid. ) . 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. 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 for Injection is unknown, advise nursing women not to breastfeed during treatment with Bortezomib for 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 for 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 for Injection treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Bortezomib for 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 for Injection and for four months after the last dose. Infertility Based on the mechanism of action and findings in animals, Bortezomib for Injection may have an effect on either male or female fertility [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. The activity and safety of Bortezomib for Injection 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 h …

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 for injection, 3.5 mg/vial a proteasome inhibitor, contains bortezomib which is an antineoplastic agent. Bortezomib is a modified dipeptidylboronic 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 for injection, 3.5 mg/vial is available for intravenous injection or subcutaneous use. Each single-dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. It also contains the inactive ingredient: 35 mg mannitol, USP. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine. Bortezomib Chemical Structure

10 OVERDOSAGE There is no known specific antidote for Bortezomib for 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 for Injection is supplied as follows: NDC Bortezomib for Injection Package Factor 83634-208-10 3.5 mg Single-Dose Vial 1 vial per carton Bortezomib for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder. Storage Conditions Unopened vials may be stored at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Protect from light. Retain in carton until time of use. Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1 . Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.