BORUZU Bortezomib 3.5 mg/1.4mL Injection, 1 vial
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Proteasome Inhibitor class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Bortezomib is used to treat multiple myeloma (a type of cancer of the bone marrow). Bortezomib is also used to treat mantle cell lymphoma (a fast-growing cancer that begins in the cells of the immune system). Bortezomib is in a class of medications called proteasome inhibitors. It works by killing cancer cells.
Read the full MedlinePlus article ↗- Bortezomib is a cancer treatment, but it's not a traditional chemotherapy drug. It belongs to a class called proteasome inhibitors. Instead of directly attacking DNA like older che...
- What exactly is bortezomib treating — is it a chemotherapy drug?
- Yes, bortezomib is always given by injection in a clinical setting — either into a vein (IV) or just under the skin (subcutaneous injection) — by a trained healthcare professional....
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🧪 Inactive Ingredients / Excipients
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💲 Pricing
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| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $606.26 | $606.26 / 1 vial |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J9054 | $24.747 / J9054 unit | — |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Bortezomib 3.5 mg/1.4mL 63759-3032-01 | Shilpa | 1 vial | — | — | FDA listed | — |
| Boruzu 3.5 mg/1.4mLthis 70121-2484-01 | Amneal | 1 vial | — | — | FDA listed | — |
| Bortezomib 2.5 mg 70511-0162-02 | MAIA | 1 injection | — | — | FDA listed | — |
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The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.
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📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 70121-2484-01 You're viewing this | 1 VIAL, SINGLE-DOSE in 1 CARTON (70121-2484-1) / 1.4 mL in 1 VIAL, SINGLE-DOSE | 2024-09-27 | Active |
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| NDC identity (package / product / labeler codes) | ✓ Available |
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| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
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| Inactive ingredients (structured) | — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available. |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | — Not published for this NDC Applies only to products approved under an NDA/ANDA; many listings are out of scope. |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | ✓ Available |
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE BORUZU 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 )
1.1Multiple Myeloma BORUZU is indicated for the treatment of adult patients with multiple myeloma.
1.2Mantle Cell Lymphoma BORUZU is indicated for the treatment of adult patients with mantle cell lymphoma.
⏱️ Dosage and Administration ▾
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 BORUZU 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 )
2.1Important Dosing Guidelines BORUZU is for intravenous or subcutaneous use only. Do not administer BORUZU 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 BORUZU is 1.3 mg/m 2 . BORUZU 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) ]. BORUZU retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with BORUZU and who have relapsed at least six months after completing prior BORUZU treatment.
Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6) ] . When administered intravenously, administer BORUZU as a 3 to 5 second bolus intravenous injection.
2.2Dosage in Previously Untreated Multiple Myeloma BORUZU 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, BORUZU is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, BORUZU is administered once weekly (Days 1, 8, 22 and 29).
At least 72 hours should elapse between consecutive doses of BORUZU. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly BORUZU (Cycles 1 to 4) Week 1 2 3 4 5 6 BORUZU (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 BORUZU (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 BORUZU (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
2.3Dosage Modification Guidelines for BORUZU When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with BORUZU 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: Dosage Modifications During Cycles of Combination BORUZU, 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 BORUZU dosing day (other than Day 1) Withhold BORUZU dose If several BORUZU doses in consecutive cycles are withheld due to toxicity Reduce BORUZU 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 BORUZU therapy until symptoms of toxicity have resolved to Grade 1 or baseline.
Then, BORUZU may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 t…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Injection: supplied as a sterile clear to light yellow solution available as a 3.5 mg/1.4 mL (2.5 mg/mL) in a single-dose vial. Injection: 3.5 mg/1.4 mL (2.5 mg/mL) in a single-dose vial. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS BORUZU 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) ] . BORUZU is contraindicated for intrathecal administration.
Fatal events have occurred with intrathecal administration of BORUZU. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration.
( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with pre-existing severe neuropathy should be treated with BORUZU 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 BORUZU therapy. ( 5.4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue BORUZU 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 BORUZU therapy to assess reversibility. ( 5.9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue BORUZU if suspected.
( 5.10 ) Embryo-Fetal Toxicity: BORUZU 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 )
5.1Peripheral Neuropathy Bortezomib 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. 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 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 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 therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.7) ] . In the bortezomib 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.
5.2Hypotension 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 dehydrated may be at increased risk of hypotension.
Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of min…
🤒 Adverse Reactions ▾
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 (≥ 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 (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 in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone. Table 9: Most Commonly Reported Adverse Reactions (≥ 10% in the Bortezomib, Melphalan and Prednisone Arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study Bortezomib, Melphalan and Prednisone (n=340) Melphalan and Prednisone (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 (< 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 * Represents High Level Term Peripheral Neuropathies NEC Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 10 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 cyc…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. ( 7.1 ) Strong CYP3A4 Inducers: Avoid concomitant use. ( 7.3 )
7.1Effects of Other Drugs on BORUZU Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3) ] which may decrease bortezomib 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.
7.2Drugs Without Clinically Significant Interactions with Bortezomib 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) ] .
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. ( 8.8 )
8.1Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, bortezomib 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 postimplantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.
8.2Lactation 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 and for two months after treatment.
8.3Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, bortezomib 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 treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with bortezomib and for seven months after the last dose.
Males Males with female partners of reproductive potential should use effective contraception during treatment with bortezomib 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) ].
8.4Pediatric Use Safety and effectiveness of bortezomib 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 of 1.3 mg/m 2 as a bolus intravenous injection on Days 1, 4, 8, and 11 of B…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, bortezomib 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 postimplantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness of bortezomib 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 of 1.3 mg/m 2 as a bolus intravenous injection on Days 1, 4, 8, and 11 of Block 1 and Days 1, 4, and 8 of Block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was ten years (range: 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/Alaska Native, 1% were Pacific Islander.
The activity was evaluated in a prespecified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL ≤ 21 years and relapsed < 36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib. There was no evidence that the addition of bortezomib had any impact on the CR rate.
No new safety concerns were observed when bortezomib was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without bortezomib. The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
🧓 Geriatric Use ▾
8.5Geriatric Use Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on bortezomib compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively]. On the bortezomib arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR + PR) vs 18% (n=21) on the dexamethasone arm.
The incidence of Grade 3 and 4 events was 64%, 78% and 75% for bortezomib patients ≤ 50, 51 to 64 and ≥ 65 years old, respectively [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving bortezomib; but greater sensitivity of some older individuals cannot be ruled out.
🆘 Overdosage ▾
10 OVERDOSAGE There is no known specific antidote for bortezomib 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 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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.
12.2Pharmacodynamics Following twice weekly administration of 1 mg/m 2 and 1.3 mg/m 2 bortezomib doses, the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed five minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 and 1.3 mg/m 2 doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m 2 and 1.3 mg/m 2 dose regimens, respectively.
12.3Pharmacokinetics Following intravenous administration of 1 mg/m 2 and 1.3 mg/m 2 doses, the mean maximum plasma concentrations of bortezomib (C max ) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. When administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m 2 dose and 89 to 120 ng/mL for the 1.3 mg/m 2 dose. Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m 2 dose to patients with multiple myeloma, the total systemic exposure after repeat dose administration (AUC last ) was equivalent for subcutaneous and intravenous administration.
The AUC last geometric mean ratio (90% confidence interval) was 0.99 (0.80 to 1.23). The C max after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL) with repeat dose administration. Distribution The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m 2 following single- or repeat-dose administration of 1 mg/m 2 or 1.3 mg/m 2 to patients with multiple myeloma.
The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL. Elimination The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m 2 dose and 76 to 108 hours after the 1.3 mg/m 2 dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 mg/m 2 and 1.3 mg/m 2 , respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m 2 , respectively.
Metabolism Bortezomib is primarily oxidatively metabolized to several inactive metabolites in vitro via cytochrome P450 (CYP) enzymes 3A4, CYP2C19, and CYP1A2, and to a lesser extent by CYP2D6 and CYP2C9. Excretion The pathways of elimination of bortezomib have not been characterized in humans. Specific Populations No clinically significant differences in the pharmacokinetics of bortezomib were observed based on age, sex, or renal impairment (including patients administered bortezomib after dialysis).
The effect of race on bortezomib pharmacokinetics is unknown. Patients with Hepatic Impairment Following administration of bortezomib doses ranging from 0.5 to 1.3 mg/m 2 , mild (total bilirubin ≤ 1 × ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN and any AST) hepatic impairment did not alter dose-normalized bortezomib AUC when compared to patients with normal hepatic function. Dose normalized mean bortezomib AUC increased by approximately 60% in patients with moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe (total bilirubin > 3 × ULN and any A…
🧬 Mechanism of Action ▾
12.1Mechanism 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.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING BORUZU ® (bortezomib injection) is a sterile clear to light yellow solution supplied as a carton containing one single-dose vial. BORUZU ® (bortezomib injection), 3.5 mg/1.4 mL (2.5 mg/mL); NDC 70121-2484-1 Store refrigerated at 2°C to 8°C (36°F to 46°F) in 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 .
📋 Description ▾
11 DESCRIPTION Bortezomib, a proteasome inhibitor, is an antineoplastic agent available for intravenous or subcutaneous injection. The chemical name for bortezomib {(1 R )-3-Methyl-1-[(2 S )-3-phenyl-2-(pyrazin-2-carboxamido)propanamido]butyl}boronic acid. The structural formula is as follows: The molecular formula of bortezomib is C 19 H 25 BN 4 O 4 ; it has a molecular weight of 384.24.
Bortezomib is freely soluble in methanol, ethanol and dimethyl sulfoxide, practically insoluble in toluene, pH range of 4 to 6.5. BORUZU is available as a single-dose vial containing 3.5 mg of bortezomib as a sterile solution. Each 1 mL of solution contains 2.5 mg bortezomib, 25 mg mannitol, sodium chloride for isotonicity and water for injection.
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💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Discuss the following with patients prior to treatment with BORUZU: Peripheral Neuropathy Advise patients to report the development or worsening of sensory and motor peripheral neuropathy to their healthcare provider [see Warnings and Precautions (5.1) ] . Hypotension Advise patients to drink adequate fluids to avoid dehydration and to report symptoms of hypotension to their healthcare provider [see Warnings and Precautions (5.2) ] . Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps.
Cardiac Toxicity Advise patients to report signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3) ] . Pulmonary Toxicity Advise patients to report symptoms of ARDS, pulmonary hypertension, pneumonitis, and pneumonia immediately to their healthcare provider [see Warnings and Precautions (5.4) ] . Posterior Reversible Encephalopathy Syndrome (PRES) Advise patients to seek immediate medical attention for signs or symptoms of PRES [see Warnings and Precautions (5.5) ] .
Gastrointestinal Toxicity Advise patients to report symptoms of gastrointestinal toxicity to their healthcare provider and to drink adequate fluids to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps [see Warnings and Precautions (5.6) ] . Thrombocytopenia/Neutropenia Advise patients to report signs or symptoms of bleeding or infection immediately to their healthcare provider [see Warnings and Precautions (5.7) ] .
Tumor Lysis Syndrome Advise patients of the risk of tumor lysis syndrome and to drink adequate fluids to avoid dehydration [see Warnings and Precautions (5.8) ] . Hepatic Toxicity Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.9) ] . Thrombotic Microangiopathy Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.10) ] .
Ability to Drive or Operate Machinery or Impairment of Mental Ability BORUZU may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions (5.2 , 5.5 )] . Embryo-Fetal Toxicity Advise females of the potential risk to the fetus and to use effective contraception during treatment with BORUZU and for seven months following the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BORUZU and for four months following the last dose. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within seven months following last dose [see Warnings and Precautions (5.11) ] . Lactation Advise women not to breastfeed while receiving BORUZU and for two months after last dose [see Use in Specific Populations (8.2) ] .
Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking. Diabetic Patients Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level. Dermal Advise patients to contact their physicians if they experience rash, severe injection site reactions [see Dosage and Administration (2.9) ] , or skin pain.
Discuss with patients the option for antiviral prophylaxis for herpes virus infection [see Adverse Reactions (6.1) ] . Other Instruct patients to contact their physicians if they develop an increase in blood pressure, bleeding, fever, constipation, or decreased appetite. Manufactured by: Amneal Oncology Pvt.
Ltd. Telangana 509301, INDIA Distributed by: Amneal Pharmaceuticals LLC…