Bortezomib for Injection is a proteasome inhibitor indicated for: treatment of patients with multiple myeloma ( 1.1 ) treatment of patients with mantle cell lymphoma ( 1.2 )
1.1Multiple Myeloma Bortezomib for Injection
(bortezomib) 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.
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 )
Warnings and precautions
Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with preexisting 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 anti-hypertensives, 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. ( 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.
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( 5.6 ) Thrombocytopenia or 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. ( 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 preexisting 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 preexisting 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.
5.2Hypotension
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 mineralocorticoids and/or sympathomimetics.
5.3Cardiac Toxicity
Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Bortezomib for Injection therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction [see Adverse Reactions (6.1) ] . Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of Bortezomib for Injection vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Bortezomib for Injection and dexamethasone groups, respectively.
The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the Bortezomib for Injection group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock.
There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving Bortezomib for Injection . Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m 2 per day) by continuous infusion with daunorubicin and Bortezomib for Injection for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with Bortezomib for Injection administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib for Injection until a prompt and comprehensive diagnostic evaluation is conducted.
(PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Bortezomib for Injection . PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis.
In patients developing PRES, discontinue Bortezomib for Injection . The safety of reinitiating Bortezomib for Injection therapy in patients previously experiencing PRES is not known.
5.6 Gastrointestinal Toxicity Bortezomib for Injection treatment can cause nausea, diarrhea, constipation, and vomiting [ see Adverse Reactions (6.1) ] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib for Injection for severe symptoms.
5.7 Thrombocytopenia/Neutropenia Bortezomib for Injection is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.
Monitor complete blood counts (CBC) frequently during treatment with Bortezomib for Injection. Measure platelet counts prior to each dose of Bortezomib for Injection . Adjust dose/schedule fo
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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.
7.2Drugs 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) ].
Pregnancy and breastfeeding
8.1Pregnancy 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.
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 Medicure at 1-800-509-0544 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 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 (< 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 Represents High Level Term Peripheral Neuropathies NEC 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 versus 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 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 < 65 and ≥ 65 years of age. Most patients were Caucasian [ see Clinical Studies (14.1) ]. Among the 331 Bortezomib for Injection -treated patients, the most commonly reported (> 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 versus 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 experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone treated patients.
The most commonly reported serious adverse reactions in the Bortezomib for Injection treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each). A total of 145 patients, including 84 (25%) of 331 patients in the Bortezomib for Injection treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions.
Among the 331 Bortezomib for Injection treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each). Four deaths were considered to be Bortezomib for Injection -related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest.
Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and 1 case of sudden death at home. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib for Injection versus Dexamethasone The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥ 10% in the Bortezomib for Injection arm are included.
Table 10: Most Commonly Reported Adverse Reactions (≥ 10% in Bortezomib for Injection arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Bortezomib for Injection versus Dexamethasone (N=663) Bortezomib for Inje
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Composition
Active ingredients
BORTEZOMIB 3.5MG/VIAL
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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