4 CONTRAINDICATIONS Bortezomib for injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib or boron. 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 products. Patients with hypersensitivity (not including local reactions) to bortezomib or boron including anaphylactic reactions. (4) Contraindicated for intrathecal administration. (4)
INDICATIONS & USAGE SECTION.
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 who have received at least 1 prior therapy (1.2) 1.1 Multiple Myeloma Bortezomib for injectionis 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 who have received at least 1 prior therapy.
DOSAGE & ADMINISTRATION SECTION.
2 DOSAGE AND ADMINISTRATION For intravenous use only (2.1) The recommended startingdose of bortezomib is 1.3 mg/m2 administered as a 3 to 5 second bolus intravenous injection (2.2, 2.4) Retreatment for multiple myeloma: May retreat starting at the last tolerated dose. (2.4) Hepatic Impairment:Use a lower starting dose for patients with moderate or severe hepatic impairment. (2.6) Dose must be individualized to prevent overdose (2.8) 2.1 Important Dosing Guidelines Bortezomib for injection is for intravenous use only. Do not administer Bortezomib for injection by any other route. The recommended starting dose of Bortezomib for injection is 1.3 mg/m2. Bortezomib for injection is administered intravenously at a concentration of 1 mg/mL [see Dosage and Administration (2.8)]. Bortezomib for injection 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 (2.4)]. Administer Bortezomib for injection as a 3 to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma Bortezomib for injection is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1. In Cycles 1to 4, Bortezomib for injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib for injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib for injection. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib for injection (Cycles 1 to 4) Week 1 2 3 4 5 6 Bortezomib for injection (1.3 mg/m2) Day 1 -- -- Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan(9 mg/m2) Prednisone(60 mg/m2) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period Once Weekly Bortezomib for injection (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 Bortezomib for injection (1.3 mg/m2) Day 1 -- -- Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m2) Prednisone (60 mg/m2) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period 2.3 Dose Modification Guidelines for Bortezomib for injection When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with Bortezomib for injection in combination with melphalan and prednisone: Platelet count should be at least 70 x 109/L and the absolute neutrophil count (ANC) should be at least 1 x 109/L Nonhematological toxicities should have resolved to Grade 1 or baseline Table 2:Dose Modifications During Cycles of Combination Bortezomib for injection, Melphalan and Prednisone Therapy Toxicity Dose modification or delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle. If platelet count is not above 30 109/L or ANC is not above 0.75 x 109/L on a Bortezomib for injection dosing day (other than Day 1) Withhold Bortezomib for injection dose If several Bortezomib for injection doses in consecutive cycles are withheld due to toxicity Reduce Bortezomib for injection dose by 1 dose level(from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) Grade 3 or higher nonhematological toxicities Withhold Bortezomib for injection therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Bortezomib for injection may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2to 0.7 mg/m2). For Bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib for injection as outlined in Table 5. For information concerning melphalan and prednisone, see manufacturer's prescribing information. Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.5 ) ]. 2.4 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Bortezomib for injection (1.3 mg/m2/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a tenday rest period (Days 12to 21). For extended therapy of more thaneight cycles, Bortezomib for injection may be administered on the standard schedule or for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) [see Clinical Studies (14.1)]. At least 72 hours should elapse between consecutive doses of bortezomib. Patients with multiple myeloma who have previously responded to treatment with bortezomib (either alone or in combination) and who have relapsed at least six months after their prior bortezomib therapy may be started on bortezomib at the last tolerated dose. Retreated patients are administered Bortezomib for injection twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of bortezomib. Bortezomib for injection may be administered either as a single agent or in combination with dexamethasone [see Clinical Studies (14.1)]. Bortezomib for injection therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings andPrecautions (5)]. Once the symptoms of the toxicity have resolved, Bortezomib for injection therapy may bereinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dosereduced to 0.7 mg/m2/dose). For dose modifications guidelines for peripheral neuropathy see section 2.5. 2.5 Dose Modifications for Peripheral Neuropathy Patients with preexisting severe neuropathy should be treated with Bortezomib for injection only after careful risk-benefit assessment. 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. For dose or schedule modification guidelines for patients who experience Bortezomib for injection-related neuropathic pain and/or peripheral neuropathy see Table 3. Table 3: Recommended Dose Modification for Bortezomib related Neuropathic Painand/or Peripheral Sensory or Motor Neuropathy Severity of Peripheral Neuropathy Signs and Symptoms* Modification of Dose and Regimen Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function No action Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**) Reduce Bortezomib for injection to 1 mg/m2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL ***) Withhold Bortezomib for injection therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of Bortezomib for injection at 0.7 mg/m2once per week. Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue Bortezomib for injection *Grading based on NCI Common Terminology Criteria CTCAE v4 **Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc; ***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 2.6 Dosage in Patients with Hepatic Impairment Do not adjust the starting dose for patients with mild hepatic impairment. Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m2per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2based on patient tolerance (see Table 4) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3 ) ]. Table 4: Recommended Starting Dose Modification for Bortezomib for injection in Patients withHepatic Impairment Bilirubin Level SGOT (AST) Levels Modification of Starting Dose Mild Less than or equal to 1x ULN More than ULN None More than 1x1.5 x ULN Any None Moderate More than 1.5 x3x ULN Any Reduce Bortezomib for injection to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. Severe More than 3x ULN Any Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. 2.7 Administration Precautions The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.8)]. Bortezomib for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 2.8 Reconstitution/Preparation for Intravenous Administration Use proper aseptic technique. Reconstitute only with 0.9% Sodium Chloride Injection, USP. The reconstituted product should be a clear and colorless solution. For each 3.5 mg single-dose vial of Bortezomib for injection reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP (Table: 5) Table 5: Reconstitution Volumes and Final Concentration for Intravenous Administration Route of Administration Bortezomib (mg/vial) Diluent (0.9% Sodium Chloride Injection, USP) Final Bortezomib Concentration (mg/mL) Intravenous 3.5 mg 3.5 mL 1 mg/mL Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezomib for injection to be administered: Intravenous Administration [1 mg/mL concentration] Bortezomib for injection dose (mg/m2) x patient BSA(m2)= Total Bortezomib for injection (mL) to be administered 1 mg/mL A sticker that indicates the route of administration is provided with each Bortezomib for injection vial. Place this sticker directly on the syringe of Bortezomib for injection once it is prepared to help alert practitioners of the correct route of administration for Bortezomib for injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used. Stability Unopened vials of Bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light. Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted Bortezomib for injection within 8 hours of preparation. When reconstituted as directed, Bortezomib for injection may be stored at 20-25C (68-77F). The reconstituted material should be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.
HOW SUPPLIED SECTION.
16 HOW SUPPLIED/STORAGE AND HANDLING 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. 3.5 mg single-dose vial NDC 43598-865-60 Store at 20-25C (68-77F).Retain in original package to protect from light. Follow guidelines for handling and disposal for cytotoxicdrugs, including the use of gloves and other protective clothing to prevent skin contact1.
DOSAGE FORMS & STRENGTHS SECTION.
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 powderfor reconstitution andwithdrawal of theappropriate individual patient dose [see Dosage and Administration (2.8)]. For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose. (3)
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
ADVERSE REACTIONS SECTION.
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 Dr.Reddy's Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Safety 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 7 describes safety data from 340 patients with previously untreated multiple myeloma whoreceived bortezomib (1.3 mg/m2) administered intravenouslyin combination with melphalan (9 mg/m2) and prednisone(60 mg/m2) 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 and melphalan/prednisone. Table 7-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 Adverse Reaction Total n(%) Toxicity Grade, n (%) 3 Total 4 Toxicity Grade,n (%) 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 Neuropathya 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 a Represents High Level Term Peripheral Neuropathies NEC Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 8 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/m2twice 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 from the bortezomib 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 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 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 treated patients, the most commonly reported adverse reactionleading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactionsleading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each). Four deaths were considered to be bortezomib 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 one case of sudden death at home. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone The most common adverse reactionsfrom the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence 10% in the bortezomib arm are included. Table 8: Most Commonly Reported Adverse Reactions ( 10% in Bortezomib arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone (N=663) Adverse Reactions All Grade 3 Grade 4 All Grade 3 Grade 4 Any Adverse Reactions 324 (98) 193 (58) 28 (8) 297 (89) 110 (33) 29 (9) Nausea 172 (52) 8 (2) 0 31 (9) 0 0 Diarrhea NOS 171 (52) 22 (7) 0 36 (11) 2 (< 1) 0 Fatigue 130 (39) 15 (5) 0 82 (25) 8 (2) 0 Peripheral neuropathiesa 115 (35) 23 (7) 2 (< 1) 14 (4) 0 1 (< 1) Thrombocytopenia 109 (33) 80 (24) 12 (4) 11 (3) 5 (2) 1 (< 1) Constipation 99 (30) 6 (2) 0 27 (8) 1 (< 1) 0 Vomiting NOS 96 (29) 8 (2) 0 10 (3) 1 (< 1) 0 Anorexia 68 (21) 8 (2) 0 8 (2) 1 (< 1) 0 Pyrexia 66 (20) 2 (< 1) 0 21 (6) 3 (< 1) 1 (< 1) Paresthesia 64 (19) 5 (2) 0 24 (7) 0 0 Anemia NOS 63 (19) 20 (6) 1 (< 1) 21 (6) 8 (2) 0 Headache NOS 62 (19) 3 (< 1) 0 23 (7) 1 (< 1) 0 Neutropenia 58 (18) 37 (11) 8 (2) 1 (< 1) 1 (< 1) 0 Rash NOS 43 (13) 3 (< 1) 0 7 (2) 0 0 Appetite decreased NOS 36 (11) 0 0 12 (4) 0 0 Dyspnea NOS 35 (11) 11 (3) 1 (< 1) 37 (11) 7 (2) 1 (< 1) Abdominal pain NOS 35 (11) 5 (2) 0 7 (2) 0 0 Weakness 34 (10) 10 (3) 0 28 (8) 8 (2) 0 aRepresents High Level Term Peripheral Neuropathies NEC Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study [see Clinical Studies (14.1)] . Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma) Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m2/dose twice weekly for two weeks followed by a ten-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). In the Phase 2 relapsed multiple myeloma clinical trials of bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each). Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each). In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis. Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety The most common adverse reactions are shown in Table 9. All adverse reactions occurring at 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patients underlying disease. Please see the discussion of specific adverse reactions that follows. Table 9: Most Commonly Reported ( 10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies using the 1.3 mg/m 2 Dose (N=1163) All Patients Multiple Myeloma N=1163 N=1008 Multiple Myeloma N=1008 Mantle Cell Lymphoma N=155 All Grade All Grade All Grade Adverse Reactions 3 3 3 Nausea 567 (49) 36 (3) 511 (51) 32 (3) 56 (36) 4 (3) Diarrhea NOS 530 (46) 83 (7) 470 (47) 72 (7) 60 (39) 11 (7) Fatigue 477 (41) 86 (7) 396 (39) 71 (7) 81 (52) 15 (10) Peripheral neuropathiesa 443 (38) 129 (11) 359 (36) 110 (11) 84 (54) 19 (12) Thrombocytopenia 369 (32) 295 (25) 344 (34) 283 (28) 25 (16) 12 (8) Vomiting NOS 321 (28) 44 (4) 286 (28) 40 (4) 35 (23) 4 (3) Constipation 296 (25) 17 (1) 244 (24) 14 (1) 52 (34) 3 (2) Pyrexia 249 (21) 16 (1) 233 (23) 15 (1) 16 (10) 1 (< 1) Anorexia 227 (20) 19 (2) 205 (20) 16 (2) 22 (14) 3 (2) Anemia NOS 209 (18) 65 (6) 190 (19) 63 (6) 19 (12) 2 (1) Headache NOS 175 (15) 8 (< 1) 160 (16) 8 (< 1) 15 (10) 0 Neutropenia 172 (15) 121 (10) 164 (16) 117 (12) 8 (5) 4 (3) Rash NOS 156 (13) 8 (< 1) 120 (12) 4 (< 1) 36 (23) 4 (3) Paresthesia 147 (13) 9 (< 1) 136 (13) 8 (< 1) 11 (7) 1 (< 1) Dizziness (excl vertigo) 129 (11) 13 (1) 101 (10) 9 (< 1) 28 (18) 4 (3) Weakness 124 (11) 31 (3) 106 (11) 28 (3) 18 (12) 3 (2) aRepresents High Level Term Peripheral Neuropathies NEC Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies Gastrointestinal Toxicity A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; Grade 4 adverse reactions were 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%). Thrombocytopenia Across the studies, bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (Days 1 to 11) and a return toward baseline during the ten-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients [see Warnings and Precautions (5.7)]. Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%). Peripheral Neuropathy Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and Grade 4 for 38C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and Grade 4 in 6.2 Postmarketing Experience The following adverse reactions have been identified from the worldwide postmarketing experience with bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Cardiac Disorders: Cardiac tamponade Ear and Labyrinth Disorders: Deafness bilateral Eye Disorders: Optic neuropathy, blindness, chalazion/blepharitis Gastrointestinal Disorders: Ischemic colitis Infections and Infestations: Progressive multifocalleukoencephalopathy (PML), ophthalmic herpes, herpesmeningoencephalitis Nervous System Disorders: Posterior reversibleencephalopathy syndrome (PRES, formerly RPLS) Respiratory, Thoracic and Mediastinal Disorders: Acutediffuse infiltrative pulmonary disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnsonsyndrome/toxic epidermal necrolysis (SJS/TEN), acutefebrile neutrophilic dermatosis (Sweets syndrome)
11 DESCRIPTION Bortezomib for injection contains bortezomib which is an antineoplastic agent. Bortezomib is a modified dipeptidyl boronic acid. The chemical name is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid.The molecular formula is C19H25BN4O4. The molecular weight is 384.24. Bortezomib has the following molecular structure: The solubility of bortezomib, as the monomeric boronic acid, in water is 0.8 to 0.9 mg/mL in a pH range of 2 to 6.5. Bortezomib for injection is available for intravenous injection use. Each single-dose vial contains 3.5 mg of bortezomib as a sterile lyophilized cake or powder. The inactive ingredients are citric acid, USP 10 mg and tromethamine, USP 8.4 mg. The product is provided as a citric acid boronic ester which, in reconstituted form, consists of the citric acid ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
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 patients 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/m2basis 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/m2and 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.
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. (2.5) Patients with preexisting severe neuropathy should be treated with Bortezomib for injection only after careful risk- benefit assessment. (2.5, 5.1) Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. (5.2) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. (5.3) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting Bortezomib for injection. (5.4) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for injection if suspected. (5.5). Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (5.6) Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. (5.7) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden (5.8). Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt Bortezomib for injection therapy to assess reversibility (5.9). Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib for injection if suspected. (5.10) Embryo-fetal Toxicity: Bortezomib can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy (5.11). 5.1 Peripheral 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 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 incidence of Grade 2 peripheral neuropathy 39% for intravenous. Grade 3 peripheral neuropathy occurred in 15% in the intravenous treatment group. 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 (2.5)]. In the bortezomib versus 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 [see Adverse Reactions (6.1)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. 5.2 Hypotension The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. 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[see Adverse Reactions (6.1)]. 5.3 Cardiac Toxicity Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of bortezomib versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib 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 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. 5.4 Pulmonary Toxicity Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving bortezomib. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with bortezomib 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. 5.5 Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. 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. The safety of reinitiating Bortezomib for injection therapy in patients previously experiencing PRES is not known. 5.6 Gastrointestinal Toxicity Bortezomib 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 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 for thrombocytopenia [see Tables 2 and 4, Dosage and Administration (2.4)]. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines. In the single-agent, relapsed multiple myeloma study of bortezomib versus dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6.The incidence of bleeding ( Grade 3) was 2% on the bortezomib arm and was < 1% in the dexamethasone arm. Table 6: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib versus Dexamethasone Pretreatment Platelet Count* Number of Patients (N=331)** Number (%) of Patients with Platelet Count 5.8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. 5.9 Hepatic Toxicity Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezomib for injection therapy to assess reversibility. There is limited re-challenge information in these patients. 5.10 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received bortezomib. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib for injection and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Bortezomib for injection. The safety of reinitiating Bortezomib for injection therapy in patients previously experiencing TTP/HUS is not known. 5.11 Embryo-fetal Toxicity Based on the mechanism of action and findings in animals, bortezomib can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2based on body surface area caused postimplantation loss and a decreased number of live fetuses [see Use in Specific Populations (8.1)]. Females of reproductive potential should avoid becoming pregnant while being treated with Bortezomib for injection. Advise females of reproductive potential that they must use contraception during treatment with Bortezomib for injection and for seven months following treatment. Advise males with female sexual partners of reproductive potential that they must use contraception during treatment with Bortezomib for injection and for four months following treatment. If Bortezomib for injection is used during pregnancy or if the patient becomes pregnant during Bortezomib for injection treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
DRUG INTERACTIONS SECTION.
7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. (7.1) Strong CYP3A4 Inducers: Avoid concomitant use. (7.3) 7.1 Effect of Other Drugs on Bortezomib Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may decrease Bortezomib for injection efficacy. Avoid coadministration with strong CYP3A4 inducers. Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may increase the risk of bortezomib toxicities. Monitor patients for signs of bortezomib toxicity and consider a Bortezomib for injection dose reduction if Bortezomib for injection must be given in combination with strong CYP3A4 inhibitors. 7.2 Drugs 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)].
NONCLINICAL TOXICOLOGY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with bortezomib.Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the six-month rat toxicity study, degenerative effects in the ovary were observed at doses 0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. 13.2 Animal Toxicology and/or Pharmacology Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses 1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed. Chronic Administration: In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for two weeks followed by one-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
USE IN SPECIFIC POPULATIONS SECTION.
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 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/m2in the rat and 0.05 mg/kg; 0.6 mg/m2 in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m2based 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/m2 based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m2) 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 breastfed child from bortezomib 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, with 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 for injection treatment. Contraception Females Advise females of reproductive potential to avoid pregnancy and use effective contraception during treatment with Bortezomib for injection and for at least seven months after the last dose. Males Males with female sexual partners of reproductive potential should use effective contraception during treatment with Bortezomib for injection and for at least 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 Additional information describing a clinical study in which efficacy was not demonstrated in pediatric patients is in the approved label for Millennium Pharmaceuticals, Inc.'s VELCADE (bortezomib) Injection. However, due to Millennium Pharmaceuticals, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric 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 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. 8.6 Renal Impairment No starting dosage adjustment of Bortezomib for injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib for injection should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No starting dosage adjustment of Bortezomib for injection is recommended for patients with mild hepatic impairment (total bilirubin 1x ULN and AST > ULN, or total bilirubin >1 to 1.5 x ULN and any AST). The exposure of bortezomib is increased in patients with moderate (total bilirubin 1.5 to 3x ULN and any AST) and severe (total bilirubin >3x ULN and any AST) hepatic impairment. Reduce the starting dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.6), Clinical Pharmacology ( 12.3) ]. 8.8 Patients with Diabetes During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib for injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.
15 REFERENCES OSHA Hazardous Drugs (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION Discuss the following with patients prior to treatment with Bortezomib for injection: 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 Bortezomib 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 avoid pregnancy and use effective contraception during treatment with Bortezomib for injection and for seven months following the final dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Bortezomib for injection 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 patients to avoid breastfeeding while receiving Bortezomib for injection 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 (2.7)], 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: Dr. Reddys Laboratories Limited Visakhapatnam 530 046- INDIA
CLINICAL STUDIES SECTION.
14 CLINICAL STUDIES 14.1 Multiple Myeloma Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma: A prospective, international, randomized (1:1), open-label clinical study (NCT00111319) of 682 patients wasconducted to determine whether bortezomib administered intravenously (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of nine cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the bortezomib study arm. The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500/microliter (33,000;587,000). Efficacy results for the trial are presented in Table 10. At a prespecified interim analysis (with median follow-up of 16.3 months), the combination of bortezomib, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered bortezomib in addition. A later, prespecified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the bortezomib, melphalan and prednisone treatment arm despite subsequent therapies including bortezomib based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the bortezomib, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85). Table 10: Summary of Efficacy Analyses in the Previously Untreated Multiple Myeloma Study Efficacy Endpoint Bortezomib, Melphalan and Prednisone n=344 Melphalan and Prednisone n=338 Time to Progression Events n (%) 101 (29) 152 (45) Mediana (months) 20.7 15 (95% CI) (17.6, 24.7) (14.1, 17.9) Hazard ratiob 0.54 (95% CI) (0.42, 0.70) p-value c 0.000002 Progression-free Survival Events n (%) 135 (39) 190 (56) Mediana (months) 18.3 14 (95% CI) (16.6, 21.7) (11.1, 15) Hazard ratiob 0.61 (95% CI) (0.49, 0.76) p-value c 0.00001 Response Rate CRd n (%) 102 (30) 12 (4) PRd n (%) 136 (40) 103 (30) nCR n (%) 5 (1) 0 CR + PRd n (%) 238 (69) 115 (34) p-valuee 6 months after receiving their most recent therapy), and screening beta2-microglobulin levels (2.5 mg/L vs >2.5 mg/L). Baseline patient and disease characteristics are summarized in Table 11. Table 11: Summary of Baseline Patient and Disease Characteristics in the Relapsed Multiple Myeloma Study Patient Characteristics Bortezomib N=333 Dexamethasone N=336 Median age in years (range) 62 (33, 84) 61 (27, 86) Gender: Male/female 56% / 44% 60% / 40% Race: Caucasian/black/other 90% / 6% / 4% 88% / 7% / 5% Karnofsky performance status score 70 13% 17% Hemoglobin 1 prior line 60% 65% Previous Therapy Any prior steroids, e.g., dexamethasone, VAD 98% 99% Any prior anthracyclines, e.g., VAD, mitoxantrone 77% 76% Any prior alkylating agents, e.g., MP, VBMCP 91% 92% Any prior thalidomide therapy 48% 50% Vinca alkaloids 74% 72% Prior stem cell transplant/other high-dose therapy 67% 68% Prior experimental or other types of therapy 3% 2% Patients in the bortezomib treatment group were to receive 8 three-week treatment cycles followed by 3 five week treatment cycles of bortezomib. Patients achieving a CR were treated for four cycles beyond first evidence of CR. Within each three-week treatment cycle, bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten-day rest period (Days 12 to 21). Within each five-week treatment cycle, bortezomib 1.3 mg/m2/dose alone was administered by intravenous bolus once weekly for four weeks on Days 1, 8, 15, and 22 followed by a 13day rest period (Days 23 to 35) [see Dosage and Administration (2.2)]. Patients in the dexamethasone treatment group were to receive 4 five-week treatment cycles followed by 5 four week treatment cycles. Within each five-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15-day rest period (Days 21 to 35). Within each four week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24-day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered bortezomib at a standard dose and schedule on a companion study.Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered bortezomib, regardless of disease status. In the bortezomib arm, 34% of patients received at least one bortezomib dose in all eight of the three week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of bortezomib doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all four of the five-week treatment cycles of therapy, and 6% received at least one dose in all nine cycles. The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 12. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria.Complete response (CR) required 1 Prior Line of Therapy Bortezomib Dex Bortezomib Dex Bortezomib Dex n=333 n=336 n=132 n=119 n=200 n=217 Time to Progression Events n (%) 147 (44) 196 (58) 55 (42) 64 (54) 92 (46) 132 (61) Median a (95% CI) 6.2 mo(4.9, 6.9) 3.5 mo(2.9, 4.2) 7 mo(6.2, 8.8) 5.6 mo(3.4, 6.3) 4.9 mo(4.2, 6.3) 2.9 mo(2.8, 3.5) Hazard ratio b (95% CI) 0.55(0.44, 0.69) 0.55(0.38, 0.81) 0.54(0.41, 0.72) p-value c 14.2 Mantle Cell Lymphoma A Phase 2 Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior Therapy The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study (NCT00063713)of 155 patients with progressive disease who had received at least one prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were Stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of bortezomib 1.3 mg/m2/dose was administered twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles.Patients achieving a CR or CRu were treated for four cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see Dosage and Administration ( 2.4, 2.5 )]. Responses to bortezomib are shown in Table 13. Response rates to bortezomib were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was four; in responding patients the median number of cycles was eight.The median time to response was 40 days (range 31 to 204 days). The median duration of follow-up was more than 13 months. Table 13: Response Outcomes in a Phase 2 Relapsed Mantle Cell Lymphoma Study Response Analyses (N = 155) N (%) 95% CI Overall Response Rate (IWRC) (CR + CRu + PR) 48 (31) (24, 39) Complete Response (CR + CRu) 12 (8) (4, 13) CR 10 (6) (3, 12) CRu 2 (1) (0, 5) Partial Response (PR) 36 (23) (17, 31) Duration of Response Median 95% CI CR + CRu + PR (N = 48) 9.3 months (5.4, 13.8) CR + CRu (N = 12) 15.4 months (13.4, 15.4) PR (N=36) 6.1 months (4.2, 9.3)
CLINICAL PHARMACOLOGY SECTION.
12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Following twice weekly administration of 1 mg/m2 and 1.3 mg/m2 bortezomib doses (n=12 per each dose level), 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/m2 doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 dose regimens, respectively. 12.3 Pharmacokinetics Following intravenous administration of 1 mg/m2and 1.3 mg/m2doses, the mean maximum plasma concentrations of bortezomib (Cmax) 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/m2dose and 89 to 120 ng/mL for the 1.3 mg/m2dose. Distribution The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single- or repeat-dose administration of 1 mg/m2 or 1.3 mg/m2 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/m2dose and 76 to 108 hours after the 1.3 mg/m2dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 mg/m2and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, 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/m2, mild (total bilirubin 1x ULN and AST > ULN, or total bilirubin >1 to 1.5 x 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 3x ULN and any AST) or severe (total bilirubin >3x ULN and any AST) hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment. Drug Interaction Studies Clinical Studies No clinically significant differences in bortezomib pharmacokinetics were observed when coadministered with dexamethasone (weak CYP3A4 inducer), omeprazole (strong CYP2C19 inhibitor), or melphalan in combination with prednisone. Strong CYP3A4 inhibitor Coadministration with ketoconazole (strong CYP3A4 inhibitor) increased bortezomib exposure by 35%. Strong CYP3A4 inducer Coadministration with rifampin (strong CYP3A4 inducer) decreased bortezomib exposure by approximately 45%. In Vitro Studies Bortezomib may inhibit CYP2C19 activity and increase exposure to drugs that are substrates for this enzyme.