BORTEZOMIB- bortexomib_injection, powder, lyophilized, for solution

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. Following twice weekly administration of 1 mg/m 2 2 2 2 2 Following intravenous administration of 1 mg/m 2 2 2 2 Distribution The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m 2 2 2 Elimination The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m 2 2 2 2 2 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. 3 mg/m 2 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.

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) Bortezomib for injection is indicated for the treatment of adult patients with multiple myeloma. Bortezomib for injection is indicated for the treatment of adult patients with mantle cell lymphoma who have received at least 1 prior therapy.

For intravenous use only ( 2. 1) The recommended starting dose of bortezomib is 1. 4 Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. 4 Hepatic Impairment:Use a lower starting dose for patients with moderate or severe hepatic impairment. 6 Dose must be individualized to prevent overdose ( 2. 8 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/m 2 [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. 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 1 to 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/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 2 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/m 2 Day 1 -- -- Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m 2 2 Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period 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 10 9 9 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 × 10 9 9 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/m 2 2 2 2 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/m 2 2 2 2 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 ) Bortezomib for injection (1. 3 mg/m 2 [see Clinical Studies ( 14. 1 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 and Precautions (5) 2 2 2 2 For dose modifications guidelines for peripheral neuropathy see section 2. 5 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 Pain and/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/m 2 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/m 2 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 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/m 2 2 2 [see Use in Specific Populations ( 8. Table 4: Recommended Starting Dose Modification for Bortezomib for injection in Patients with Hepatic Impairment Bilirubin Level SGOT (AST) Levels Modification of Starting Dose Mild Less than or equal to More than ULN None More than Any None Moderate More than Any Reduce Bortezomib for injection to 0. 7 mg/m 2 2 2 Severe More than Any Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. 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 Use proper aseptic technique. Reconstitute only with 0. 9% Sodium Chloride Injection, USP 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 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/m 2 2 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°-25°C (68°-77°F). 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.

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. 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. gov/medwatch 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 who received bortezomib (1. 3 mg/m 2 2 2 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 Melphalan and Prednisone Body System Adverse Reaction Total Toxicity Grade, n (%) 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 a 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 35 (10) 1 (< 1) 0 21 (6) 0 0 a 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/m 2 [see Clinical Studies ( 14. 1 Among the 331 bortezomib-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-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 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 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 reactions from the relapsed multiple myeloma study are shown in Table 8 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 neuropathies a 115 (35) 23 (7) 2 (< 1) 14 (4) 0 1 (< 1) Thrombocytopeni a 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 a 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/m 2 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 patient’s 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 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 neuropathies a 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 Neutropeni a 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) a 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) Peripheral Neuropathy Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and >=Grade 4 for <1% of patients. Eight percent (8%) of patients discontinued bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%). In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced >= Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3. 8 months from first onset. In the Phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced >= Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one grade or more from the last dose of bortezomib. Hypotension The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and >= Grade 4 in < 1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, < 1% of patients experienced hypotension associated with a syncopal reaction. Neutropenia Neutrophil counts decreased during the bortezomib dosing period (Days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and >= Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in <1% of patients and <1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of >=Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%). Asthenic Conditions (Fatigue, Malaise, Weakness, Asthenia) Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and >= Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and >= Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma. Pyrexia Pyrexia (>38°C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and >= Grade 4 in <1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to bortezomib discontinuation in <1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of >= Grade 3 pyrexia was 1% in patients with multiple myeloma. Herpes Virus Infection Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%). Retreatment in Relapsed Multiple Myeloma A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in Tables 8 and 9 ; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of >=Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of >=Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12. The most commonly reported serious adverse reactions were thrombocytopenia (3. 8%), diarrhea (2. 3%), and herpes zoster and pneumonia (1. Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%). Two deaths considered to be bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis. Additional Adverse Reactions from Clinical Studies The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors. Blood and Lymphatic System Disorders: Cardiac Disorders: Ear and Labyrinth Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: , Immune System Disorders: Infections and Infestations: Injury, Poisoning and Procedural Complications: Investigations: Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Renal and Urinary Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: 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: Ear and Labyrinth Disorders: Eye Disorders: Gastrointestinal Disorders: Infections and Infestations: Nervous System Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders:.

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.

Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. 8 Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12. 1) 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. 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 2 2 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 2 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. 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 use effective contraception during treatment with Bortezomib for injection and for least seven months after the last dose. Males Males with female partners of reproductive potential should use effective contraception during treatment with Bortezomib for injection and for four months after the last dose. Infertility Based on the mechanism of action and findings in animals, Bortezomib for injection may have an effect on either male or female fertility [ see Nonclinical Toxicology (13. 1) 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. 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. 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. 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 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. 5x 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. 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 antidiabetic medication.

Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. 1 Strong CYP3A4 Inducers: Avoid concomitant use. 3) Strong CYP3A4 Inducers [see Clinical Pharmacology (12. 3 Strong CYP3A4 Inhibitors [see Clinical Pharmacology (12. 3 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.

OVERDOSAGE
There is no known specific antidote for Bortezomib for injection overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given. Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m 2 2
NONCLINICAL TOXICOLOGY
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/m 2 2 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 postdose. 2 mg/m 2 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.
CLINICAL STUDIES
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 was conducted to determine whether bortezomib administered intravenously (1. 3 mg/m 2 2 2 2 2 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. 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. Table 10: Summary of Efficacy Analyses in the Previously Untreated Multiple Myeloma Study Efficacy Endpoint Bortezomib, n=344 Melphalan and Prednisone n=338 Time to Progression Events n (%) 101 (29) 152 (45) Median a 20. 7 15 (95% CI) (17. 9) Hazard ratio b 0. 54 (95% CI) (0. 70) p-value c 0. 000002 Progression-Free Survival Events n (%) 135 (39) 190 (56) Median a 18. 3 14 (95% CI) (16. 1, 15) Hazard ratio b 0. 61 (95% CI) (0. 76) p-value c 0. 00001 Response Rate CR d 102 (30) 12 (4) PR d 136 (40) 103 (30) nCR n (%) 5 (1) 0 CR + PR d 238 (69) 115 (34) p-value e <10 -10 Overall Survival at Median Follow-Up of 36. 7 Months Events (deaths) n (%) 109 (32) 148 (44) Median a Not Reached 43. 1 (95% CI) (46. 8, NR) Hazard ratio b 0. 65 (95% CI) (0. 84) p-value c 0. 00084 Note: All results are based on the analysis performed at a median follow-up duration of 16. 3 months except for the overall survival analysis a b 2 c 2 d e TTP was statistically significantly longer on the bortezomib, melphalan and prednisone arm (see Figure 1 Figure 1: Time to Progression Bortezomib, Melphalan and Prednisone vs Melphalan and Prednisone Overall survival was statistically significantly longer on the bortezomib, melphalan and prednisone arm (see Figure 2). (median follow-up 60. 1 months) Figure 2: Overall Survival Bortezomib, Melphalan and Prednisone vs Melphalan and Prednisone Randomized, Clinical Study in Relapsed Multiple Myeloma of Bortezomib vs Dexamethasone A prospective Phase 3, international, randomized (1:1), stratified, open-label clinical study (NCT00048230) enrolling 669 patients was designed to determine whether bortezomib resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade >=2 peripheral neuropathy or platelet counts <50,000/muL. A total of 627 patients were evaluable for response. Stratification factors were based on the number of lines of prior therapy the patient had previously received (one previous line vs more than one line of therapy), time of progression relative to prior treatment (progression during or within six months of stopping their most recent therapy vs relapse >6 months after receiving their most recent therapy), and screening beta 2 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 <100 g/L 32% 28% Platelet count <75 x 109/L 6% 4% Disease Characteristics Type of myeloma (%): IgG/IgA/Light chain 60% / 23% / 12% 59% / 24% / 13% Median beta 2 3. 6 Median albumin (g/L) 39 39 Creatinine clearance <=30 mL/min [n (%)] 17 (5%) 11 (3%) Median Duration of Multiple Myeloma Since Diagnosis (Years) 3. 1 Number of Prior Therapeutic Lines of Treatment Median 2 2 1 prior line 40% 35% >1 prior line 60% 65% Previous Therapy Any prior steroids, e. , dexamethasone, VAD 98% 99% Any prior anthracyclines, e. , VAD, mitoxantrone 77% 76% Any prior alkylating agents, e. , 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 + Table 12: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Study Efficacy Endpoint All Patients 1 Prior Line of Therapy > 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 147 (44) 196 (58) 55 (42) 64 (54) 92 (46) 132 (61) Median a 6. 5) Hazard ratio b 0. 72) p-value c <0. 0001 Overall Survival 51 (15) 84 (25) 12 (9) 24 (20) 39 (20) 60 (28) Hazard ratio b 0. 97) p-value c,d <0. 05 Response Rate e n=315 n=312 n=128 n=110 n=187 n=202 CR f 20 (6) 2 (<1) 8 (6) 2 (2) 12 (6) 0 (0) PR f 101 (32) 54 (17) 49 (38) 27 (25) 52 (28) 27 (13) nCR f,g 21 (7) 3 (<1) 8 (6) 2 (2) 13 (7) 1 (<1) CR + PR f 121 (38) 56 (18) 57 (45) 29 (26) 64 (34) 27 (13) p-value h <0. 0001 a b c d e f g h TTP was statistically significantly longer on the bortezomib arm (see Figure 3). Figure 3: Time to Progression Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study) As shown in Figure 4 Figure 4: Overall Survival Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study) * Patients remaining after the indicated timepoint dagger p-value from log-rank test For the 121 patients achieving a response (CR or PR) on the bortezomib arm, the median duration was 8 months (95% CI: 6. 5 months) compared to 5. 6 months (95% CI: 4. 2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the bortezomib arm regardless of beta 2 A Randomized Phase 2 Dose-Response Study in Relapsed Multiple Myeloma An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive bortezomib 1 mg/m 2 2 The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m 2 2 A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma Patients from the two Phase 2 studies, who in the investigators’ opinion would experience additional clinical benefit continued to receive bortezomib beyond 8 cycles on an extension study. Sixty-three (63) patients from the Phase 2 multiple myeloma studies were enrolled and received a median of seven additional cycles of bortezomib therapy for a total median of 14 cycles (range 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard three-week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. [see Adverse Reactions ( 6. 1 A Single-Arm Trial of Retreatment in Relapsed Multiple Myeloma A single arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with bortezomib. One hundred and thirty patients (>=18 years of age) with multiple myeloma who previously had at least partial response on a bortezomib -containing regimen (median of two prior lines of therapy [range 1 to 7]) were retreated upon progression with bortezomib administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade >=2. At least six months after prior bortezomib therapy, bortezomib was restarted at the last tolerated dose of 1. 3 mg/m 2 2 The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38. 5% (95% CI: 30. One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6. 5 months and the range was 0. 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/m 2 [see Dosage and Administratio ( 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. 8) CR + CRu (N = 12) 15. 4 months (13. 4) PR (N=36) 6. 1 months (4.
REFERENCES
“OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

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