BORTEZOMIB- bortezomib_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 in vivo Following twice weekly administration of 1 mg/m 2 2 2 2 2 Following intravenous administration of 1 mg/m 2 2 max 2 2 Following an intravenous bolus or subcutaneous injection of a 1. 3 mg/m 2 last last max 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 for injection 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 ( 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.

For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. 10 The recommended starting dose of bortezomib for injection is 1. 6 Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. 6 Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. 8 Dose must be individualized to prevent overdose. 10 Bortezomib for injection is for intravenous or subcutaneous use only. Do not administer bortezomib for injection by any other route. Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered. The recommended starting dose of bortezomib for injection is 1. 3 mg/m 2 [see Dosage and Administration ( 2. Bortezomib for injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib for injection and who have relapsed at least six months after completing prior bortezomib for injection treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration ( 2. 6 )] When administered intravenously, 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 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 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 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 x 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 one 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 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. 7 )] Bortezomib for injection (1. 3 mg/m 2 Table 3 Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly Bortezomib for Injection (6, Three Week Cycles) * Week 1 2 3 Bortezomib for injection (1. 3 mg/m 2 Day 1 -- -- Day 4 -- Day 8 Day 11 rest period Rituximab (375 mg/m 2 2 2 Day 1 -- -- -- -- rest period Prednisone (100 mg/m 2 Day 1 Day 2 Day 3 Day 4 Day 5 -- -- rest period * Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6. Prior to the first day of each cycle (other than Cycle 1): Platelet count should be at least 100 x 10 9 9 Hemoglobin should be at least 8 g/dL (at least 4. 96 mmol/L) Nonhematologic toxicity should have recovered to Grade 1 or baseline Interrupt bortezomib for injection treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy [see Table 5, Warnings and Precautions ( 5 Table 4 Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination Bortezomib for Injection, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy Toxicity Dose Modification or Delay Hematological Toxicity Grade 3 or higher neutropenia, or a platelet count not at or above 25 x 10 9 Withhold bortezomib for injection therapy for up to 2 weeks until the patient has an ANC at or above 0. 75 x 10 9 9 If, after bortezomib for injection has been withheld, the toxicity does not resolve, discontinue bortezomib for injection. If toxicity resolves such that the patient has an ANC at or above 0. 75 x 10 9 9 2 2 2 2 Grade 3 or higher nonhematological toxicities Withhold bortezomib for injection therapy until symptoms of the toxicity have resolved to Grade 2 or better. 3 mg/m 2 2 2 2 Table 5 For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information. Bortezomib for injection (1. 3 mg/m 2 [see Clinical Studies ( 14 )] Patients with multiple myeloma who have previously responded to treatment with bortezomib for injection (either alone or in combination) and who have relapsed at least six months after their prior bortezomib for injection therapy may be started on bortezomib for injection 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 for injection. 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. 7 Starting bortezomib for injection subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing 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 5. Table 5: Recommended Dose Modification for Bortezomib for Injection-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) dagger Reduce bortezomib for injection to 1 mg/m 2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL double dagger 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. 0 dagger double dagger 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 Table 6) [see Use in Specific Populations ( 8. 7 ), Clinical Pharmacology ( 12. Table 6: 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 1x ULN More than ULN None More than 1x to 1. 5x ULN Any None Moderate More than 1. 5x to 3x ULN Any Reduce bortezomib for injection to 0. 7 mg/m 2 2 2 Severe More than 3x ULN 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. 10 )] When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. If local injection site reactions occur following bortezomib for injection administration subcutaneously, a less concentrated bortezomib for injection solution (1 mg/mL instead of 2. 5 mg/mL) may be administered subcutaneously [see Dosage and Administration ( 2. 10 )] [see Dosage and Administration ( 2. 10 )] Bortezomib for injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Use proper aseptic technique. Reconstitute only with 0. 9% sodium chloride Different volumes of 0. 9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2. 5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered [see Dosage and Administration ( 2. 9 )] For each 3. 5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0. 9% sodium chloride based on route of administration (Table 7) Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration Route of Administration Bortezomib Diluent Final Bortezomib Concentration Intravenous 3. 5 mL 1 mg/mL Subcutaneous 3. 5 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 =Total bortezomib for injection volume (mL) to be administered 1 mg/mL Subcutaneous Administration [2. 5 mg/mL concentration] Bortezomib for Injection dose (mg/m 2 2 =Total bortezomib for injection volume (mL) to be administered 2. 5 mg/mL Stickers that indicate the route of administration are provided with each bortezomib for injection vial. These stickers should be placed directly on the syringe of bortezomib for injection once bortezomib for injection 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 eight hours of preparation. When reconstituted as directed, bortezomib for injection may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. The reconstituted material may 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 NorthStar RxLLC at 1-800-206-7821 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 9 2 2 2 The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone. Table 9: Most Commonly Reported Adverse Reactions (>=10% in the Bortezomib, Melphalan and Prednisone Arm) with Grades 3 and >=4 Intensity in the Previously Untreated Multiple Myeloma Study Bortezomib, Melphalan and Prednisone Melphalan and Prednisone (n=340) (n=337) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 >=4 n (%) 3 >=4 Blood and Lymphatic System Disorders Thrombocytopenia 164 (48) 60 (18) 57 (17) 140 (42) 48 (14) 39 (12) Neutropenia 160 (47) 101 (30) 33 (10) 143 (42) 77 (23) 42 (12) Anemia 109 (32) 41 (12) 4 (1) 156 (46) 61 (18) 18 (5) Leukopenia 108 (32) 64 (19) 8 (2) 93 (28) 53 (16) 11 (3) Lymphopenia 78 (23) 46 (14) 17 (5) 51 (15) 26 (8) 7 (2) Gastrointestinal Disorders Nausea 134 (39) 10 (3) 0 70 (21) 1 (<1) 0 Diarrhea 119 (35) 19 (6) 2 (1) 20 (6) 1 (<1) 0 Vomiting 87 (26) 13 (4) 0 41 (12) 2 (1) 0 Constipation 77 (23) 2 (1) 0 14 (4) 0 0 Abdominal pain upper 34 (10) 1 (<1) 0 20 (6) 0 0 Nervous System Disorders Peripheral neuropathy * 156 (46) 42 (12) 2 (1) 4 (1) 0 0 Neuralgia 117 (34) 27 (8) 2 (1) 1 (<1) 0 0 Paresthesia 42 (12) 6 (2) 0 4 (1) 0 0 General Disorders and Administration Site Conditions Fatigue 85 (25) 19 (6) 2 (1) 48 (14) 4 (1) 0 Asthenia 54 (16) 18 (5) 0 23 (7) 3 (1) 0 Pyrexia 53 (16) 4 (1) 0 19 (6) 1 (<1) 1 (<1) Infections and Infestations Herpes Zoster 39 (11) 11 (3) 0 9 (3) 4 (1) 0 Metabolism and Nutrition Disorders Anorexia 64 (19) 6 (2) 0 19 (6) 0 0 Skin and Subcutaneous Tissue Disorders Rash 38 (11) 2 (1) 0 7 (2) 0 0 Psychiatric Disorders Insomnia 35 (10) 1 (<1) 0 21 (6) 0 0 * Represents High Level Term Peripheral Neuropathies NEC Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 10 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 10. All adverse reactions with incidence >=10% in the bortezomib arm are included. Table 10: 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) Bortezomib ( N=331) Dexamethasone 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* 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 * Represents 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 )] Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous vs Intravenous in Relapsed Multiple Myeloma The safety and efficacy of bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1. 3 mg/m 2 Table 11 Table 11: Most Commonly Reported Adverse Reactions (>=10%), with Grade 3 and >=4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of Bortezomib Subcutaneous vs Intravenous Subcutaneous Intravenous (N=147) (N=74) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 >=4 n (%) 3 >=4 Blood and Lymphatic System Disorders Anemia 28 (19) 8 (5) 0 17 (23) 3 (4) 0 Leukopenia 26 (18) 8 (5) 0 15 (20) 4 (5) 1 (1) Neutropenia 34 (23) 15 (10) 4 (3) 20 (27) 10 (14) 3 (4) Thrombocytopenia 44 (30) 7 (5) 5 (3) 25 (34) 7 (9) 5 (7) Gastrointestinal Disorders Diarrhea 28 (19) 1 (1) 0 21 (28) 3 (4) 0 Nausea 24 (16) 0 0 10 (14) 0 0 Vomiting 13 (9) 3 (2) 0 8 (11) 0 0 General Disorders and Administration Site Conditions Asthenia 10 (7) 1 (1) 0 12 (16) 4 (5) 0 Fatigue 11 (7) 3 (2) 0 11 (15) 3 (4) 0 Pyrexia 18 (12) 0 0 6 (8) 0 0 Nervous System Disorders Neuralgia 34 (23) 5 (3) 0 17 (23) 7 (9) 0 Peripheral neuropathies* 55 (37) 8 (5) 1 (1) 37 (50) 10 (14) 1 (1) Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least one dose of study medication * Represents High Level Term Peripheral Neuropathies NEC In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade >=3 adverse reactions. Differences of >=5% were reported in neuralgia (3% subcutaneous vs 9% intravenous), peripheral neuropathies (6% subcutaneous vs 15% intravenous), neutropenia (13% subcutaneous vs 18% intravenous), and thrombocytopenia (8% subcutaneous vs 16% intravenous). A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only two (1%) patients were reported as having severe reactions, one case of pruritus and one case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of six days. Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group). Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib Subcutaneous vs Intravenous The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each). In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%). Two patients (1%) in the subcutaneous treatment group and one (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency. Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma Table 12 2 2 2 2 2 Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% vs R-CHOP 5%). Table 12: Most Commonly Reported Adverse Reactions (>=5%) with Grades 3 and >=4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study VcR-CAP (n=240) R-CHOP (n=242) Body System Adverse Reactions All n (%) Toxicity Grade 3 n (%) Toxicity Grade >=4 n (%) All n (%) Toxicity Grade 3 n (%) Toxicity Grade >=4 n (%) Blood and L ymphatic S ystem D isorders Neutropenia 209 (87) 32 (13) 168 (70) 172 (71) 31 (13) 125 (52) Leukopenia 116 (48) 34 (14) 69 (29) 87 (36) 39 (16) 27 (11) Anemia 106 (44) 27 (11) 4 (2) 71 (29) 23 (10) 4 (2) Thrombocytopenia 172 (72) 59 (25) 76 (32) 42 (17) 9 (4) 3 (1) Febrile neutropenia 41 (17) 24 (10) 12 (5) 33 (14) 17 (7) 15 (6) Lymphopenia 68 (28) 25 (10) 36 (15) 28 (12) 15 (6) 2 (1) Nervous S ystem D isorders Peripheral neuropathy * 71 (30) 17 (7) 1 (<1) 65 (27) 10 (4) 0 Hypoesthesia 14 (6) 3 (1) 0 13 (5) 0 0 Paresthesia 14 (6) 2 (1) 0 11 (5) 0 0 Neuralgia 25 (10) 9 (4) 0 1 (<1) 0 0 General D isorders and A dministration S ite C onditions Fatigue 43 (18) 11 (5) 1 (<1) 38 (16) 5 (2) 0 Pyrexia 48 (20) 7 (3) 0 23 (10) 5 (2) 0 Asthenia 29 (12) 4 (2) 1 (<1) 18 (7) 1 (<1) 0 Edema peripheral 16 (7) 1 (<1) 0 13 (5) 0 0 Gastrointestinal D isorders Nausea 54 (23) 1 (<1) 0 28 (12) 0 0 Constipation 42 (18) 1 (<1) 0 22 (9) 2 (1) 0 Stomatitis 20 (8) 2 (1) 0 19 (8) 0 1 (<1) Diarrhea 59 (25) 11 (5) 0 11 (5) 3 (1) 1 (<1) Vomiting 24 (10) 1 (<1) 0 8 (3) 0 0 Abdominal distension 13 (5) 0 0 4 (2) 0 0 Infections and I nfestations Pneumonia 20 (8) 8 (3) 5 (2) 11 (5) 5 (2) 3 (1) Skin and S ubcutaneous T issue D isorders Alopecia 31 (13) 1 (<1) 1 (<1) 33 (14) 4 (2) 0 Metabolism and N utrition D isorders Hyperglycemia 10 (4) 1 (<1) 0 17 (7) 10 (4) 0 Decreased appetite 36 (15) 2 (1) 0 15 (6) 1 (<1) 0 Vascular D isorders Hypertension 15 (6) 1 (<1) 0 3 (1) 0 0 Psychiatric D isorders Insomnia 16 (7) 1 (<1) 0 8 (3) 0 0 Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. * Represents High Level Term Peripheral Neuropathies NEC The incidence of herpes zoster reactivation was 4. 6% in the VcR-CAP arm and 0. 8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment. The incidences of Grade >=3 bleeding events were similar between the two arms (four patients in the VcR-CAP arm and three patients in the R-CHOP arm). All of the Grade >=3 bleeding events resolved without sequelae in the VcR-CAP arm. Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (<1%; two patients). 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 13 Table 13: 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 All Patients (N=1163) Multiple Myeloma (N=1008) Mantle Cell Lymphoma (N=155) Adverse Reactions All >=Grade 3 All >=Grade 3 All >=Grade 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* 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) * Represents 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 )] 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 and <1% in patients with mantle cell lymphoma. 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 10, 11, and 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, boron, or mannitol. Reactions have included anaphylactic reactions [see 6. 1) Bortezomib for injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib for injection. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 Contraindicated for intrathecal administration.

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 )] (see Data) 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 a 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, bortezomib for injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. Pregnancy TestingConduct pregnancy testing in females of reproductive potential prior to initiating bortezomib for injection treatment. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with bortezomib for injection and for seven months after the last dose. MalesMales with female partners of reproductive potential should use effective contraception during treatment with bortezomib for injection and for four months after the last dose. InfertilityBased 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 Safety and effectiveness have not been established in pediatric patients. The activity and safety of bortezomib in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, nonrandomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in three blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; Block 2 included cyclophosphamide, etoposide and methotrexate; Block 3 included high-dose cytosine arabinoside and asparaginase. Bortezomib was administered at a dose of 1. 3 mg/m 2 The activity was evaluated in a prespecified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL <=21 years and relapsed <36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib. There was no evidence that the addition of bortezomib had any impact on the CR rate. No new safety concerns were observed when bortezomib was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without bortezomib. The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults. 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. 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. 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. 3 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 Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology ( 12. 3 )] Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [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 in vitro in vivo 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 14 Table 14: 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) Median* (months) 20. 9) Hazard ratio dagger 0. 70) p-value double dagger 0. 000002 Progression-Free Survival Events n (%) 135 (39) 190 (56) Median* (months) 18. 0) Hazard ratio dagger 0. 76) p-value dagger 0. 00001 Response Rate CR section 102 (30) 12 (4) PR section 136 (40) 103 (30) nCR n (%) 5 (1) 0 CR + PR section 238 (69) 115 (34) p-value paragraph <10 -10 Overall Survival at Median Follow-Up of 36. 7 Months Events (deaths) n (%) 109 (32) 148 (44) Median* (months) Not Reached(46. 8, NR) Hazard ratio dagger 0. 84) p-value dagger 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. * Kaplan-Meier estimate dagger 2 double dagger 2 section paragraph TTP was statistically significantly longer on the bortezomib, melphalan and prednisone arm (see Figure 1). (median follow-up 16. 3 months) 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/µL. 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 15 Table 15: 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. 0 (33, 84) 61. 0 (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 × 10 9 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. 0 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/m 2 2 [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 16 - + Table 16: 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* 6. 5) Hazard ratio dagger 0. 72) p-value double dagger <0. 0001 Overall Survival 51 (15) 84 (25) 12 (9) 24 (20) 39 (20) 60 (28) Hazard ratio dagger 0. 97) p-value double dagger, section <0. 05 Response Rate paragraph n=315 n=312 n=128 n=110 n=187 n=202 CR # 20 (6) 2 (<1) 8 (6) 2 (2) 12 (6) 0 (0) PR # 101 (32) 54 (17) 49 (38) 27 (25) 52 (28) 27 (13) nCR #, spade 21 (7) 3 (<1) 8 (6) 2 (2) 13 (7) 1 (<1) CR + PR # 121 (38) 56 (18) 57 (45) 29 (26) 64 (34) 27 (13) p-value heart <0. 0001 * Kaplan-Meier estimate dagger double dagger section paragraph # spade heart 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, bortezomib had a significant survival advantage relative to dexamethasone (p <0. The median follow-up was 8. Figure 4: Overall Survival Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study) For the 121 patients achieving a response (CR or PR) on the bortezomib arm, the median duration was 8. 0 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 Randomized, Open-Label Clinical Study of Bortezomib Subcutaneous vs Intravenous in Relapsed Multiple Myeloma An open-label, randomized, Phase 3 noninferiority study (NCT00722566) compared the efficacy and safety of the subcutaneous administration of bortezomib vs the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1. 3 mg/m 2 Stratification factors were based on the number of lines of prior therapy the patient had received (one previous line vs more than one line of therapy), and international staging system (ISS) stage (incorporating beta 2 The baseline demographic and other characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range: 38 to 88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was <=70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67. 5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2. 93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous. This study met its primary (noninferiority) objective that single agent subcutaneous bortezomib retains at least 60% of the overall response rate after four cycles relative to single agent intravenous bortezomib. The results are provided in Table 17 Table 17: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Study of Bortezomib Subcutaneous vs Intravenous Subcutaneous Bortezomib Intravenous Bortezomib Intent to Treat Population ( n=148) ( n=74) Primary Endpoint Response Rate at 4 Cycles ORR (CR + PR) n(%) 63 (43) 31 (42) Ratio of Response Rates (95% CI) 1. 40) CR n (%) 11 (7) 6 (8) PR n (%) 52 (35) 25 (34) nCR n (%) 9 (6) 4 (5) Secondary Endpoints Response Rate at 8 Cycles ORR (CR + PR) 78 (53) 38 (51) CR n (%) 17 (11) 9 (12) PR n (%) 61 (41) 29 (39) nCR n (%) 14 (9) 7 (9) Median Time to Progression, months 10. 4 Median Progression-Free Survival, months 10. 0 1 Year Overall Survival (%)* 72. 7 * Median duration of follow-up is 11. 8 months 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 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. 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 Randomized, Open-Label Clinical Study in Patients with Previously Untreated Mantle Cell Lymphoma A randomized, open-label, Phase 3 study (NCT00722137) was conducted in 487 adult patients with previously untreated mantle cell lymphoma (Stage II, III or IV) who were ineligible or not considered for bone marrow transplantation to determine whether bortezomib administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) resulted in improvement in progression-free survival (PFS) when compared to the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This clinical study utilized independent pathology confirmation and independent radiologic response assessment. Patients in the VcR-CAP treatment arm received bortezomib (1. 3 mg/m 2 2 2 2 2 Median patient age was 66 years, 74% were male, 66% were Caucasian and 32% were Asian. Sixty-nine percent of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of three (high-intermediate) or higher and 76% had Stage IV disease. The majority of the patients in both groups received six or more cycles of treatment, 84% in the VcR-CAP group and 83% in the R-CHOP group. Median number of cycles received by patients in both treatment arms was six with 17% of patients in the R-CHOP group and 14% of subjects in the VcR-CAP group receiving up to two additional cycles. The efficacy results for PFS, CR and ORR with a median follow-up of 40 months are presented in Table 18 Table 18 and Figure 6 (see Table 18, Figure 5). Table 18: Summary of Efficacy Analyses in the Previously Untreated Mantle Cell Lymphoma Study Efficacy Endpoint VcR-CAP n=243 ) R-CHOP n=244 ) Progression- F ree Survival (by independent radiographic assessment) Events n (%) 133 (55) 165 (68) Median* (months) 25(20, 32) 14(12, 17) Hazard ratio dagger 0. 79) p-value double dagger <0. 001 Complete Response Rate section n (%)(95% CI) 108 (44)(38, 51) 82 (34)(28, 40) Overall Response Rate (CR + Cru + PR) paragraph n (%) 214 (88) 208 (85) (95% CI) (83, 92) (80, 89) Overall Survival Events n (%) 103 (42) 138 (57) Median* (months) 91(71, NE) 56(47, 69) Hazard Ratio dagger 0. 85) Note: All results are based on the analysis performed at a median follow-up duration of 40 months except for the overall survival analysis, which was performed at a median follow-up of 78. CI = Confidence Interval; IPI = International Prognostic Index; LDH = Lactate dehydrogenase * Based on Kaplan-Meier product limit estimates. dagger double dagger section paragraph Figure 5: Progression-Free Survival VcR-CAP vs R-CHOP (previously Untreated Mantle Cell Lymphoma Study) Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. Figure 6: Overall Survival VcR-CAP vs R-CHOP (previously Untreated Mantle Cell Lymphoma Study) Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. 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 Administration ( 2. Responses to bortezomib are shown in Table 19 Table 19: 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
1. "OSHA Hazardous Drugs" (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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