OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known specific antidote for bortezomib overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension 5.2) and thrombocytopenia 5.7). In the event of an overdosage, the patients vital signs should be monitored and appropriate supportive care given. Studies in monkeys and dogs showed that intravenous bortezomib doses as low as times the recommended clinical dose on mg/m basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of mg/m and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at hour post-administration, with progression to death in 12 to 14 hours following drug administration.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel Bortezomib For Injection Vial LabelNDC 63323-721-10 761210BORTEZOMIBFOR INJECTION3.5 mg per vialFOR INTRAVENOUS USE ONLYSingle-Dose Vial.Discard Unused Portion.Rx only. Principal Display Panel Bortezomib For Injection Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Additional information describing 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Following twice weekly administration of mg/m and 1.3 mg/m bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between and 1.3 mg/m doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the mg/m and 1.3 mg/m dose regimens, respectively.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following intravenous administration of mg/m and 1.3 mg/m doses, the mean maximum plasma concentrations of bortezomib (C max) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. When administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the mg/m dose and 89 to 120 ng/mL for the 1.3 mg/m dose. Distribution:The mean distribution volume of bortezomib ranged from approximately 498 to 1,884 L/m following single- or multiple-dose administration of mg/m or 1.3 mg/m 2. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1,000 ng/mL.. Elimination:The mean elimination half-life of bortezomib after multiple dosing ranged from 40 hours to 193 hours after the mg/m dose and 76 hours to 108 hours after the 1.3 mg/m dose. The mean total body clearances was 102 L/h and 112 L/h following the first dose for doses of mg/m and 1.3 mg/m 2, respectively, and ranged from 15 L/h to 32 L/h following subsequent doses for doses of and 1.3 mg/m 2, respectively. Metabolism: The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug. In vitro studies indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Excretion: The pathways of elimination of bortezomib have not been characterized in humans. Specific Populations:Age: Analyses of data after the first dose of Cycle (Day 1) in patients who had received intravenous doses of mg/m and 1.3 mg/m showed that both dose-normalized AUC and max tend to be less in younger patients. Patients less than 65 years of age had about 25% lower mean dose-normalized AUC and max than those greater than or equal to 65 years of age Sex: Sex has no clinically important effect on bortezomib exposure. Hepatic Impairment: Mild hepatic impairment had no clinically important effect on dose-normalized AUC or max. The dose-normalized mean AUC was increased by approximately 60% in patients with moderate hepatic impairment (defined as total bilirubin greater than 1.5 to times the upper limit of normal and any AST) or severe hepatic impairment (defined as total bilirubin greater than times the upper limit of normal and any AST) see Dosage and Administration 2.6) and Use in Specific Populations 8.7) ]. Renal Impairment: Dose-normalized AUC and max was comparable for patients with creatinine clearance (CLcr) from 59 mL/min/1.73 2 to less than 20 mL/min/1.73 2 compared to patients with CLcr greater than or equal to 60 mL/min/1.73 2 see Use in Specific Populations 8.6) ]. Drug Interaction Studies. Effect of Other Drugs on Bortezomib: The coadministration of omeprazole, strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib. The coadministration of ketoconazole, strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35%.The coadministration of rifampin, strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Decreases greater than 45% may occur, as the drug interaction trial was not designed to evaluate the maximum effect of rifampin on bortezomib exposure.. Effect of Bortezomib on Other Drugs: Bortezomib inhibits CYP2C19 activity in vitro and the coadministration of Bortezomib for Injection with sensitive or narrow therapeutic CYP2C19 substrates may increase their exposure. Bortezomib did not inhibit CYP1A2, 2C9, 2D6, or 3A4 in vitro. Bortezomib did not induce the CYP3A4 or 1A2 activity in vitro.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following 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)] 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)] Most commonly reported adverse reactions (incidence >= 20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Safety Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 MyelomaTable describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m 2) administered intravenously in combination with melphalan (9 mg/m 2) and prednisone (60 mg/m 2) in prospective randomized study. The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.Table 7: Most Commonly Reported Adverse Reactions (>= 10% in the Bortezomib, Melphalan and Prednisone arm) with Grades and >= Intensity in the Previously Untreated Multiple Myeloma Studya Represents High Level Term Peripheral Neuropathies NEC Bortezomib, Melphalan andPrednisone(n=340)Melphalan and Prednisone(n=337)Toxicity Grade, (%)Toxicity Grade, (%)System Organ ClassPreferred TermTotal (%)3>= 4Total (%)3>= 4Blood and lymphatic system disordersThrombocytopenia164 (48)60 (18)57 (17)140 (42)48 (14)39 (12)Neutropenia160 (47)101 (30)33 (10)143 (42)77 (23)42 (12)Anemia109 (32)41 (12)4 (1)156 (46)61 (18)18 (5)Leukopenia108 (32)64 (19)8 (2)93 (28)53 (16)11 (3)Lymphopenia78 (23)46 (14)17 (5)51 (15)26 (8)7 (2)Gastrointestinal disordersNausea134 (39)10 (3)070 (21)1 (< 1)0Diarrhea119 (35)19 (6)2 (1)20 (6)1 (< 1)0Vomiting87 (26)13 (4)041 (12)2 (1)0Constipation77 (23)2 (1)014 (4)00Abdominal Pain Upper34 (10)1 (< 1)020 (6)00Nervous system disordersPeripheral Neuropathy 156 (46)42 (12)2 (1)4 (1)00Neuralgia117 (34)27 (8)2 (1)1 (< 1)00Paresthesia42 (12)6 (2)04 (1)00General disorders and administration siteconditionsFatigue85 (25)19 (6)2 (1)48 (14)4 (1)0Asthenia54 (16)18 (5)023 (7)3 (1)0Pyrexia53 (16)4 (1)019 (6)1 (< 1)1 (< 1)Infections and infestationsHerpes Zoster39 (11)11 (3)09 (3)4 (1)0Metabolism and nutrition disordersAnorexia64 (19)6 (2)019 (6)00Skin and subcutaneous tissue disordersRash38 (11)2 (1)07 (2)00Psychiatric disordersInsomnia35 (10)1 (< 1)021 (6)00. Relapsed Multiple Myeloma Randomized Study of Bortezomib versus DexamethasoneThe safety data described below and in Table reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m twice weekly for out of weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on weekly schedule. Duration of treatment was up to 11 cycles (9 months) with median duration of cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and to prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients 65 and >= 65 years of age. Most patients were Caucasian [see Clinical Studies 14.1)] Among the 331 bortezomib-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 Grade adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced Grade adverse reaction. All individual dexamethasone-related Grade adverse reactions were less than 1%.. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib versus DexamethasoneSerious adverse reactions are defined as any reaction that results in death, is life-threatening, requireshospitalization or prolongs current hospitalization, results in significant disability, or is deemed to be an important medical event. total of 80 (24%) patients from the bortezomib treatment arm experienced 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%) of332 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: case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: cases of sepsis, case of bacterial meningitis, and case of sudden death at home.. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib versus DexamethasoneThe most common adverse reactions from the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence >= 10% in the bortezomib arm are included. Table 8: Most Commonly Reported Adverse Reactions (>= 10% in Bortezomib arm), with Grades and Intensity in the Relapsed Multiple Myeloma Study of Bortezomib versus Dexamethasone (N=663)a Represents High Level Term Peripheral Neuropathies NEC Preferred TermAllBortezomib(N=331)Grade 3Grade 4AllDexamethasone(N=332)Grade 3Grade 4Adverse Reactions324 (98)193 (58)28 (8)297 (89)110 (33)29 (9)Nausea172 (52)8 (2)031 (9)00Diarrhea NOS171 (52)22 (7)036 (11)2 (< 1)0Fatigue130 (39)15 (5)082 (25)8 (2)0Peripheral neuropathies 115 (35)23 (7)2 (< 1)14 (4)01 (< 1)Thrombocytopenia109 (33)80 (24)12 (4)11 (3)5 (2)1 (< 1)Constipation99 (30)6 (2)027 (8)1 (< 1)0Vomiting NOS96 (29)8 (2)010 (3)1 (< 1)0Anorexia68 (21)8 (2)08 (2)1 (< 1)0Pyrexia66 (20)2 (< 1)021 (6)3 (< 1)1 (< 1)Paresthesia64 (19)5 (2)024 (7)00Anemia NOS63 (19)20 (6)1 (< 1)21 (6)8 (2)0Headache NOS62 (19)3 (< 1)023 (7)1 (< 1)0Neutropenia58 (18)37 (11)8 (2)1 (< 1)1 (< 1)0Rash NOS43 (13)3 (< 1)07 (2)00Appetite decreased NOS36 (11)0012 (4)00Dyspnea NOS35 (11)11 (3)1 (< 1)37 (11)7 (2)1 (< 1)Abdominal pain NOS35 (11)5 (2)07 (2)00Weakness34 (10)10 (3)028 (8)8 (2)0. Safety Experience from the Phase Open-Label Extension Study in Relapsed Multiple MyelomaIn the phase extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for 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 and studies of single agent bortezomib 1.3 mg/m 2/dose twice weekly for weeks followed by 10-day rest period in 1,163 patients with previously-treated multiple myeloma (N=1,008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase Open-Label Study of bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least episode of >= Grade toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).In the Phase 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 SafetyA total of 26% of patients experienced 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 SafetyThe most common adverse reactions are shown in Table 9. All adverse reactions occurring at >= 10% are included. In the absence of randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patients underlying disease. Please see the discussion of specific adverse reactions that follows. Table 9: Most Commonly Reported (>= 10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies using the 1.3 mg/m Dose (N=1,163) Represents High Level Term Peripheral Neuropathies NEC All PatientsMultiple MyelomaMantle Cell Lymphoma(N=1,163)(N=1,008)(N=155)Preferred TermAll>= Grade 3All>= Grade 3All>= Grade 3Nausea567 (49)36 (3)511 (51)32 (3)56 (36)4 (3)Diarrhea NOS530 (46)83 (7)470 (47)72 (7)60 (39)11 (7)Fatigue477 (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)Thrombocytopenia369 (32)295 (25)344 (34)283 (28)25 (16)12 (8)Vomiting NOS321 (28)44 (4)286 (28)40 (4)35 (23)4 (3)Constipation296 (25)17 (1)244 (24)14 (1)52 (34)3 (2)Pyrexia249 (21)16 (1)233 (23)15 (1)16 (10)1 (< 1)Anorexia227 (20)19 (2)205 (20)16 (2)22 (14)3 (2)Anemia NOS209 (18)65 (6)190 (19)63 (6)19 (12)2 (1)Headache NOS175 (15)8 (< 1)160 (16)8 (< 1)15 (10)0Neutropenia172 (15)121 (10)164 (16)117 (12)8 (5)4 (3)Rash NOS156 (13)8 (< 1)120 (12)4 (< 1)36 (23)4 (3)Paresthesia147 (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)Weakness124 (11)31 (3)106 (11)28 (3)18 (12)3 (2). Description of Selected Adverse Reactions from the Integrated Phase and Relapsed Multiple Myeloma and Phase Relapsed Mantle Cell Lymphoma Studies. Gastrointestinal ToxicityA 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 adverse reactions occurred in 14% of patients; >= Grade adverse reactions were <= 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).. ThrombocytopeniaAcross the studies, bortezomib-associated thrombocytopenia was characterized by decrease in platelet count during the dosing period (days to 11) and return toward baseline during the 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade in 22%, >= Grade in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients [see Warnings and Precautions 5.7)] Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of >= Grade thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%). Peripheral NeuropathyOverall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade for 11% of patients and >= Grade 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 versus dexamethasone phase relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced >= Grade peripheral neuropathy and had dose adjustments, 48% had improved or resolved with median of 3.8 months from first onset.In the phase relapsed multiple myeloma studies, among the 30 patients who experienced Grade peripheral neuropathy resulting in discontinuation or who experienced >= Grade peripheral neuropathy, 73% reported improvement or resolution with median time of 47 days to improvement of one Grade or more from the last dose of bortezomib.. HypotensionThe incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade or in the majority of patients and Grade in 2% and >= Grade in< 1%. Two percent (2%) of patients had hypotension reported as 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 syncopal reaction.. NeutropeniaNeutrophil counts decreased during the bortezomib dosing period (days to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade in 8% of patients and >= Grade in 2%. Neutropenia was reported as 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 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 in 7% and >= Grade in 1% of patients. Asthenia was reported as Grade in 2% and >= Grade 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.. PyrexiaPyrexia (> 38oC) was reported as an adverse reaction for 21% of patients. The reaction was Grade in 1% and >= Grade in 1%. Pyrexia was reported as 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 pyrexia was 1% in patients with multiple myeloma and 1% in patients with mantle cell lymphoma.. Herpes Virus InfectionConsider using antiviral prophylaxis in subjects being treated with Bortezomib for Injection. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in to 3% in subjects treated with bortezomib and 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%).. Additional Adverse Reactions from Clinical StudiesThe 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: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia Cardiac disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardia Ear and labyrinth disorders: Hearing impaired, vertigo Eye disorders: Diplopia and blurred vision, conjunctival infection, irritation Gastrointestinal disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux General disorders and administration site conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis Hepatobiliary disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure Immune system disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema Infections and infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter-related infection Injury, poisoning and procedural complications: Catheter-related complication, skeletal fracture, subdural hematoma Investigations: Weight decreased Metabolism and nutrition disorders: Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity Nervous system disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack Psychiatric disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation Renal and urinary disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension Skin and subcutaneous tissue disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus Vascular disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension 6.2 Postmarketing Experience. The following adverse reactions have been identified from the worldwide postmarketing experience with bortezomib. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Cardiac disorders: Cardiac tamponade Ear and labyrinth disorders: Deafness bilateral Eye disorders: Optic neuropathy, blindness Gastrointestinal disorders: Ischemic colitis Infections and infestations: Progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis Nervous system disorders: Posterior reversible encephalopathy syndrome (PRES, formerly RPLS) Respiratory, thoracic and mediastinal disorders: Acute diffuse infiltrative pulmonary disease Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweets syndrome).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses >= 1.2 mg/m induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed. Chronic Administration: In animal studies at dose and schedule similar to that recommended for patients (twice weekly dosing for weeks followed by 1-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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with bortezomib.Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses >= 0.3 mg/m (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m 2.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bortezomib is reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is 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 variety of cancer cell types in vitro. Bortezomib causes delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. 12.2 Pharmacodynamics. Following twice weekly administration of mg/m and 1.3 mg/m bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between and 1.3 mg/m doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the mg/m and 1.3 mg/m dose regimens, respectively. 12.3 Pharmacokinetics. Following intravenous administration of mg/m and 1.3 mg/m doses, the mean maximum plasma concentrations of bortezomib (C max) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. When administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the mg/m dose and 89 to 120 ng/mL for the 1.3 mg/m dose. Distribution:The mean distribution volume of bortezomib ranged from approximately 498 to 1,884 L/m following single- or multiple-dose administration of mg/m or 1.3 mg/m 2. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1,000 ng/mL.. Elimination:The mean elimination half-life of bortezomib after multiple dosing ranged from 40 hours to 193 hours after the mg/m dose and 76 hours to 108 hours after the 1.3 mg/m dose. The mean total body clearances was 102 L/h and 112 L/h following the first dose for doses of mg/m and 1.3 mg/m 2, respectively, and ranged from 15 L/h to 32 L/h following subsequent doses for doses of and 1.3 mg/m 2, respectively. Metabolism: The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug. In vitro studies indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Excretion: The pathways of elimination of bortezomib have not been characterized in humans. Specific Populations:Age: Analyses of data after the first dose of Cycle (Day 1) in patients who had received intravenous doses of mg/m and 1.3 mg/m showed that both dose-normalized AUC and max tend to be less in younger patients. Patients less than 65 years of age had about 25% lower mean dose-normalized AUC and max than those greater than or equal to 65 years of age Sex: Sex has no clinically important effect on bortezomib exposure. Hepatic Impairment: Mild hepatic impairment had no clinically important effect on dose-normalized AUC or max. The dose-normalized mean AUC was increased by approximately 60% in patients with moderate hepatic impairment (defined as total bilirubin greater than 1.5 to times the upper limit of normal and any AST) or severe hepatic impairment (defined as total bilirubin greater than times the upper limit of normal and any AST) see Dosage and Administration 2.6) and Use in Specific Populations 8.7) ]. Renal Impairment: Dose-normalized AUC and max was comparable for patients with creatinine clearance (CLcr) from 59 mL/min/1.73 2 to less than 20 mL/min/1.73 2 compared to patients with CLcr greater than or equal to 60 mL/min/1.73 2 see Use in Specific Populations 8.6) ]. Drug Interaction Studies. Effect of Other Drugs on Bortezomib: The coadministration of omeprazole, strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib. The coadministration of ketoconazole, strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35%.The coadministration of rifampin, strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Decreases greater than 45% may occur, as the drug interaction trial was not designed to evaluate the maximum effect of rifampin on bortezomib exposure.. Effect of Bortezomib on Other Drugs: Bortezomib inhibits CYP2C19 activity in vitro and the coadministration of Bortezomib for Injection with sensitive or narrow therapeutic CYP2C19 substrates may increase their exposure. Bortezomib did not inhibit CYP1A2, 2C9, 2D6, or 3A4 in vitro. Bortezomib did not induce the CYP3A4 or 1A2 activity in vitro.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Multiple Myeloma. Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma:A prospective, international, randomized (1:1), open-label clinical study of 682 patients was conducted to determine whether bortezomib administered intravenously (1.3 mg/m 2) in combination with melphalan (9 mg/m 2) and prednisone (60 mg/m 2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m 2) and prednisone (60 mg/m 2) in patients with previously untreated multiple myeloma. Treatment was administered for maximum of cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the bortezomib study arm. The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, median hemoglobin of 105 g/L (64;165), and median platelet count of 221,500/microliter (33,000;587,000).Efficacy results for the trial are presented in Table 10. At pre-specified 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. later, pre-specified analysis of overall survival (with median follow-up of 36.7 months with hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in 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 hazard ratio of 0.695 (95% CI: 0.57, 0.85). Table 10: Summary of Efficacy Analyses in the Previously Untreated Multiple Myeloma StudyNote: All results are based on the analysis performed at median follow-up duration of 16.3 months except for the overall survival analysis.a Kaplan-Meier estimate Hazard ratio estimate is based on Cox proportional-hazard model adjusted for stratification factors: beta2-microglobulin, albumin, and region. hazard ratio less than indicates an advantage for bortezomib, melphalan and prednisone p-value based on the stratified log-rank test adjusted for stratification factors: beta2-microglobulin, albumin, and region EBMT criteria p-value for Response Rate (CR PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors TTP was statistically significantly longer on the bortezomib, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months) Efficacy EndpointBortezomib,Melphalan andPrednisonen=344Melphalan andPrednisonen=338Time to ProgressionEvents (%)101 (29)152 (45)Median (months) 20.715(95% CI)(17.6, 24.7)(14.1, 17.9)Hazard ratio 0.54(95% CI)(0.42, 0.70)p-value 0.000002Progression-free SurvivalEvents (%)135 (39)190 (56)Median (months) 18.314(95% CI)(16.6, 21.7)(11.1, 15)Hazard ratio 0.61(95% CI)(0.49, 0.76)p-value 0.00001Response RateCR n (%) 102 (30)12 (4)PR dn (%) 136 (40)103 (30)nCR (%)5 (1)0CR PR dn (%) 238 (69)115 (34)p-value <10 -10 Overall Survival at median follow up of 36.7 monthsEvents (deaths) (%)109 (32)148 (44)Median a(months) Not Reached43.1(95% CI)(46.2, NR)(34.8, NR)Hazard ratio 0.65(95% CI)(0.51, 0.84)p-value 0.00084Figure 1: Time to Progression Bortezomib, Melphalan and Prednisone versus 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 versus Melphalan and Prednisone Figure 1. Figure 2. Randomized, Clinical Study in Relapsed Multiple Myeloma of Bortezomib versus DexamethasoneA prospective phase 3, international, randomized (1:1), stratified, open-label clinical study enrolling 669patients 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 to prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade >= peripheral neuropathy or platelet counts 50,000/uL. 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 (1 previous line versus more than line of therapy), time of progression relative to prior treatment (progression during or within months of stopping their most recent therapy versus relapse 6 months after receiving their most recent therapy), and screening 2-microglobulin levels (<= 2.5 mg/L versus 2.5 mg/L). Baseline patient and disease characteristics are summarized in Table 11. Table 11: Summary of Baseline Patient and Disease Characteristics in the Relapsed Multiple Myeloma StudyPatient CharacteristicsBortezomib N=333DexamethasoneN=336Median age in years (range)62 (33, 84)61 (27, 86)Gender: Male/female56% 44%60% 40%Race: Caucasian/Black/other90% 6% 4%88% 7% 5%Karnofsky performance status score <= 7013%17%Hemoglobin <100 g/L32%28%Platelet count 75 10 9/L 6%4%Disease Characteristics Type of myeloma (%): IgG/IgA/Light chain Median 2-microglobulin (mg/L) Median albumin (g/L) Creatinine clearance <= 30 mL/min [n (%)] 60% 23% 12% 3.7 39 17 (5%) 59% 24% 13% 3.6 39 11 (3%) Median Duration of Multiple Myeloma SinceDiagnosis (Years)3.53.1Number of Prior Therapeutic Lines of Treatment Median22 prior line40%35% >1 prior line60%65%Previous Therapy Any prior steroids, e.g., dexamethasone, VAD98%99% Any prior anthracyclines, e.g., VAD, mitoxantrone77%76% Any prior alkylating agents, e.g., MP, VBMCP91%92% Any prior thalidomide therapy48%50% Vinca alkaloids74%72% Prior stem cell transplant/other high-dose therapy67%68% Prior experimental or other types of therapy3%2%Patients in the bortezomib treatment group were to receive eight 3-week treatment cycles followed by three 5-week treatment cycles of bortezomib. Patients achieving CR were treated for cycles beyond first evidence of CR. Within each 3-week treatment cycle, bortezomib 1.3 mg/m 2/dose alone was administered by intravenous bolus twice weekly for weeks on Days 1, 4, 8, and 11 followed by 10-day rest period (Days 12 to 21). Within each 5-week treatment cycle, bortezomib 1.3 mg/m 2/dose alone was administered by intravenous bolus once weekly for weeks on Days 1, 8, 15, and 22 followed by 13-day rest period (Days 23 to 35) [see Dosage and Administration 2.2)] Patients in the dexamethasone treatment group were to receive four 5-week treatment cycles followed by five 4-week treatment cycles. Within each 5-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days to 4, to 12, and 17 to 20 followed by 15-day rest period (Days 21 to 35). Within each 4-week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days to followed by 24-day rest period (Days to 28). Patients with documented progressive disease on dexamethasone were offered bortezomib at standard dose and schedule on companion study. Following 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 of the3-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 range of to 44. In the dexamethasone arm, 40% of patients received at least one dose in all of the 5-week treatment cycles of therapy, and 6% received at least one dose in all cycles.The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 12. Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required 5% plasma cells in the marrow, 100% reduction in M- protein, and negative immunofixation test (IF -). Partial response (PR) requires >= 50% reduction in serum myeloma protein and >= 90% reduction of urine myeloma protein on at least occasions for minimum of at least weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis; however, M-protein was still detectable by immunofixation (IF +). Table 12: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Studya Kaplan-Meier estimate Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. hazard ratio less than indicates an advantage for bortezomibc p-value based on the stratified log-rank test including randomization stratification factors Precise p-value cannot be rendered Response population includes patients who had measurable disease at baseline and received at least dose of study drug EBMT criteria; nCR meets all EBMT criteria for CR but has positive IF. Under EBMT criteria nCR is in the PR category In patients, the IF was unknown p-value for Response Rate (CR PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors Efficacy EndpointAll Patients1 Prior Line ofTherapy> Prior Line ofTherapyBortezomibDexBortezomibDexBortezomibDexn=333n=336n=132n=119n=200n=217Time to ProgressionEvents (%) 147 (44) 196 (58) 55 (42) 64 (54) 92 (46) 132 (61) Median (95% CI) 6.2 mo (4.9, 6.9) 3.5 mo (2.9, 4.2) mo (6.2, 8.8) 5.6 mo (3.4, 6.3) 4.9 mo (4.2, 6.3) 2.9 mo (2.8, 3.5) Hazard ratio (95% CI) 0.55 (0.44, 0.69) 0.55 (0.38, 0.81) 0.54 (0.41, 0.72) p-value <0.00010.0019<0.0001Overall SurvivalEvents (deaths) (%) 51 (15) 84 (25) 12 (9) 24 (20) 39 (20) 60 (28) Hazard ratio (95% CI) 0.57 (0.40, 0.81) 0.39 (0.19, 0.81) 0.65 (0.43, 0.97) p-value c,d 0.05< 0.05< 0.05Response RatePopulation n 627 n=315 n=312 n=128 n=110 n=187 n=202 CR n (%) 20 (6)2 (<1)8 (6)2 (2)12 (6)0 (0)PR n(%) 101 (32)54 (17)49 (38)27 (25)52 (28)27 (13)nCR f,g n(%) 21 (7)3 (<1)8 (6)2 (2)13 (7)1 (<1)CR PR n (%) 121 (38)56 (18)57 (45)29 (26)64 (34)27 (13)p-value <0.00010.0035<0.0001TTP was statistically significantly longer on the bortezomib arm (see Figure 3). Figure 3: Time to Progression Bortezomib versus Dexamethasone (relapsed multiple myeloma study) As shown in Figure bortezomib had significant survival advantage relative to dexamethasone (p 0.05). The median follow-up was 8.3 months. Figure 4: Overall Survival Bortezomib versus Dexamethasone (relapsed multiple myeloma study) For the 121 patients achieving response (CR or PR) on the bortezomib arm, the median duration was months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the bortezomib arm regardless of 2-microglobulin levels at baseline. Figure 3. Figure 4. Randomized Phase Dose-Response Study in Relapsed Multiple MyelomaAn open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive bortezomib mg/m or 1.3 mg/m intravenous bolus twice weekly for weeks on Days 1, 4, 8, and 11 followed by 10-day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of bortezomib on this trial was years, and patients had received median of prior line of treatment (median of prior therapies). single complete response was seen at each dose. The overall response rates (CR PR) were 30% (8/27) at mg/m and 38% (10/26) at 1.3 mg/m 2. A Phase Open-Label Extension Study in Relapsed Multiple MyelomaPatients from the two phase studies, who in the investigators opinion would experience additional clinicalbenefit, continued to receive bortezomib beyond cycles on an extension study. Sixty-three (63) patients from the phase multiple myeloma studies were enrolled and received median of additional cycles of bortezomib therapy for total median of 14 cycles (range 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 3-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)] . 14.2 Mantle Cell Lymphoma. Phase Single-arm Clinical Study in Relapsed Mantle Cell Lymphoma After Prior TherapyThe safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma were evaluated in anopen-label, single-arm, multicenter study of 155 patients with progressive disease who had received at least 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. total of thirty seven percent (37%) of patients were refractory to their last prior therapy. An intravenousbolus injection of bortezomib 1.3 mg/m 2/dose was administered twice weekly for weeks on Days 1, 4, 8, and 11 followed by 10-day rest period (Days 12 to 21) for maximum of 17 treatment cycles. Patients achieving CR or CRu were treated for cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see Dosage and Administration 2.4, 2.5)] Responses to bortezomib are shown in Table 13. Response rates to bortezomib were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was 4; in responding patients the median number of cycles was 8. 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 Phase Relapsed Mantle Cell Lymphoma StudyResponse 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) CR10 (6)(3, 12) CRu2 (1)(0, 5) Partial Response (PR)36 (23)(17, 31)Duration of ResponseMedian95% CI CR CRu PR (N 48)9.3 months(5.4, 13.8) CR CRu (N 12)15.4 months(13.4, 15.4) PR (N=36)6.1 months(4.2, 9.3).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Bortezomib for Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, boric acid or glycine. 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.. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, boric acid or glycine, including anaphylactic reactions. 4) Contraindicated for intrathecal administration. 4) Patients with hypersensitivity (not including local reactions) to bortezomib, boron, boric acid or glycine, including anaphylactic reactions. 4) Contraindicated for intrathecal administration. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Bortezomib for Injection is an antineoplastic agent available for intravenous injection. Each single-dose vial contains 3.5 mg of bortezomib, 10.5 mg boric acid, 25 mg glycine as sterile lyophilized powder.The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1- [[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. Bortezomib has the following chemical structure:The molecular weight of bortezomib is 384.24 and its molecular formula is 19H 25BN 4O 4. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in pH range of to 6.5.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravenous use only. Exercise caution when calculating the volume to be administered. 2.1, 2.8.) The recommended starting dose of Bortezomib for Injection is 1.3 mg/m administered as 3 to second bolus intravenous injection. 2.2, 2.4) Hepatic Impairment: Use lower starting dose for patients with moderate or severe hepatic impairment. 2.6) Dose must be individualized to prevent overdose. 2.8) For intravenous use only. Exercise caution when calculating the volume to be administered. 2.1, 2.8.) The recommended starting dose of Bortezomib for Injection is 1.3 mg/m administered as 3 to second bolus intravenous injection. 2.2, 2.4) Hepatic Impairment: Use lower starting dose for patients with moderate or severe hepatic impairment. 2.6) Dose must be individualized to prevent overdose. 2.8) 2.1 Important Dosing Guidelines. Bortezomib for Injection is for intravenous use only. Do not administer Bortezomib for Injection by any other route.The recommended starting dose of Bortezomib for Injection is 1.3 mg/m 2. Bortezomib for Injection may be administered intravenously at concentration of mg/mL [see Dosage and Administration 2.8)] When administered intravenously, Bortezomib for Injection is administered as 3 to second bolus intravenous injection.. 2.2 Dosage in Previously Untreated Multiple Myeloma. Bortezomib for Injection is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles to 4, Bortezomib for Injection is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 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 MyelomaTwice Weekly Bortezomib (Cycles to 4)Week123456Bortezomib for Injection (1.3 mg/m 2) Day 1----Day 4Day 8Day 11rest periodDay 22Day 25Day 29Day 32rest periodMelphalan (9 mg/m 2) Prednisone (60 mg/m 2) Day 1Day 2Day 3Day 4----rest period--------rest periodOnce Weekly Bortezomib for Injection (Cycles to when used in combination with Melphalan and Prednisone)Week123456Bortezomib for Injection (1.3 mg/m 2) Day 1----Day 8rest periodDay 22Day 29rest periodMelphalan (9 mg/m 2) Prednisone (60 mg/m 2) Day 1Day 2Day 3Day 4----rest period--------rest period. 2.3 Dose Modification Guidelines for Bortezomib for Injection When Given in Combination with Melphalan and Prednisone. Prior to initiating any cycle of therapy with Bortezomib for Injection in combination with melphalan and prednisone:Platelet count should be at least 70 10 9/L and the absolute neutrophil count (ANC) should be at least x 10 9/L Non-hematological toxicities should have resolved to Grade or baselineTable 2: Dose Modifications during Cycles of Combination Bortezomib for Injection, Melphalan and Prednisone TherapyToxicityDose Modification or DelayHematological toxicity during cycle: If prolonged Grade neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycleConsider reduction of the melphalan dose by 25% in the next cycleIf platelet count is not above 30 10 9/L or ANC is not above 0.75 10 9/L on Bortezomib for Injection dosing day (other than day 1) Withhold Bortezomib for Injection doseIf several Bortezomib for Injection doses in consecutive cycles are withheld due to toxicity Reduce Bortezomib for Injection dose by dose level (from 1.3 mg/m to mg/m 2, or from mg/m to 0.7 mg/m 2) Grade or higher non-hematological toxicitiesWithhold Bortezomib for Injection therapy until symptoms of toxicity have resolved to Grade or baseline. Then, Bortezomib for Injection may be reinitiated with one dose level reduction (from 1.3 mg/m to mg/m 2, or from mg/m to 0.7 mg/m 2). For bortezomib-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib for Injection as outlined in Table 3. For information concerning melphalan and prednisone, see manufacturers prescribing information.Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration 2.5)] . Platelet count should be at least 70 10 9/L and the absolute neutrophil count (ANC) should be at least x 10 9/L Non-hematological toxicities should have resolved to Grade or baseline. 2.4 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma. Bortezomib for Injection (1.3 mg/m 2/dose) is administered twice weekly for weeks (Days 1, 4, 8, and 11) followed by 10-day rest period (Days 12 to 21). For extended therapy of more than cycles, Bortezomib for Injection may be administered on the standard schedule or, for relapsed multiple myeloma, on maintenance schedule of once weekly for weeks (Days 1, 8, 15, and 22) followed by 13-day rest period (Days 23 to 35) [see Clinical Studies 14)] At least 72 hours should elapse between consecutive doses of Bortezomib for Injection. Bortezomib for Injection therapy should be withheld at the onset of any Grade non-hematological or Grade hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions 5)] Once the symptoms of the toxicity have resolved, Bortezomib for Injection therapy may be reinitiated at 25% reduced dose (1.3 mg/m 2/dose reduced to mg/m 2/dose; mg/m 2/dose reduced to 0.7 mg/m 2/dose). For dose modifications guidelines for peripheral neuropathy see section 2.5.. 2.5 Dose Modifications for 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 decrease in the dose and/or 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 for Injection-related Neuropathic Pain and/or Peripheral Sensory or Motor NeuropathyGrading based on NCI Common Terminology Criteria CTCAE v4.0Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etcSelf care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedriddenSeverity of Peripheral NeuropathySigns and SymptomsModification of Dose and RegimenGrade (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of functionNo actionGrade with pain or Grade (moderate symptoms; limiting instrumental Activities of Daily Living (ADL))Reduce Bortezomib for Injection to mg/m Grade with pain or Grade (severe symptoms; limiting self care ADL )Withhold Bortezomib for Injection therapy until toxicity resolves. When toxicity resolves reinitiate with reduced dose of Bortezomib for Injection at 0.7 mg/m once per week. Grade (life-threatening consequences; urgent intervention indicated)Discontinue Bortezomib for Injection. 2.6 Dosage in Patients with Hepatic Impairment. Do not adjust the starting dose for patients with mild hepatic impairment.Start patients with moderate or severe hepatic impairment at reduced dose of 0.7 mg/m per injection during the first cycle, and consider subsequent dose escalation to mg/m or further dose reduction to 0.5 mg/m based on patient tolerance (see Table 4) [see Use in Specific Populations 8.7) and Clinical Pharmacology 12.3)] Table 4: Recommended Starting Dose Modification for Bortezomib for Injection in Patients with Hepatic ImpairmentAbbreviations: SGOT serum glutamic oxaloacetic transaminase; AST aspartate aminotransferase; ULN upper limit of the normal range.Bilirubin LevelSGOT (AST)LevelsModification of Starting DoseMildLess than or equal to times ULNMore than ULNNoneMore than to 1.5 times ULNAnyNoneModerateMore than 1.5 to times ULN AnyReduce dose to 0.7 mg/m in thefirst cycle. Consider dose escalation to mg/m or further dose reduction to 0.5 mg/m in subsequent cycles based on patient tolerability. SevereMore than times ULNAny. 2.7 Administration Precautions. The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Use caution in calculating the dose to prevent overdose [see Dosage and Administration 2.8)] Bortezomib for Injection is cytotoxic drug. Use procedures for proper handling and disposal [see How Supplied/Storage and Handling 16)] . 2.8 Reconstitution/Preparation for Intravenous Administration. Use proper aseptic technique. Reconstitute only with 0.9% sodium chloride. The reconstituted product should be clear and colorless solution. For each 3.5 mg single-dose vial of Bortezomib for Injection reconstitute with the following volume of 0.9% sodium chloride Table 5): Table 5: Reconstitution Volumes and Final Concentration for Intravenous AdministrationRoute ofadministrationBortezomib(mg/vial)Diluent(0.9% SodiumChloride)Final Bortezomibconcentration(mg/mL)Intravenous3.5 mg3.5 mL1 mg/mLDose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equation 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) patient BSA (m 2) Total Bortezomib for Injection volume (mL) to be administered1 mg/mLA sticker that indicates the route of administration is provided with each Bortezomib for Injection vial. The sticker 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.Bortezomib for Injection contains no antimicrobial preservative. Administer reconstituted Bortezomib for Injection within hours of preparation. When reconstituted as directed, Bortezomib for Injection may be stored at 25C (77F). 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 hours in syringe; however, total storage time for the reconstituted material must not exceed hours when exposed to normal indoor lighting.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. Intravenous Administration [1 mg/mL concentration].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 3.5 mg of bortezomib as white to off-white lyophilized powder in single-dose vial for reconstitution [see Dosage and Administration 2.8)] . For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized powder for reconstitution. 3).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with bortezomib.Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses >= 0.3 mg/m (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m 2. 13.2 Animal Toxicology and/or Pharmacology. Cardiovascular Toxicity: Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses >= 1.2 mg/m induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed. Chronic Administration: In animal studies at dose and schedule similar to that recommended for patients (twice weekly dosing for weeks followed by 1-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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration with strong CYP3A4 inhibitors can increase bortezomib exposure. Monitor for signs of bortezomib toxicity in patients receiving Bortezomib for Injection with strong CYP3A4 inhibitors. 7.1) Coadministration with strong CYP3A4 inducers can decrease bortezomib exposure. Avoid strong CYP3A4 inducers. 7.3) Coadministration with strong CYP3A4 inhibitors can increase bortezomib exposure. Monitor for signs of bortezomib toxicity in patients receiving Bortezomib for Injection with strong CYP3A4 inhibitors. 7.1) Coadministration with strong CYP3A4 inducers can decrease bortezomib exposure. Avoid strong CYP3A4 inducers. 7.3) 7.1 Effect of Strong CYP3A4 Inhibitors on Bortezomib. Monitor patients for signs of bortezomib toxicity and consider Bortezomib for Injection dose reduction if Bortezomib for Injection must be given with strong CYP3A4 inhibitors.. 7.3 Effect of Strong CYP3A4 Inducers on Bortezomib. Avoid strong CYP3A4 inducers. The coadministration of strong CYP3A4 inducer is expected to decrease the exposure of Bortezomib for Injection. Efficacy may be reduced when Bortezomib for Injection is coadministered with strong CYP3A4 inducers. Avoid St. Johns Wort Hypericum perforatum), as it may decrease Bortezomib exposure unpredictably. 7.4 Effect of Dexamethasone on Bortezomib. The coadministration of dexamethasone had no effect on bortezomib exposure.. 7.5 Effect of Melphalan-Prednisone on Bortezomib. The coadministration of melphalan-prednisone had no clinically important effect on bortezomib exposure.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients >= 65 were longer on bortezomib compared to dexamethasone [5.5 mo versus 4.3 mo, and mo versus 4.9 mo, respectively]. On the bortezomib arm, 40% (n=46) of evaluable patients aged >= 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade and events was 64%, 78% and 75% for bortezomib patients <= 50, 51 to 64 and >= 65 years old, respectively [see Adverse Reactions 6.1) and 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Bortezomib for Injection is supplied in 10 mL vial containing 3.5 mg of bortezomib as white to off-white cake or powder in single-dose vial for reconstitution (after reconstitution the solution is clear and colorless).Product No.NDC No.Strength76121063323-721-103.5 mg10 mL single-dose vial, packaged individually.Unopened vials may be stored at 20C to 25oC (68F to 77oF); excursions permitted from 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Retain in original package to protect from light.The vial stopper is not made with natural rubber latex.Follow guidelines for handling and disposal for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact 1. 15).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Bortezomib for Injection is proteasome inhibitor indicated for:treatment of patients with multiple myeloma 1.1) treatment of patients with mantle cell lymphoma who have received at least prior therapy 1.2) treatment of patients with multiple myeloma 1.1) treatment of patients with mantle cell lymphoma who have received at least prior therapy 1.2) 1.1 Multiple Myeloma. Bortezomib for Injection is indicated for the treatment of patients with multiple myeloma.. 1.2 Mantle Cell Lymphoma. Bortezomib for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least prior therapy.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Discuss the following with patients prior to treatment with Bortezomib for Injection:. Ability to Drive or Operate Machinery or Impairment of Mental Ability: Bortezomib for Injection may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions 5.2)]. Dehydration/Hypotension: Patients receiving Bortezomib for Injection therapy may experience vomiting and/or diarrhea. Advise patients how to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps [see Warnings and Precautions 5.2)] . Embryo-fetal Toxicity: Advise females of the potential risk to the fetus and to avoid pregnancy during treatment with Bortezomib for Injection. Advise female patients to use effective contraceptive measures to prevent pregnancy during treatment with Bortezomib for Injection and for months following cessation of therapy. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for months following cessation of therapy. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within months following treatment [see Warnings and Precautions 5.10)] . Lactation: Advise patients to avoid breastfeeding while receiving Bortezomib for Injection and for months after treatment [see Use in Specific Populations 8.2)] . Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking. Diabetic Patients: Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level [see Use in Specific Populations 8.8)] . Peripheral Neuropathy and Nervous System: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, burning feeling in the feet or hands, or weakness in the arms or legs. Advise patients to contact their physicians if they experience symptoms possibly indicative of PRES [see Warnings and Precautions 5.5)] or PML, such as convulsion, persistent headache, reduced eyesight, blurred vision, confusion, lethargy, altered ability to think, or difficulty walking. Cardiac: Advise patients to contact their physicians if they experience swelling of the feet, ankles, or legs or other heart-related problems [see Warnings and Precautions 5.3)] . Respiratory: Advise patients to contact their physicians if they experience shortness of breath, cough, or other lung problems [see Warnings and Precautions 5.4)] . Hepatic: Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain [see Warnings and Precautions 5.9)] . Dermal: Advise patients to contact their physicians if they experience rash, severe injection site reactions [see Dosage and Administration 2.7)] or skin pain. Discuss with patients the option for antiviral prophylaxis for herpes virus infection [see Adverse Reactions 6.1)] . Other: Instruct patients to contact their physicians if they develop an increase in blood pressure, bleeding, fever, constipation, or decreased appetite. U.S. Patent 8,962,572Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451289C Logo.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 for Injection is unknown, advise nursing women not to breastfeed during treatment with Bortezomib for Injection and for months after treatment.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Bortezomib is reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is 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 variety of cancer cell types in vitro. Bortezomib causes delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology 12.1)] and findings in animals, Bortezomib for Injection can cause fetal harm when administered to pregnant woman. There are no studies with the use of bortezomib in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose [see Data] Advise pregnant women of the potential risk to the fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataBortezomib 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 in the rat and 0.05 mg/kg; 0.6 mg/m in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m based on body surface area. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately0.5 times the clinical dose of 1.3 mg/m based on body surface area). Pregnant rabbits given bortezomib during organogenesis at dose of 0.05 mg/kg (0.6 mg/m 2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration 2.8) 6/2018.

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html OSHA Hazardous Drugs (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1 Multiple Myeloma. Bortezomib for Injection is indicated for the treatment of patients with multiple myeloma.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication. 8.8) Patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication. 8.8) 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology 12.1)] and findings in animals, Bortezomib for Injection can cause fetal harm when administered to pregnant woman. There are no studies with the use of bortezomib in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose [see Data] Advise pregnant women of the potential risk to the fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataBortezomib 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 in the rat and 0.05 mg/kg; 0.6 mg/m in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m based on body surface area. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately0.5 times the clinical dose of 1.3 mg/m based on body surface area). Pregnant rabbits given bortezomib during organogenesis at dose of 0.05 mg/kg (0.6 mg/m 2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. 8.2 Lactation. Risk SummaryThere 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 for Injection is unknown, advise nursing women not to breastfeed during treatment with Bortezomib for Injection and for months after treatment.. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals, bortezomib can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating Bortezomib for Injection treatment.. Contraception. FemalesAdvise females of reproductive potential to avoid pregnancy during treatment with Bortezomib for Injection and for months following cessation of therapy.. MalesMales with female sexual partners of reproductive potential should use effective contraception during treatment with Bortezomib for Injection and for months following cessation of therapy.. 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)] . 8.4 Pediatric Use. Additional information describing clinical study in which efficacy was not demonstrated in pediatric patients is in the approved label for Millennium Pharmaceuticals, Inc.s VELCADE (bortezomib) Injection. However, due to Millennium Pharmaceuticals, Inc.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.. 8.5 Geriatric Use. Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients >= 65 were longer on bortezomib compared to dexamethasone [5.5 mo versus 4.3 mo, and mo versus 4.9 mo, respectively]. On the bortezomib arm, 40% (n=46) of evaluable patients aged >= 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade and events was 64%, 78% and 75% for bortezomib patients <= 50, 51 to 64 and >= 65 years old, respectively [see Adverse Reactions 6.1) and Clinical Studies 14.1)] No overall differences in safety or effectiveness were observed between patients >= age 65 and younger patients receiving bortezomib; but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Patients with Renal Impairment. The pharmacokinetics of bortezomib are not influenced by the degree of renal impairment. Dosing adjustments of Bortezomib for Injection are not necessary for patients with renal insufficiency. Since dialysis may reduce bortezomib concentrations, Bortezomib for Injection should be administered after the dialysis procedure [see Clinical Pharmacology 12.3)] . 8.7 Patients with Hepatic Impairment. Reduce the starting dose in patients with moderate (bilirubin greater than 1.5 to times upper limit of normal (ULN) and any AST) and severe (bilirubin greater than times ULN and any AST) hepatic impairment [see Dosage and Administration 2.6), Clinical Pharmacology 12.3)]. 8.8 Patients with Diabetes. During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib for Injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Peripheral Neuropathy: Manage with dose modification or discontinuation. 2.5) Patients with pre-existing severe neuropathy should be treated with Bortezomib for Injection only after careful risk-benefit assessment. 2.5, 5.1) Hypotension: Use caution when treating patients taking anti hypertensives, with history of syncope, or with dehydration. 5.2) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. 5.3) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. 5.4) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for Injection if suspected. 5.5) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. 5.6) Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. 5.7) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. 5.8) Hepatic Toxicity: Monitor hepatic enzymes during treatment. 5.9) Embryo-fetal Toxicity: Bortezomib can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to avoid pregnancy. 5.10) Peripheral Neuropathy: Manage with dose modification or discontinuation. 2.5) Patients with pre-existing severe neuropathy should be treated with Bortezomib for Injection only after careful risk-benefit assessment. 2.5, 5.1) Hypotension: Use caution when treating patients taking anti hypertensives, with history of syncope, or with dehydration. 5.2) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. 5.3) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. 5.4) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for Injection if suspected. 5.5) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. 5.6) Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. 5.7) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. 5.8) Hepatic Toxicity: Monitor hepatic enzymes during treatment. 5.9) Embryo-fetal Toxicity: Bortezomib can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to avoid pregnancy. 5.10) 5.1 Peripheral Neuropathy. Bortezomib treatment causes peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including >= Grade 3) during treatment with bortezomib. Patients should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy during Bortezomib for Injection therapy may require decrease in the dose and/or less dose-intense schedule [see Dosage and Administration 2.5)] In the bortezomib versus dexamethasone phase relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with >= Grade peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade neuropathy or who had >= Grade peripheral neuropathy in the phase multiple myeloma studies [see Adverse Reactions 6.1)] The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. 5.2 Hypotension. The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics [see Adverse Reactions 6.1)] . 5.3 Cardiac Toxicity. Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of bortezomib versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was <= 1% for each individual reaction in the bortezomib group. In the dexamethasone group the incidence was <= 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.. 5.4 Pulmonary Toxicity. Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving bortezomib. Some of these events have been fatal.In clinical trial, the first two patients given high-dose cytarabine (2g/m per day) by continuous infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with bortezomib administration in the absence of left heart failure or significant pulmonary disease.In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib for Injection until prompt and comprehensive diagnostic evaluation is conducted.. 5.5 Posterior Reversible Encephalopathy Syndrome (PRES). Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. PRES is rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Bortezomib for Injection. The safety of reinitiating Bortezomib for Injection therapy in patients previously experiencing PRES is not known.. 5.6 Gastrointestinal Toxicity. Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions 6.1)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib for Injection for severe symptoms. 5.7 Thrombocytopenia/Neutropenia. Bortezomib is associated with thrombocytopenia and neutropenia that follow cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.Monitor complete blood counts (CBC) frequently during treatment with Bortezomib for Injection. Measure platelet counts prior to each dose of Bortezomib for Injection. Adjust dose/schedule for thrombocytopenia [see Table and Dosage and Administration 2.4)] Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with Bortezomib. Support with transfusions and supportive care, according to published guidelines. In the single-agent, relapsed multiple myeloma study of bortezomib versus dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6. The incidence of bleeding (>= Grade 3) was 2% on the bortezomib arm and was 1% in the dexamethasone arm. Table 6: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib versus DexamethasoneA baseline platelet count of 50,000/uL was required for study eligibility Data were missing at baseline for patient PretreatmentPlatelet CountNumber of Patients (N=331)Number (%) of Patients with Platelet Count 10,000/uL Number (%) of Patients with Platelet Count 10,000 to 25,000/uL>= 75,000/uL3098 (3%)36 (12%)>= 50,000/uL to 75,000/uL142 (14%)11 (79%)>= 10,000/uL to 50,000/uL71 (14%)5 (71%). 5.8 Tumor Lysis Syndrome. Tumor lysis syndrome has been reported with bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.. 5.9 Hepatic Toxicity. Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezomib for injection therapy to assess reversibility. There is limited rechallenge information in these patients.. 5.10 Embryo-fetal Toxicity. Based on the mechanism of action and findings in animals, bortezomib can cause fetal harm when administered to pregnant woman. Bortezomib administered to rabbits during organogenesis at dose approximately 0.5 times the clinical dose of 1.3 mg/m based on body surface area caused post-implantation loss and decreased number of live fetuses [see Use in Specific Populations 8.1)]. Females of reproductive potential should avoid becoming pregnant while being treated with Bortezomib for Injection. Advise females of reproductive potential that they must use contraception during treatment with Bortezomib for Injection and for months following cessation of therapy. Advise males with female sexual partners of reproductive potential that they must use contraception during treatment with Bortezomib for Injection and for months following cessation of therapy. If Bortezomib for Injection is used during pregnancy or if the patient becomes pregnant during Bortezomib for Injection treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations 8.1, 8.3) and Nonclinical Toxicology 13.1)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Safety Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 MyelomaTable describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in prospective randomized study.The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.Table 8: Most Commonly Reported Adverse Reactions (>= 10% in the Bortezomib, Melphalan and Prednisone arm) with Grades and >= Intensity in the Previously Untreated Multiple Myeloma StudyBortezomib, Melphalan and PrednisoneMelphalan and Prednisone(n=340)(n=337)Body SystemTotalToxicity Grade, (%)TotalToxicity Grade, (%)Adverse Reactionn (%)3>= 4n (%)3>= 4Blood and Lymphatic System Disorders Thrombocytopenia164 (48)60 (18)57 (17)140 (42)48 (14)39 (12) Neutropenia160 (47)101 (30)33 (10)143 (42)77 (23)42 (12) Anemia109 (32)41 (12)4 (1)156 (46)61 (18)18 (5) Leukopenia108 (32)64 (19)8 (2)93 (28)53 (16)11 (3) Lymphopenia78 (23)46 (14)17 (5)51 (15)26 (8)7 (2)Gastrointestinal Disorders Nausea134 (39)10 (3)070 (21)1 (<1)0 Diarrhea119 (35)19 (6)2 (1)20 (6)1 (<1)0 Vomiting87 (26)13 (4)041 (12)2 (1)0 Constipation77 (23)2 (1)014 (4)00 Abdominal Pain Upper34 (10)1 (<1)020 (6)00Nervous System Disorders Peripheral Neuropathya 156 (46)42 (12)2 (1)4 (1)00 Neuralgia117 (34)27 (8)2 (1)1 (<1)00 Paresthesia42 (12)6 (2)04 (1)00General Disorders and Administration Site Conditions Fatigue85 (25)19 (6)2 (1)48 (14)4 (1)0 Asthenia54 (16)18 (5)023 (7)3 (1)0 Pyrexia53 (16)4 (1)019 (6)1 (<1)1 (<1)Infections and Infestations Herpes Zoster39 (11)11 (3)09 (3)4 (1)0Metabolism and Nutrition Disorders Anorexia64 (19)6 (2)019 (6)00Skin and Subcutaneous Tissue Disorders Rash38 (11)2 (1)07 (2)00Psychiatric Disorders Insomnia35 (10)1 (<1)021 (6)00a Represents High Level Term Peripheral Neuropathies NEC. Relapsed Multiple Myeloma Randomized Study of Bortezomib versus DexamethasoneThe safety data described below and in Table reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m2 twice weekly for out of weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on weekly schedule. Duration of treatment was up to 11 cycles (9 months) with median duration of cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and to prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients 65 and >= 65 years of age. Most patients were Caucasian [see Clinical Studies (14.1)].Among the 331 bortezomib-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 Grade adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced Grade adverse reaction. All individual dexamethasone-related Grade adverse reactions were less than 1%.. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib versus DexamethasoneSerious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs current hospitalization, results in significant disability, or is deemed to be an important medical event. total of 80 (24%) patients from the bortezomib treatment arm experienced 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: case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: cases of sepsis, case of bacterial meningitis, and case of sudden death at home.. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib versus DexamethasoneThe most common adverse reactions from the relapsed multiple myeloma study are shown in Table 9. All adverse reactions with incidence >= 10% in the bortezomib arm are included.Table 9: Most Commonly Reported Adverse Reactions (>= 10% in Bortezomib arm), with Grades and Intensity in the Relapsed Multiple Myeloma Study of Bortezomib versus Dexamethasone (N=663)a Represents High Level Term Peripheral Neuropathies NECBortezomibN=331DexamethasoneN=332Adverse ReactionsAllGrade 3Grade 4AllGrade 3Grade 4Any Adverse Reactions324 (98)193 (58)28 (8)297 (89)110 (33)29 (9)Nausea172 (52)8 (2)031 (9)00Diarrhea NOS171 (52)22 (7)036 (11)2 (<1)0Fatigue130 (39)15 (5)082 (25)8 (2)0Peripheral neuropathiesa 115 (35)23 (7)2 (<1)14 (4)01 (<1)Thrombocytopenia109 (33)80 (24)12 (4)11 (3)5 (2)1 (<1)Constipation99 (30)6 (2)027 (8)1 (<1)0Vomiting NOS96 (29)8 (2)010 (3)1 (<1)0Anorexia68 (21)8 (2)08 (2)1 (<1)0Pyrexia66 (20)2 (<1)021 (6)3 (<1)1 (<1)Paresthesia64 (19)5 (2)024 (7)00Anemia NOS63 (19)20 (6)1 (<1)21 (6)8 (2)0Headache NOS62 (19)3 (<1)023 (7)1 (<1)0Neutropenia58 (18)37 (11)8 (2)1 (<1)1 (<1)0Rash NOS43 (13)3 (<1)07 (2)00Appetite decreased NOS36 (11)0012 (4)00Dyspnea NOS35 (11)11 (3)1 (<1)37 (11)7 (2)1 (<1)Abdominal pain NOS35 (11)5 (2)07 (2)00Weakness34 (10)10 (3)028 (8)8 (2)0. Safety Experience from the Phase Open-Label Extension Study in Relapsed Multiple MyelomaIn the phase extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for 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 and studies of single agent bortezomib 1.3 mg/m2/dose twice weekly for weeks followed by 10-day rest period in 1,163 patients with previously-treated multiple myeloma (N=1,008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase Open-Label Study of bortezomib subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least episode of >= Grade toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).In the Phase 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 SafetyA total of 26% of patients experienced 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 SafetyThe most common adverse reactions are shown in Table 10. All adverse reactions occurring at >= 10% are included. In the absence of randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patients underlying disease. Please see the discussion of specific adverse reactions that follows.Table 10: 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/m2 Dose (N=1,163) Represents High Level Term Peripheral Neuropathies NECAll Patients N=1163Multiple Myeloma N=1008Mantle Cell Lymphoma N=155Adverse ReactionsAll>= Grade 3All>= Grade 3All>= Grade 3Nausea567 (49)36 (3)511 (51)32 (3)56 (36)4 (3)Diarrhea NOS530 (46)83 (7)470 (47)72 (7)60 (39)11 (7)Fatigue477 (41)86 (7)396 (39)71 (7)81 (52)15 (10)Peripheral neuropathies443 (38)129 (11)359 (36)110 (11)84 (54)19 (12)Thrombocytopenia369 (32)295 (25)344 (34)283 (28)25 (16)12 (8)Vomiting NOS321 (28)44 (4)286 (28)40 (4)35 (23)4 (3)Constipation296 (25)17 (1)244 (24)14 (1)52 (34)3 (2)Pyrexia249 (21)16 (1)233 (23)15 (1)16 (10)1 (<1)Anorexia227 (20)19 (2)205 (20)16 (2)22 (14)3 (2)Anemia NOS209 (18)65 (6)190 (19)63 (6)19 (12)2 (1)Headache NOS175 (15)8 (<1)160 (16)8 (<1)15 (10)0Neutropenia172 (15)121 (10)164 (16)117 (12)8 (5)4 (3)Rash NOS156 (13)8 (<1)120 (12)4 (<1)36 (23)4 (3)Paresthesia147 (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)Weakness124 (11)31 (3)106 (11)28 (3)18 (12)3 (2). Description of Selected Adverse Reactions from the Integrated Phase and Relapsed Multiple Myeloma and Phase Relapsed Mantle Cell Lymphoma Studies. Gastrointestinal ToxicityA 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 adverse reactions occurred in 14% of patients; >= Grade adverse reactions were <= 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).. ThrombocytopeniaAcross the studies, bortezomib-associated thrombocytopenia was characterized by decrease in platelet count during the dosing period (days to 11) and return toward baseline during the 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade in 22%, >= Grade in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients [see Warnings and Precautions (5.7)]. Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of >= Grade thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).. Peripheral NeuropathyOverall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade for 11% of patients and >= Grade 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 versus dexamethasone phase relapsed multiple myeloma study, among the 62 bortezomib- treated patients who experienced >= Grade peripheral neuropathy and had dose adjustments, 48% had improved or resolved with median of 3.8 months from first onset.In the phase relapsed multiple myeloma studies, among the 30 patients who experienced Grade peripheral neuropathy resulting in discontinuation or who experienced >= Grade peripheral neuropathy, 73% reported improvement or resolution with median time of 47 days to improvement of one Grade or more from the last dose of bortezomib.. HypotensionThe incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade or in the majority of patients and Grade in 2% and >= Grade in 1%. Two percent (2%) of patients had hypotension reported as 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 syncopal reaction.. NeutropeniaNeutrophil counts decreased during the bortezomib dosing period (days to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade in 8% of patients and >= Grade in 2%. Neutropenia was reported as 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 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 in 7% and >= Grade in 1% of patients. Asthenia was reported as Grade in 2% and >= Grade 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.. PyrexiaPyrexia (> 38oC) was reported as an adverse reaction for 21% of patients. The reaction was Grade in 1% and >= Grade in 1%. Pyrexia was reported as 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 pyrexia was 1% in patients with multiple myeloma and 1% in patients with mantle cell lymphoma.. Herpes Virus InfectionConsider using antiviral prophylaxis in subjects being treated with Bortezomib for Injection. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in to 3% in subjects treated with bortezomib and 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 MyelomaA 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 and 10; 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 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of >= Grade peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).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 patient with cerebrovascular accident and one in patient with sepsis.. Additional Adverse Reactions from Clinical StudiesThe 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: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopeniaCardiac disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardiaEar and labyrinth disorders: Hearing impaired, vertigoEye disorders: Diplopia and blurred vision, conjunctival infection, irritationGastrointestinal disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal refluxGeneral disorders and administration site conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitisHepatobiliary disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failureImmune system disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edemaInfections and infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter-related infectionInjury, poisoning and procedural complications: Catheter-related complication, skeletal fracture, subdural hematomaInvestigations: Weight decreasedMetabolism and nutrition disorders: Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremiaMusculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremityNervous system disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attackPsychiatric disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideationRenal and urinary disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferativeRespiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertensionSkin and subcutaneous tissue disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritusVascular disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No starting dosage adjustment of Bortezomib for Injection is recommended for patients with mild hepatic impairment (total bilirubin <= 1x ULN and AST ULN, or total bilirubin 1 to 1.5x 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 (2.6), Clinical Pharmacology (12.3)].

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No starting dosage adjustment of Bortezomib for Injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib for Injection should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)].