Stability

Unopened vials of Bortezomib for Injection are stable until the date indicated on the package when stored in the original package protected from light.

Bortezomib for Injection contains no antimicrobial preservative. Administer reconstituted Bortezomib for Injection within eight hours of preparation. When reconstituted as directed, Bortezomib for Injection may be stored at 25ºC (77ºF). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma

Table 9 describes safety data from 340 patients with previously untreated multiple myeloma who received Bortezomib for Injection (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.

The safety profile of Bortezomib for Injection in combination with melphalan/prednisone is consistent with the known safety profiles of both Bortezomib for Injection and melphalan/prednisone.

Relapsed Multiple Myeloma Randomized Study of Bortezomib for Injection vs Dexamethasone

The safety data described below and in Table 10 reflect exposure to either Bortezomib for Injection (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib for Injection was administered intravenously at doses of 1.3 mg/m2 twice weekly for two out of three weeks (21 day cycle). After eight, 21 day cycles patients continued therapy for three, 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian [see Clinical Studies (14.1)].

Among the 331 Bortezomib for Injection-treated patients, the most commonly reported (>20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (>20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the Bortezomib for Injection-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib for Injection vs Dexamethasone

Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the Bortezomib for Injection treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the Bortezomib for Injection treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).

A total of 145 patients, including 84 (25%) of 331 patients in the Bortezomib for Injection treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 Bortezomib for Injection-treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).

Four deaths were considered to be Bortezomib for Injection-related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and one case of sudden death at home.

Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib for Injection vs Dexamethasone

The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥10% in the Bortezomib for Injection arm are included.

Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma

In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged Bortezomib for Injection treatment. These patients were treated for a total of 5.3 to 23 months, including time on Bortezomib for Injection in the prior Bortezomib for Injection study [see Clinical Studies (14.1)].

Safety Experience from the Phase 3 Open-Label Study of Bortezomib for Injection Subcutaneous vs Intravenous in Relapsed Multiple Myeloma

The safety and efficacy of Bortezomib for Injection administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m2. This was a randomized, comparative study of Bortezomib for Injection subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 11 reflect exposure to either Bortezomib for Injection subcutaneous (N=147) or Bortezomib for Injection intravenous (N=74) [see Clinical Studies (14.1)].

In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥3 adverse reactions. Differences of ≥5% were reported in neuralgia (3% subcutaneous vs 9% intravenous), peripheral neuropathies (6% subcutaneous vs 15% intravenous), neutropenia (13% subcutaneous vs 18% intravenous), and thrombocytopenia (8% subcutaneous vs 16% intravenous).

A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only two (1%) patients were reported as having severe reactions, one case of pruritus and one case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of six days.

Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib for Injection Subcutaneous vs Intravenous

The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

Two patients (1%) in the subcutaneous treatment group and one (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.

Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma

Table 12 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received Bortezomib for Injection (1.3 mg/m2) administered intravenously in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and prednisone (100 mg/m2) (VcR-CAP) in a prospective randomized study.

Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% vs R-CHOP 5%).

The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment.

The incidences of Grade ≥3 bleeding events were similar between the two arms (four patients in the VcR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥3 bleeding events resolved without sequelae in the VcR-CAP arm.

Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (<1%; two patients).

Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma)

Safety data from Phase 2 and 3 studies of single agent Bortezomib for Injection 1.3 mg/m2/dose twice weekly for two weeks followed by a ten day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 open-label study of Bortezomib for Injection subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib for Injection was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (>20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib for Injection administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib for Injection was not associated with tissue damage.

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each).

Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).

In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.

Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety

The most common adverse reactions are shown in Table 13. All adverse reactions occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.

Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies

Gastrointestinal Toxicity

A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥Grade 4 adverse reactions were ≤1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).

Thrombocytopenia

Across the studies, Bortezomib for Injection-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (Days 1 to 11) and a return toward baseline during the ten day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in Bortezomib for Injection discontinuation in 2% of patients [see Warnings and Precautions (5.7)]. Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).

Peripheral Neuropathy

Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥Grade 4 for <1% of patients. Eight percent (8%) of patients discontinued Bortezomib for Injection 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 for Injection vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 Bortezomib for Injection-treated patients who experienced ≥Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.

In the Phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one grade or more from the last dose of Bortezomib for Injection.

Hypotension

The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with Bortezomib for Injection. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥Grade 4 in <1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, <1% of patients experienced hypotension associated with a syncopal reaction.

Neutropenia

Neutrophil counts decreased during the Bortezomib for Injection dosing period (Days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in <1% of patients and <1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).

Asthenic Conditions (Fatigue, Malaise, Weakness, Asthenia)

Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and ≥Grade 4 in <1% of patients. Asthenia was reported as Grade 3 in 2% and ≥Grade 4 in <1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and <1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.

Pyrexia

Pyrexia (>38ºC) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥Grade 4 in <1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to Bortezomib for Injection discontinuation in <1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥Grade 3 pyrexia was 1% in patients with multiple myeloma and <1% in patients with mantle cell lymphoma.

Herpes Virus Infection

Consider using antiviral prophylaxis in subjects being treated with Bortezomib for Injection. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with Bortezomib for Injection (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with Bortezomib for Injection and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the Bortezomib for Injection, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).

Retreatment in Relapsed Multiple Myeloma

A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous Bortezomib for Injection. The safety profile of patients in this trial is consistent with the known safety profile of Bortezomib for Injection-treated patients with relapsed multiple myeloma as demonstrated in Tables 10, 11, and 13; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. 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 for Injection-related occurred within 30 days of the last Bortezomib for Injection dose; one in a patient with cerebrovascular accident and one in a patient with sepsis.

Additional Adverse Reactions from Clinical Studies

The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with Bortezomib for Injection 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

Strong CYP3A4 Inducers

Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may decrease Bortezomib for Injection efficacy. Avoid coadministration with strong CYP3A4 inducers.

Strong CYP3A4 Inhibitors

Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may increase the risk of bortezomib toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors.

Risk Summary

Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals, Bortezomib for Injection can cause fetal harm when administered to a pregnant woman. There are no studies with the use of Bortezomib for Injection in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data). Advise pregnant women of the potential risk to the fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Bortezomib for Injection is unknown, advise nursing women not to breastfeed during treatment with Bortezomib for Injection and for two months after treatment.

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential prior to initiating Bortezomib for Injection treatment.

Contraception

Infertility

Based on the mechanism of action and findings in animals, Bortezomib for Injection may have an effect on either male or female fertility [see Nonclinical Toxicology (13.1)].

Distribution

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single- or repeat-dose administration of 1 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.

Elimination

The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of bortezomib were observed based on age, sex, or renal impairment (including patients administered Bortezomib for Injection after dialysis). The effect of race on bortezomib pharmacokinetics is unknown.

Drug Interaction Studies

Cardiovascular Toxicity

Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours postdose. Doses ≥1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.

Chronic Administration

In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for two weeks followed by one week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.

Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma

A prospective, international, randomized (1:1), open-label clinical study (NCT00111319) of 682 patients was conducted to determine whether Bortezomib for Injection administered intravenously (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of nine cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the Bortezomib for Injection study arm.

The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500/microliter (33,000;587,000).

Efficacy results for the trial are presented in Table 14. At a prespecified interim analysis (with median follow-up of 16.3 months), the combination of Bortezomib for Injection, 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 for Injection in addition. A later, prespecified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the Bortezomib for Injection, melphalan and prednisone treatment arm despite subsequent therapies including Bortezomib for Injection 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 for Injection, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85).

TTP was statistically significantly longer on the Bortezomib for Injection, melphalan and prednisone arm (see Figure 1). (median follow-up 16.3 months)

Figure 1: Time to Progression Bortezomib for Injection, Melphalan and Prednisone vs Melphalan and Prednisone

Overall survival was statistically significantly longer on the Bortezomib for Injection, melphalan and prednisone arm (see Figure 2). (median follow-up 60.1 months)

Figure 2: Overall Survival Bortezomib for Injection, Melphalan and Prednisone vs Melphalan and Prednisone

Randomized, Clinical Study in Relapsed Multiple Myeloma of Bortezomib for Injection vs Dexamethasone

A prospective Phase 3, international, randomized (1:1), stratified, open-label clinical study (NCT00048230) enrolling 669 patients was designed to determine whether Bortezomib for Injection resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade ≥2 peripheral neuropathy or platelet counts <50,000/μL. A total of 627 patients were evaluable for response.

Stratification factors were based on the number of lines of prior therapy the patient had previously received (one previous line vs more than one line of therapy), time of progression relative to prior treatment (progression during or within six months of stopping their most recent therapy vs relapse >6 months after receiving their most recent therapy), and screening beta2-microglobulin levels (≤2.5 mg/L vs >2.5 mg/L).

Baseline patient and disease characteristics are summarized in Table 15.

Patients in the Bortezomib for Injection treatment group were to receive 8, three week treatment cycles followed by 3, five week treatment cycles of Bortezomib for Injection. Patients achieving a CR were treated for four cycles beyond first evidence of CR. Within each three week treatment cycle, Bortezomib for Injection 1.3 mg/m2/dose alone was administered by intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21). Within each five week treatment cycle, Bortezomib for Injection 1.3 mg/m2/dose alone was administered by intravenous bolus once weekly for four weeks on Days 1, 8, 15, and 22 followed by a 13 day rest period (Days 23 to 35) [see Dosage and Administration (2.2)].

Patients in the dexamethasone treatment group were to receive 4, five week treatment cycles followed by 5, four week treatment cycles. Within each five week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15 day rest period (Days 21 to 35). Within each four week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24 day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered Bortezomib for Injection at a standard dose and schedule on a companion study. Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered Bortezomib for Injection, regardless of disease status.

In the Bortezomib for Injection arm, 34% of patients received at least one Bortezomib for Injection dose in all eight of the three week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of Bortezomib for Injection doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all four of the five week treatment cycles of therapy, and 6% received at least one dose in all nine cycles.

The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 16. 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 a negative immunofixation test (IF-). Partial response (PR) requires ≥50% reduction in serum myeloma protein and ≥90% reduction of urine myeloma protein on at least two occasions for a minimum of at least six 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+).

TTP was statistically significantly longer on the Bortezomib for Injection arm (see Figure 3).

Figure 3: Time to Progression Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study)

As shown in Figure 4, Bortezomib for Injection had a significant survival advantage relative to dexamethasone (p <0.05). The median follow-up was 8.3 months.

Figure 4: Overall Survival Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study)

For the 121 patients achieving a response (CR or PR) on the Bortezomib for Injection arm, the median duration was 8.0 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 for Injection arm regardless of beta2-microglobulin levels at baseline.

Randomized, Open-Label Clinical Study of Bortezomib for Injection Subcutaneous vs Intravenous in Relapsed Multiple Myeloma

An open-label, randomized, Phase 3 noninferiority study (NCT00722566) compared the efficacy and safety of the subcutaneous administration of Bortezomib for Injection vs the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m2 of Bortezomib for Injection by either the subcutaneous (n=148) or intravenous (n=74) route for eight cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with Bortezomib for Injection alone after four cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after Bortezomib for Injection administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/μL were excluded. A total of 218 patients were evaluable for response.

Stratification factors were based on the number of lines of prior therapy the patient had received (one previous line vs more than one line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III).

The baseline demographic and other characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range: 38 to 88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous.

This study met its primary (noninferiority) objective that single agent subcutaneous Bortezomib for Injection retains at least 60% of the overall response rate after four cycles relative to single agent intravenous Bortezomib for Injection. The results are provided in Table 17.

A Randomized, Phase 2 Dose-Response Study in Relapsed Multiple Myeloma

An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive Bortezomib for Injection 1 mg/m2 or 1.3 mg/m2 intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of Bortezomib for Injection on this trial was two years, and patients had received a median of one prior line of treatment (median of three prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m2 and 38% (10/26) at 1.3 mg/m2.

A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma

Patients from the two Phase 2 studies, who in the investigators' opinion would experience additional clinical benefit, continued to receive Bortezomib for Injection beyond 8 cycles on an extension study. Sixty-three (63) patients from the Phase 2 multiple myeloma studies were enrolled and received a median of seven additional cycles of Bortezomib for Injection therapy for a total median of 14 cycles (range: 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty- seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard three week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged Bortezomib for Injection treatment [see Adverse Reactions (6.1)].

A Single-Arm Trial of Retreatment in Relapsed Multiple Myeloma

A single-arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with Bortezomib for Injection. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a Bortezomib for Injection-containing regimen (median of two prior lines of therapy [range: 1 to 7]) were retreated upon progression with Bortezomib for Injection administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade ≥2. At least six months after prior Bortezomib for Injection therapy, Bortezomib for Injection was restarted at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤1 mg/m2 (n=37) and given on Days 1, 4, 8 and 11 every three weeks for maximum of eight cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with Bortezomib for Injection to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of Bortezomib for Injection retreatment cycles.

The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38.5% (95% CI: 30.1, 47.4). One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6.5 months and the range was 0.6 to 19.3 months.

A Randomized, Open-Label Clinical Study in Patients with Previously Untreated Mantle Cell Lymphoma

A randomized, open-label, Phase 3 study (NCT00722137) was conducted in 487 adult patients with previously untreated mantle cell lymphoma (Stage II, III or IV) who were ineligible or not considered for bone marrow transplantation to determine whether Bortezomib for Injection administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) resulted in improvement in progression-free survival (PFS) when compared to the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This clinical study utilized independent pathology confirmation and independent radiologic response assessment.

Patients in the VcR-CAP treatment arm received Bortezomib for Injection (1.3 mg/m2) administered intravenously on Days 1, 4, 8, and 11 (rest period Days 12 to 21); rituximab (375 mg/m2) on Day 1; cyclophosphamide (750 mg/m2) on Day 1; doxorubicin (50 mg/m2) on Day 1; and prednisone (100 mg/m2) on Day 1 through Day 5 of the 21 day treatment cycle. For patients with a response first documented at Cycle 6, two additional treatment cycles were allowed.

Median patient age was 66 years, 74% were male, 66% were Caucasian and 32% were Asian. Sixty- nine percent of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of three (high-intermediate) or higher and 76% had Stage IV disease.

The majority of the patients in both groups received six or more cycles of treatment, 84% in the VcR-CAP group and 83% in the R-CHOP group. Median number of cycles received by patients in both treatment arms was six with 17% of patients in the R-CHOP group and 14% of subjects in the VcR-CAP group receiving up to two additional cycles.

The efficacy results for PFS, CR and ORR with a median follow-up of 40 months are presented in Table 18. The response criteria used to assess efficacy were based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma (IWRC). Final overall survival results at a median follow-up of 78.5 months are also presented in Table 18 and Figure 6. The combination of VcR-CAP resulted in statistically significant prolongation of PFS compared with R-CHOP (see Table 18, Figure 5).

Figure 5: Progression-Free Survival VcR-CAP vs R-CHOP (previously Untreated Mantle Cell Lymphoma Study)

Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone;

VcR-CAP = Bortezomib for Injection, rituximab, cyclophosphamide, doxorubicin, and prednisone.

Figure 6: Overall Survival VcR-CAP vs R-CHOP (previously Untreated Mantle Cell Lymphoma Study)

Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone;

VcR-CAP = Bortezomib for Injection, rituximab, cyclophosphamide, doxorubicin, and prednisone.

A Phase 2 Single-Arm Clinical Study in Relapsed Mantle Cell Lymphoma after Prior Therapy

The safety and efficacy of Bortezomib for Injection in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study (NCT00063713) of 155 patients with progressive disease who had received at least one prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were Stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty-seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of Bortezomib for Injection 1.3 mg/m2/dose was administered twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for four cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see Dosage and Administration (2.6, 2.7)].

Responses to Bortezomib for Injection are shown in Table 19. Response rates to Bortezomib for Injection were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was four; in responding patients the median number of cycles was eight. The median time to response was 40 days (range: 31 to 204 days). The median duration of follow-up was more than 13 months.