The following adverse reactions are also discussed in other sections of the labeling:

• Peripheral Neuropathy [see WARNINGS and PRECAUTIONS; DOSAGE AND ADMINISTRATION (Table 3)]
• Hypotension [see WARNINGS and PRECAUTIONS]
• Cardiac Disorders [see WARNINGS and PRECAUTIONS]
• Pulmonary Disorders [see WARNINGS and PRECAUTIONS]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS and PRECAUTIONS]
• Gastrointestinal Adverse Events [see WARNINGS and PRECAUTIONS]
• Thrombocytopenia/Neutropenia [see WARNINGS and PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS and PRECAUTIONS]
• Hepatic Events [see WARNINGS and PRECAUTIONS]

Clinical Trials Safety Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma

Table 5 describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective randomized study.

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

Table 5: Most Commonly Reported Adverse Events ( ≥ 10% in VELCADE, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study

Relapsed Multiple Myeloma Randomized Study

The safety data described below and in Table 6 reflect exposure to either VELCADE (n=331) or dexamethasone (n=332) in a study of patients with multiple myeloma. VELCADE was administered intravenously at doses of 1.3 mg/m² twice weekly for 2 out of 3 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 (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 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 events was similar in men and women, and in patients < 65 and 65 years of age. Most patients were Caucasian. [see Clinical Studies)]

Among the 331 VELCADE treated patients, the most commonly reported events overall were asthenic conditions (61%), diarrhea and nausea (each 57%), constipation (42%), peripheral neuropathy NEC (36%), vomiting, pyrexia, thrombocytopenia, and psychiatric disorders (each 35%), anorexia and appetite decreased (34%), paresthesia and dysesthesia (27%), anemia and headache (each 26%), and cough (21%). The most commonly reported adverse events reported among the 332 patients in the dexamethasone group were psychiatric disorders (49%), asthenic conditions (45%), insomnia (27%), anemia (22%), and diarrhea and lower respiratory/lung infections (each 21%). Fourteen percent (14%) of patients in the VELCADE treated arm experienced a Grade 4 adverse event; the most common toxicities were thrombocytopenia (4%), neutropenia (2%) and hypercalcemia (2%). Sixteen percent (16%) of dexamethasone treated patients experienced a Grade 4 adverse event; the most common toxicity was hyperglycemia (2%).

Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study

Serious adverse events are defined as any event, regardless of causality, 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 144 (44%) patients from the VELCADE treatment arm experienced an SAE during the study, as did 144 (43%) dexamethasone-treated patients. The most commonly reported SAEs in the VELCADE treatment arm were pyrexia (6%), diarrhea (5%), dyspnea and pneumonia (4%), and vomiting (3%). In the dexamethasone treatment group, the most commonly reported SAEs were pneumonia (7%), pyrexia (4%), and hyperglycemia (3%).

A total of 145 patients, including 84 (25%) of 331 patients in the VELCADE treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse events assessed as drug-related by the investigators. Among the 331 VELCADE treated patients, the most commonly reported drug-related event leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported drug-related events leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).

Four deaths were considered to be VELCADE related in this relapsed multiple myeloma study: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.

Most Commonly Reported Adverse Events in the Relapsed Multiple Myeloma Study

The most common adverse events from the relapsed multiple myeloma study are shown in Table 6. All adverse events with incidence ≥ 10% in the VELCADE arm are included.

Table 6: Most Commonly Reported Adverse Events ( ≥ 10% in VELCADE arm),with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study (N=663)

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 VELCADE treatment. These patients were treated for a total of 5.3 to 23 months, including time on VELCADE in the prior VELCADE study. [see Clinical Studies]

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

Safety data from phase 2 and 3 studies of single agent VELCADE 1.3 mg/m²/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. [see Clinical Studies]

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated) (39%), thrombocytopenia and appetite decreased (including anorexia) (each 36%), pyrexia (34%), vomiting (33%), and anemia (29%). Twenty percent (20%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%).

Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the Integrated Summary of Safety

A total of 50% of patients experienced SAEs during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

Adverse events thought by the investigator to be drug-related and leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), asthenic conditions (3%) and thrombocytopenia and diarrhea (each 2%).

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 Events in the Integrated Summary of Safety

The most common adverse events are shown in Table 7. All adverse events occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.

Table 7: Most Commonly Reported ( ≥ 10% Overall) Adverse Events in Integrated Analyses of Relapsed Multiple Myeloma and Mantle Cell Lymphoma Studies using the 1.3 mg/m² Dose (N=1163)

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

Gastrointestinal Events

A total of 87% of patients experienced at least one GI disorder. The most common GI disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other GI disorders included dyspepsia and dysgeusia. Grade 3 GI events occurred in 18% of patients; Grade 4 events were 1%. GI events were considered serious in 11% of patients. Five percent (5%) of patients discontinued due to a GI event. Nausea was reported more often in patients with multiple myeloma (57%) compared to patients with mantle cell lymphoma (44%). [see WARNINGS and PRECAUTIONS]

Thrombocytopenia

Across the studies, VELCADE 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 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 36% of patients. Thrombocytopenia was Grade 3 in 24%, ≥ Grade 4 in 5%, and serious in 3% of patients, and the event resulted in VELCADE discontinuation in 2% of patients [see WARNINGS and PRECAUTIONS]. Thrombocytopenia was reported more often in patients with multiple myeloma (38%) compared to patients with mantle cell lymphoma (21%). The incidence of ≥ Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (32%) compared to patients with mantle cell lymphoma (11%). [see WARNINGS and PRECAUTIONS]

Peripheral Neuropathy

Overall, peripheral neuropathy NEC occurred in 39% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and Grade 4 for < 1% of patients. Eight percent (8%) of patients discontinued VELCADE due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (55%) compared to patients with multiple myeloma (37%).

In the relapsed multiple myeloma study, among the 87 patients who experienced ≥ Grade 2 peripheral neuropathy, 51% had improved or resolved with a median of 3.5 months from first onset.

Among the patients with peripheral neuropathy in the phase 2 multiple myeloma studies that was Grade 2 and led to discontinuation or was Grade 3, 73% (24 of 33) reported improvement or resolution following VELCADE dose adjustment, with a median time to improvement of one Grade or more from the last dose of VELCADE of 33 days. [see WARNINGS and PRECAUTIONS]

Hypotension

The incidence of hypotension (postural hypotension, orthostatic hypotension and hypotension NOS) was 13% in patients treated with VELCADE. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 3% and ≥ Grade 4 in < 1%. Three percent (3%) of patients had hypotension reported as an SAE, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (12%) and those with mantle cell lymphoma (15%). In addition, 2% of patients experienced hypotension and had a syncopal event. Doses of antihypertensive medications may need to be adjusted in patients receiving VELCADE. [see WARNINGS and PRECAUTIONS]

Neutropenia

Neutrophil counts decreased during the VELCADE dosing period (days 1 to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 17% of patients and was Grade 3 in 9% of patients and ≥ Grade 4 in 3%. Neutropenia was reported as a serious event in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (18%) compared to patients with mantle cell lymphoma (6%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (14%) compared to patients with mantle cell lymphoma (4%). [see WARNINGS and PRECAUTIONS]

Asthenic conditions (Fatigue, Malaise, Weakness)

Asthenic conditions were reported in 64% of patients. Asthenia was Grade 3 for 16% and ≥ Grade 4 in < 1% of patients. Four percent (4%) of patients discontinued treatment due to asthenia. Asthenic conditions were reported in 62% of patients with multiple myeloma and 72% of patients with mantle cell lymphoma.

Pyrexia

Pyrexia ( > 38°C) was reported as an adverse event for 34% of patients. The event was Grade 3 in 3% and ≥ Grade 4 in < 1%. Pyrexia was reported as a serious adverse event in 6% of patients and led to VELCADE discontinuation in < 1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (37%) compared to patients with mantle cell lymphoma (19%). The incidence of ≥ Grade 3 pyrexia was 3% in patients with multiple myeloma and 1% in patients with mantle cell lymphoma.

Herpes Virus Infection

Physicians should consider using antiviral prophylaxis in subjects being treated with VELCADE. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with VELCADE (13%) than in the control groups (4-5%). Herpes simplex was seen in 2-8% in subjects treated with VELCADE and 1-5% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the VELCADE, 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%). In the postmarketing experience, rare cases of herpes meningoencephalitis and ophthalmic herpes have been reported.

Additional Adverse Events from Clinical Studies

The following clinically important SAEs that are not described above have been reported in clinical trials in patients treated with VELCADE 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: Disseminated intravascular coagulation, 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: 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: Injection site erythema, neuralgia, injection site pain, irritation, 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, urinary tract infection, herpes viral infection, listeriosis, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter related infection

Injury, poisoning and procedural complications: Catheter related complication, skeletal fracture, subdural hematoma

Metabolism and nutrition disorders: Hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia

Nervous system disorders: Ataxia, coma, dysarthria, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, hemorrhagic stroke, motor dysfunction, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack, reversible posterior leukoencephalopathy syndrome

Psychiatric disorders: Agitation, confusion, 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, 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

Vascular disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, peripheral embolism, pulmonary embolism, pulmonary hypertension

Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with VELCADE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, acute diffuse infiltrative pulmonary disease, toxic epidermal necrolysis, herpes meningoencephalitis and ophthalmic herpes.

Ketoconazole: Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. [see Pharmacokinetics] Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). [see Pharmacokinetics]

Melphalan-Prednisone: Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. [see Pharmacokinetics]

Omeprazole: Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. [see Pharmacokinetics]

Cytochrome P450: Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. [see Pharmacokinetics]

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