SIDE EFFECTS

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 Toxicity[see WARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]
• Posterior Reversible Encephalopathy Syndrome (PRES) [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Toxicity [see WARNINGS AND PRECAUTIONS]
• Thrombocytopenia/Neutropenia [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Hepatic Toxicity [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 clinical practice.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma

Table 7 describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE (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 VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

Table 7: Most Commonly Reported Adverse Reactions ( ≥ 10% in the VELCADE, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study

Relapsed Multiple Myeloma Randomized Study of VELCADE versus Dexamethasone

The safety data described below and in Table 8 reflect exposure to either VELCADE (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. VELCADE was administered intravenously at doses of 1.3 mg/m²twice 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 reactions 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 ( > 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies NEC (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 VELCADE-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasonetreated 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 VELCADE versus 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 VELCADE 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 VELCADE 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 VELCADE treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 VELCADE 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 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 Reactions in the Relapsed Multiple Myeloma Study of VELCADE versus Dexamethasone

The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence ≥ 10% in the VELCADE arm are included.

Table 8: Most Commonly Reported Adverse Reactions ( ≥ 10% in VELCADE arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of VELCADE versus Dexamethasone (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].

Safety Experience from the Phase 3 Open-Label Study of VELCADE Subcutaneous versus Intravenous in Relapsed Multiple Myeloma

The safety and efficacy of VELCADE 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 VELCADE subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 9 reflect exposure to either VELCADE subcutaneous (n=147) or VELCADE intravenous (n=74) [see Clinical Studies].

Table 9: Most Commonly Reported Adverse Reactions ( ≥ 10%), with Grade 3 and ≥ 4 Intensity in theRelapsed Multiple Myeloma Study (N=221) of VELCADE Subcutaneous versus Intravenous

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 versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).

A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 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 6 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 VELCADE Subcutaneous versus 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 1 (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.

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. This analysis does not include data from the Phase 3 Open-Label Study of VELCADE subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of VELCADE 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 NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

In the Phase 2 relapsed multiple myeloma clinical trials of VELCADE administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of VELCADE 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 NEC, 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 10. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.

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

Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 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, 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 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥ Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in VELCADE discontinuation in 2% of patients. 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 NEC 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 VELCADE 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 VELCADE versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62 VELCADE-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 VELCADE.

Hypotension

The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with VELCADE. 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 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 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).

Asthenic conditions (Fatigue, Malaise, Weakness, Asthenia)

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

Pyrexia

Pyrexia ( > 38°C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in < 1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to VELCADE 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 VELCADE. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with VELCADE (ranging between 6-11%) than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with VELCADE and 1-3% 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%).

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 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: 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

Postmarketing Experience

The following adverse reactions have been identified from the worldwide postmarketing 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, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet's syndrome), herpes meningoencephalitis, optic neuropathy, blindness and ophthalmic herpes.

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