ADVERSE REACTIONS
Randomized Open-Label Phase 3 Multiple Myeloma Study
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 Phase 3 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 the phase 3 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 Phase 3 Multiple Myeloma Study
The most common adverse events from the phase 3 multiple myeloma study are shown in Table 7. All adverse events with incidence ≥10% in the VELCADE arm are included.
Table 7: Most Commonly Reported Adverse Events (≥10% in VELCADE arm), with Grades 3 and 4 Intensity in the Phase 3 Multiple Myeloma Study (N=663) | Treatment Group |
| VELCADE (n=331) [n (%)] | Dexamethasone (n=332) [n (%)] |
| All Events | Grade 3 Events | Grade 4 Events | All Events | Grade 3 Events | Grade 4 Events |
a Peripheral neuropathy includes all terms under peripheral neuropathy NEC, (peripheral neuropathy NOS, peripheral neuropathy aggravated, peripheral sensory neuropathy, and peripheral motor neuropathy, and neuropathy NOS). |
Adverse Event | 331 (100) | 203 (61) | 45 (14) | 327 (98) | 146 (44) | 52 (16) |
Asthenic conditions | 201 (61) | 39 (12) | 1 (<1) | 148 (45) | 20 (6) | 0 |
Diarrhea | 190 (57) | 24 (7) | 0 | 69 (21) | 6 (2) | 0 |
Nausea | 190 (57) | 8 (2) | 0 | 46 (14) | 0 | 0 |
Constipation | 140 (42) | 7 (2) | 0 | 49 (15) | 4 (1) | 0 |
Peripheral neuropathya | 120 (36) | 24 (7) | 2 (<1) | 29 (9) | 1 (<1) | 1 (<1) |
Vomiting | 117 (35) | 11 (3) | 0 | 20 (6) | 4 (1) | 0 |
Pyrexia | 116 (35) | 6 (2) | 0 | 54 (16) | 4 (1) | 1 (<1) |
Thrombocytopenia | 115 (35) | 85 (26) | 12 (4) | 36 (11) | 18 (5) | 4 (1) |
Psychiatric disorders | 117 (35) | 9 (3) | 2 (<1) | 163 (49) | 26 (8) | 3 (<1) |
Anorexia and appetite decreased | 112 (34) | 9 (3) | 0 | 31 (9) | 1 (<1) | 0 |
Paresthesia and dysesthesia | 91 (27) | 6 (2) | 0 | 38 (11) | 1 (<1) | 0 |
Anemia | 87 (26) | 31 (9) | 2 (<1) | 74 (22) | 32 (10) | 3 (<1) |
Headache | 85 (26) | 3 (<1) | 0 | 43 (13) | 2 (<1) | 0 |
Cough | 70 (21) | 2 (<1) | 0 | 35 (11) | 1 (<1) | 0 |
Dyspnea | 65 (20) | 16 (5) | 1 (<1) | 58 (17) | 9 (3) | 2 (<1) |
Neutropenia | 62 (19) | 40 (12) | 8 (2) | 5 (2) | 4 (1) | 0 |
Rash | 61 (18) | 4 (1) | 0 | 20 (6) | 0 | 0 |
Insomnia | 60 (18) | 1 (<1) | 0 | 90 (27) | 5 (2) | 0 |
Abdominal pain | 53 (16) | 6 (2) | 0 | 12 (4) | 1 (<1) | 0 |
Bone pain | 52 (16) | 12 (4) | 0 | 50 (15) | 9 (3) | 0 |
Lower respiratory/lung infections | 48 (15) | 12 (4) | 2 (<1) | 69 (21) | 24 (7) | 1 (<1) |
Pain in limb | 50 (15) | 5 (2) | 0 | 24 (7) | 2 (<1) | 0 |
Back pain | 46 (14) | 10 (3) | 0 | 33 (10) | 4 (1) | 0 |
Arthralgia | 45 (14) | 3 (<1) | 0 | 35 (11) | 5 (2) | 0 |
Dizziness (excl. vertigo) | 45 (14) | 3 (<1) | 0 | 34 (10) | 0 | 0 |
Nasopharyngitis | 45 (14) | 1 (<1) | 0 | 22 (7) | 0 | 0 |
Herpes zoster | 42 (13) | 6 (2) | 0 | 15 (5) | 4 (1) | 1 (<1) |
Muscle cramps | 41 (12) | 0 | 0 | 50 (15) | 3 (<1) | 0 |
Myalgia | 39 (12) | 1 (<1) | 0 | 18 (5) | 1 (<1) | 0 |
Rigors | 37 (11) | 0 | 0 | 8 (2) | 0 | 0 |
Edema lower limb | 35 (11) | 0 | 0 | 43 (13) | 1 (<1) | 0 |
The Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma
In the phase 2 extension study of 63 patients noted above (see CLINICAL STUDIES) no new cumulative or new long-term toxicities were observed with prolonged VELCADE treatment.
Integrated Summary of Safety (Multiple Myeloma and Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with multiple myeloma (N=1008) and 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.
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 8. 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 8: Most Commonly Reported (≥10% Overall) Adverse Events in Integrated Analyses of Multiple Myeloma and Mantle Cell Lymphoma Studies using the 1.3 mg/m2 Dose (N=1163) | All Patients (N=1163) | Multiple Myeloma (N=1008) | Mantle Cell Lymphoma (N=155) |
Adverse Events | All Events | ≥Grade 3 | All Events | ≥Grade 3 | All Events | ≥Grade 3 |
a Peripheral neuropathy includes all terms under peripheral neuropathy NEC (peripheral neuropathy NOS, peripheral neuropathy aggravated, peripheral sensory neuropathy, and peripheral motor neuropathy, and neuropathy NOS). |
Asthenic conditions | 740 (64) | 189 (16) | 628 (62) | 160 (16) | 112 (72) | 29 (19) |
Nausea | 640 (55) | 43 (4) | 572 (57) | 39 (4) | 68 (44) | 4 (3) |
Diarrhea | 604 (52) | 96 (8) | 531 (53) | 85 (8) | 73 (47) | 11 (7) |
Constipation | 481 (41) | 26 (2) | 404 (40) | 22 (2) | 77 (50) | 4 (3) |
Peripheral neuropathya | 457 (39) | 134 (12) | 372 (37) | 114 (11) | 85 (55) | 20 (13) |
Thrombocytopenia | 421 (36) | 337 (29) | 388 (38) | 320 (32) | 33 (21) | 17 (11) |
Appetite decreased | 417 (36) | 30 (3) | 357 (35) | 25 (2) | 60 (39) | 5 (3) |
Pyrexia | 401 (34) | 36 (3) | 371 (37) | 34 (3) | 30 (19) | 2 (1) |
Vomiting | 385 (33) | 57 (5) | 343 (34) | 53 (5) | 42 (27) | 4 (3) |
Anemia | 333 (29) | 124 (11) | 306 (30) | 120 (12) | 27 (17) | 4 (3) |
Edema | 262 (23) | 10 (<1) | 218 (22) | 6 (<1) | 44 (28) | 4 (3) |
Paresthesia and dysesthesia | 254 (22) | 16 (1) | 240 (24) | 14 (1) | 14 (9) | 2 (1) |
Headache | 253 (22) | 17 (1) | 227 (23) | 17 (2) | 26 (17) | 0 |
Dyspnea | 244 (21) | 59 (5) | 209 (21) | 52 (5) | 35 (23) | 7 (5) |
Cough | 232 (20) | 5 (<1) | 202 (20) | 5 (<1) | 30 (19) | 0 |
Insomnia | 232 (20) | 7 (<1) | 199 (20) | 6 (<1) | 33 (21) | 1 (<1) |
Rash | 213 (18) | 10 (<1) | 170 (17) | 6 (<1) | 43 (28) | 4 (3) |
Arthralgia | 199 (17) | 27 (2) | 179 (18) | 25 (2) | 20 (13) | 2 (1) |
Neutropenia | 195 (17) | 143 (12) | 185 (18) | 137 (14) | 10 (6) | 6 (4) |
Dizziness (excluding vertigo) | 195 (17) | 18 (2) | 159 (16) | 13 (1) | 36 (23) | 5 (3) |
Pain in limb | 179 (15) | 36 (3) | 172 (17) | 36 (4) | 7 (5) | 0 |
Abdominal pain | 170 (15) | 30 (3) | 146 (14) | 22 (2) | 24 (15) | 8 (5) |
Bone pain | 166 (14) | 37 (3) | 163 (16) | 37 (4) | 3 (2) | 0 |
Back pain | 151 (13) | 39 (3) | 150 (15) | 39 (4) | 1 (<1) | 0 |
Hypotension | 147 (13) | 37 (3) | 124 (12) | 32 (3) | 23 (15) | 5 (3) |
Herpes zoster | 145 (12) | 22 (2) | 131 (13) | 21 (2) | 14 (9) | 1 (<1) |
Nasopharyngitis | 139 (12) | 2 (<1) | 126 (13) | 2 (<1) | 13 (8) | 0 |
Upper respiratory tract infection | 138 (12) | 2 (<1) | 114 (11) | 1 (<1) | 24 (15) | 1 (<1) |
Myalgia | 136 (12) | 9 (<1) | 121 (12) | 9 (<1) | 15 (10) | 0 |
Pneumonia | 134 (12) | 72 (6) | 120 (12) | 65 (6) | 14 (9) | 7 (5) |
Muscle cramps | 125 (11) | 1 (<1) | 118 (12) | 1 (<1) | 7 (5) | 0 |
Dehydration | 120 (10) | 40 (3) | 109 (11) | 33 (3) | 11 (7) | 7 (5) |
Anxiety | 118 (10) | 6 (<1) | 111 (11) | 6 (<1) | 7 (5) | 0 |
Description of Selected Adverse Events from the Phase 2 and 3 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 rare (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 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 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%).
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 phase 3 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 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 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 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 (>38ºC) 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.
Reactivation of Herpes Virus Infection
Reactivation of herpes virus infections, including herpes zoster and herpes simplex was reported in 13% and 7% of patients, respectively. This included ophthalmic herpes zoster and ophthalmic herpes simplex each in <1% of patients. Multidermatomal herpes zoster also has been reported. Herpes reactivation was reported as a serious event in 2% of patients and led to discontinuation of VELCADE in <1% of patients. In the phase 3 multiple myeloma study, herpes reactivation was more common in patients treated with VELCADE (13% herpes zoster, 8% herpes simplex) than in patients treated with dexamethasone (5% herpes zoster, 5% herpes simplex). In the postmarketing experience, rare cases of herpes meningoencephalitis and ophthalmic herpes have been reported.
Additional Adverse Events from Clinical Studies and Post-Marketing
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
Post-Marketing Experience
Clinically significant adverse events are listed here if they have been reported during post-approval use of VELCADE and either they have not been reported in clinical trials, or they have been reported in clinical trials, but their occurrence in the post-approval setting is considered meaningful:
Atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, acute diffuse infiltrative pulmonary disease and toxic epidermal necrolysis.
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