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VELCADE is a brand name for Bortezomib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE VELCADE is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma ( 1.1 ) treatment of adult patients with mantle cell lymphoma ( 1.2 ) 1.1 Multiple Myeloma VELCADE is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. 3 mg/m 2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.
6 ) Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. 6 ) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. 8 ) Dose must be individualized to prevent overdose.
1 Important Dosing Guidelines VELCADE is for intravenous or subcutaneous use only. Do not administer VELCADE by any other route. Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered.
3 mg/m 2 . 10) ] . VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least six months after completing prior VELCADE treatment. 6) ] .
When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection. 2 Dosage in Previously Untreated Multiple Myeloma VELCADE is administered in combination with oral melphalan and oral prednisone for 9, six week treatment cycles as shown in Table 1 .
In Cycles 1 to 4, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE.
7 mg/m 2 ) Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of toxicity have resolved to Grade 1 or baseline. 7 mg/m 2 ). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 .
For information concerning melphalan and prednisone, see manufacturer's prescribing information. 7) ] . 3 mg/m 2 ) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 3 .
VELCADE is administered first followed by rituximab. VELCADE is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21. For patients with a response first documented at Cycle 6, two additional VcR-CAP cycles are recommended.
10) ] Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.
gov/medwatch . 1 Clinical Trials 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.
3 mg/m 2 ) administered intravenously in combination with melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) 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 9:
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 VELCADE, Melphalan and Prednisone Melphalan and Prednisone (n=340) (n=337) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 Blood and Lymphatic System Disorders Thrombocytopenia 164 (48) 60 (18) 57 (17) 140 (42) 48 (14) 39 (12) Neutropenia 160 (47) 101 (30) 33 (10) 143 (42) 77 (23) 42 (12) Anemia 109 (32) 41 (12) 4 (1) 156 (46) 61 (18) 18 (5) Leukopenia 108 (32) 64 (19) 8 (2) 93 (28) 53 (16) 11 (3) Lymphopenia 78 (23) 46 (14) 17 (5) 51 (15) 26 (8) 7 (2) Gastrointestinal Disorders Nausea 134 (39) 10 (3) 0 70 (21) 1 (<1) 0 Diarrhea 119 (35) 19 (6) 2 (1) 20 (6) 1 (<1) 0 Vomiting 87 (26) 13 (4) 0 41 (12) 2 (1) 0 Constipation 77 (23) 2 (1) 0 14 (4) 0 0 Abdominal pain upper 34 (10) 1 (<1) 0 20 (6) 0 0 Nervous System Disorders Peripheral neuropathy Represents High Level Term Peripheral Neuropathies NEC 156 (46) 42 (12) 2 (1) 4 (1) 0 0 Neuralgia 117 (34) 27 (8) 2 (1) 1 (<1) 0 0 Paresthesia 42 (12) 6 (2) 0 4 (1) 0 0 General Disorders and Administration Site Conditions Fatigue 85 (25) 19 (6) 2 (1) 48 (14) 4 (1) 0 Asthenia 54 (16) 18 (5) 0 23 (7) 3 (1) 0 Pyrexia 53 (16) 4 (1) 0 19 (6) 1 (<1) 1 (<1) Infections and Infestations Herpes Zoster 39 (11) 11 (3) 0 9 (3) 4 (1) 0 Metabolism and Nutrition Disorders Anorexia 64 (19) 6 (2) 0 19 (6) 0 0 Skin and Subcutaneous Tissue Disorders Rash 38 (11) 2 (1) 0 7 (2) 0 0 Psychiatric Disorders Insomnia 35 (10) 1 (<1) 0 21 (6) 0 0 Relapsed Multiple Myeloma Randomized Study of VELCADE vs Dexamethasone The safety data described below and in Table 10 reflect exposure to either VELCADE (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma.
5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. 7 ) Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. 1 ) Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.
2 ) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. 3 ) Pulmonary Toxicity: Acute respiratory syndromes have occurred.
Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. 4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.
5 ) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. 6 ) Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment.
7 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. 8 ) Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt VELCADE therapy to assess reversibility. 9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms.
Discontinue VELCADE if suspected. 10 ) Embryo-Fetal Toxicity: VELCADE can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception.
1 Peripheral Neuropathy VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE.
4 CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. 1) ] . VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE.
Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration. ( 4 )
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At least 72 hours should elapse between consecutive doses of VELCADE.
Table 3:
Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly VELCADE (6, Three Week Cycles) Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6. 96 mmol/L) Nonhematologic toxicity should have recovered to Grade 1 or baseline Interrupt VELCADE treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy [see Table 5, Warnings and Precautions (5) ] .
For dose adjustments, see Table 4 below. 75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L. If, after VELCADE has been withheld, the toxicity does not resolve, discontinue VELCADE. 7 mg/m 2 ). Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of the toxicity have resolved to Grade 2 or better.
7 mg/m 2 ). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 . For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information.
3 mg/m 2 /dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, VELCADE may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35) [see Clinical Studies (14) ] .
At least 72 hours should elapse between consecutive doses of VELCADE. Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least six months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose.
Retreated patients are administered VELCADE twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of VELCADE. 1) ] . VELCADE therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (5) ] .
7 mg/m 2 /dose). 7 . 7 Dose Modifications for Peripheral Neuropathy Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. For dose or schedule modification guidelines for patients who experience VELCADE-related neuropathic pain and/or peripheral neuropathy, see Table 5 .
0 Modification of Dose and Regimen Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function No action Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL) Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
) Reduce VELCADE to 1 mg/m 2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden ) Withhold VELCADE therapy until toxicity resolves.
7 mg/m 2 once per week. 8 Dosage in Patients with Hepatic Impairment Do not adjust the starting dose for patients with mild hepatic impairment. 3) ] .
Table 6:
Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment Bilirubin Level SGOT (AST) Levels Modification of Starting Dose Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.
7 mg/m 2 in the first cycle. 5 mg/m 2 in subsequent cycles based on patient tolerability. 5 mg) may exceed the usual dose required. 10) ] . When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated.
New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. 10) ] . 10) ] . VELCADE is a hazardous drug. Follow applicable special handling and disposal procedures.
10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration Use proper aseptic technique. 9% sodium chloride . The reconstituted product should be a clear and colorless solution. 9% sodium chloride are used to reconstitute the product for the different routes of administration.
5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). 9) ] . 5 mg/mL Dose must be individualized to prevent overdosage. 5 mg/mL Stickers that indicate the route of administration are provided with each VELCADE vial.
These stickers should be placed directly on the syringe of VELCADE once VELCADE is prepared to help alert practitioners of the correct route of administration for VELCADE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
If any discoloration or particulate matter is observed, the reconstituted product should not be used. Stability Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.
VELCADE contains no antimicrobial preservative. Administer reconstituted VELCADE within eight hours of preparation. When reconstituted as directed, VELCADE may be stored at 25°C (77°F). 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.
3 mg/m 2 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. 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. 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. 1) ] . Among the 331 VELCADE-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 VELCADE-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 VELCADE 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 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: 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 VELCADE 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 VELCADE arm are included.
Table 10:
Most Commonly Reported Adverse Reactions (≥10% in VELCADE Arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of VELCADE vs Dexamethasone (N=663) VELCADE (N=331) Dexamethasone (N=332) Adverse Reactions All Grade 3 Grade 4 All Grade 3 Grade 4 Any Adverse Reactions 324 (98) 193 (58) 28 (8) 297 (89) 110 (33) 29 (9) Nausea 172 (52) 8 (2) 0 31 (9) 0 0 Diarrhea NOS 171 (52) 22 (7) 0 36 (11) 2 (<1) 0 Fatigue 130 (39) 15 (5) 0 82 (25) 8 (2) 0 Peripheral neuropathies Represents High Level Term Peripheral Neuropathies NEC 115 (35) 23 (7) 2 (<1) 14 (4) 0 1 (<1) Thrombocytopenia 109 (33) 80 (24) 12 (4) 11 (3) 5 (2) 1 (<1) Constipation 99 (30) 6 (2) 0 27 (8) 1 (<1) 0 Vomiting NOS 96 (29) 8 (2) 0 10 (3) 1 (<1) 0 Anorexia 68 (21) 8 (2) 0 8 (2) 1 (<1) 0 Pyrexia 66 (20) 2 (<1) 0 21 (6) 3 (<1) 1 (<1) Paresthesia 64 (19) 5 (2) 0 24 (7) 0 0 Anemia NOS 63 (19) 20 (6) 1 (<1) 21 (6) 8 (2) 0 Headache NOS 62 (19) 3 (<1) 0 23 (7) 1 (<1) 0 Neutropenia 58 (18) 37 (11) 8 (2) 1 (<1) 1 (<1) 0 Rash NOS 43 (13) 3 (<1) 0 7 (2) 0 0 Appetite decreased NOS 36 (11) 0 0 12 (4) 0 0 Dyspnea NOS 35 (11) 11 (3) 1 (<1) 37 (11) 7 (2) 1 (<1) Abdominal pain NOS 35 (11) 5 (2) 0 7 (2) 0 0 Weakness 34 (10) 10 (3) 0 28 (8) 8 (2) 0 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.
1) ] . 3 mg/m 2 . This was a randomized, comparative study of VELCADE subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. 1) ] .
Table 11:
Most Commonly Reported Adverse Reactions (≥10%), with Grade 3 and ≥4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of VELCADE Subcutaneous vs Intravenous Subcutaneous Intravenous (N=147) (N=74) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least one dose of study medication Blood and Lymphatic System Disorders Anemia 28 (19) 8 (5) 0 17 (23) 3 (4) 0 Leukopenia 26 (18) 8 (5) 0 15 (20) 4 (5) 1 (1) Neutropenia 34 (23) 15 (10) 4 (3) 20 (27) 10 (14) 3 (4) Thrombocytopenia 44 (30) 7 (5) 5 (3) 25 (34) 7 (9) 5 (7) Gastrointestinal Disorders Diarrhea 28 (19) 1 (1) 0 21 (28) 3 (4) 0 Nausea 24 (16) 0 0 10 (14) 0 0 Vomiting 13 (9) 3 (2) 0 8 (11) 0 0 General Disorders and Administration Site Conditions Asthenia 10 (7) 1 (1) 0 12 (16) 4 (5) 0 Fatigue 11 (7) 3 (2) 0 11 (15) 3 (4) 0 Pyrexia 18 (12) 0 0 6 (8) 0 0 Nervous System Disorders Neuralgia 34 (23) 5 (3) 0 17 (23) 7 (9) 0 Peripheral neuropathies Represents High Level Term Peripheral Neuropathies NEC 55 (37) 8 (5) 1 (1) 37 (50) 10 (14) 1 (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 VELCADE 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. 3 mg/m 2 ) administered intravenously in combination with rituximab (375 mg/m 2 ), cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and prednisone (100 mg/m 2 ) (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%).
Table 12:
Most Commonly Reported Adverse Reactions (≥5%) with Grades 3 and ≥4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study VcR-CAP (n=240) R-CHOP (n=242) Body System Adverse Reactions All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥4 n (%) All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥4 n (%) Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone.
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). 3 mg/m 2 /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 VELCADE subcutaneous vs 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 (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 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, 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. 3 mg/m 2 Dose (N=1163) All Patients (N=1163) Multiple Myeloma (N=1008) Mantle Cell Lymphoma (N=155) Adverse Reactions All ≥Grade 3 All ≥Grade 3 All ≥Grade 3 Nausea 567 (49) 36 (3) 511 (51) 32 (3) 56 (36) 4 (3) Diarrhea NOS 530 (46) 83 (7) 470 (47) 72 (7) 60 (39) 11 (7) Fatigue 477 (41) 86 (7) 396 (39) 71 (7) 81 (52) 15 (10) Peripheral neuropathies Represents High Level Term Peripheral Neuropathies NEC 443 (38) 129 (11) 359 (36) 110 (11) 84 (54) 19 (12) Thrombocytopenia 369 (32) 295 (25) 344 (34) 283 (28) 25 (16) 12 (8) Vomiting NOS 321 (28) 44 (4) 286 (28) 40 (4) 35 (23) 4 (3) Constipation 296 (25) 17 (1) 244 (24) 14 (1) 52 (34) 3 (2) Pyrexia 249 (21) 16 (1) 233 (23) 15 (1) 16 (10) 1 (<1) Anorexia 227 (20) 19 (2) 205 (20) 16 (2) 22 (14) 3 (2) Anemia NOS 209 (18) 65 (6) 190 (19) 63 (6) 19 (12) 2 (1) Headache NOS 175 (15) 8 (<1) 160 (16) 8 (<1) 15 (10) 0 Neutropenia 172 (15) 121 (10) 164 (16) 117 (12) 8 (5) 4 (3) Rash NOS 156 (13) 8 (<1) 120 (12) 4 (<1) 36 (23) 4 (3) Paresthesia 147 (13) 9 (<1) 136 (13) 8 (<1) 11 (7) 1 (<1) Dizziness (excl vertigo) 129 (11) 13 (1) 101 (10) 9 (<1) 28 (18) 4 (3) Weakness 124 (11) 31 (3) 106 (11) 28 (3) 18 (12) 3 (2) 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, 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 ten day rest period during each treatment cycle.
Overall, thrombocytopenia was reported in 32% of patients. 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 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%). 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 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 (>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 to 11%) than in the control groups (3 to 4%).
Herpes simplex was seen in 1 to 3% in subjects treated with VELCADE and 1 to 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%).
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 VELCADE. The safety profile of patients in this trial is consistent with the known safety profile of VELCADE-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%.
3%. 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 VELCADE-related occurred within 30 days of the last VELCADE 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 VELCADE administered as monotherapy or in combination with other chemotherapeutics.
These studies were conducted in patients with hematological malignancies and in solid tumors. 2 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: Cardiac Disorders: Cardiac tamponade Ear and Labyrinth Disorders: Deafness bilateral Eye Disorders: Optic neuropathy, blindness, chalazion/blepharitis Gastrointestinal Disorders: Ischemic colitis Infections and Infestations: Progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis Nervous System Disorders: Posterior reversible encephalopathy syndrome (PRES, formerly RPLS), Guillain-Barré syndrome, demyelinating polyneuropathy Respiratory, Thoracic and Mediastinal Disorders: Acute diffuse infiltrative pulmonary disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweet's syndrome)
Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous.
1) ] . Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. 7) ] . In the VELCADE vs dexamethasone Phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption.
Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the Phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
1) ] . These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension.
Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. 1) ] . Patients with risk factors for, or existing heart disease should be frequently monitored.
In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group.
In the dexamethasone group the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
4 Pulmonary Toxicity Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving VELCADE.
Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m 2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted.
5 Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.
Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.
1) ] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. 7 Thrombocytopenia/Neutropenia VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle.
The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.
Monitor complete blood counts (CBC) frequently during treatment with VELCADE. Measure platelet counts prior to each dose of VELCADE. 6) ] . Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with VELCADE.
Support with transfusions and supportive care, according to published guidelines. In the single agent, relapsed multiple myeloma study of VELCADE vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline.
The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 8 . The incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and was <1% in the dexamethasone arm.
Table 8:
Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of VELCADE vs Dexamethasone Pretreatment Platelet Count A baseline platelet count of 50,000/µL was required for study eligibility Number of Patients (N=331) Data were missing at baseline for one patient Number (%) of Patients with Platelet Count <10,000/µL Number (%) of Patients with Platelet Count 10,000 to 25,000/µL ≥75,000/µL 309 8 (3%) 36 (12%) ≥50,000/µL to <75,000/µL 14 2 (14%) 11 (79%) ≥10,000/µL to <50,000/µL 7 1 (14%) 5 (71%) In the combination study of VELCADE with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12 .
2% in the R-CHOP arm (three patients). Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm. The incidence of neutropenia (≥Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm.
The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm. 8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with VELCADE therapy.
Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. 9 Hepatic Toxicity Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions.
Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited rechallenge information in these patients. 10 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received VELCADE.
Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop VELCADE and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing TTP/HUS is not known.
11 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, VELCADE can cause fetal harm when administered to a pregnant woman. 1) ] . Advise females of reproductive potential to use effective contraception during treatment with VELCADE and for seven months following treatment.
Advise males with female partners of reproductive potential to use effective contraception during treatment with VELCADE and for four months following treatment. 1) ] .