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Velcade

"The U.S. Food and Drug Administration today approved Pomalyst (pomalidomide) to treat patients with multiple myeloma whose disease progressed after being treated with other cancer drugs.

Multiple myeloma is a form of blood cancer that p"...

Velcade

Velcade Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Velcade (bortezomib) is used to treat multiple myeloma and mantle cell lymphoma, and is sometimes given after other cancer medications have been tried without successful treatment. It is an antineoplastic agent. Common side effects include dizziness, lightheadedness, nausea, vomiting, loss of appetite, diarrhea, constipation, tiredness, weakness, or blurred vision.

The recommended starting dose of Velcade is 1.3 mg/mē. It may be administered intravenously (IV) at a concentration of 1 mg/mL, or subcutaneously (under the skin) at a concentration of 2.5 mg/mL. Velcade for Injection is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles. Velcade may interact with dexamethasone, rifabutin, rifampin, rifapentine, St. John's wort, antibiotics, antifungals, antidepressants, barbiturates, diabetes medications you take by mouth, HIV/AIDS medicine, medicines to treat narcolepsy, or seizure medication. Tell your doctor all medications you are taking. Velcade is not recommended for use during pregnancy. It may cause harm to a fetus. Use reliable form(s) of birth control during treatment with this drug. It is not known whether this drug passes into breast milk. Breast-feeding is not recommended while using this drug due to the potential risk to the nursing infant.

Our Velcade (bortezomib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Patient Information in Detail?

Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.

Velcade in Detail - Patient Information: Side Effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Bortezomib may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

Also call your doctor at once if you have:

  • new or worsening nerve problems such as numbness, burning, pain, weakness, or tingly feeling;
  • a light-headed feeling, like you might pass out;
  • dry cough and trouble breathing;
  • severe headache, confusion, and/or seizure (convulsions);
  • bloody or tarry stools, vomit that looks like blood or coffee grounds;
  • severe constipation;
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • fever, chills, body aches, flu symptoms;
  • red bumps, spreading skin rash, painful skin lesions on your arms, face, or neck;
  • feeling short of breath, even with mild exertion;
  • fast or slow heart rate, weak pulse, lower back pain, blood in your urine;
  • urinating less than usual or not at all;
  • muscle weakness, tightness, or contraction, overactive reflexes; or
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • mild nausea, vomiting, upset stomach;
  • diarrhea, constipation, bloating;
  • headache, mild dizziness;
  • muscle pain, bone or joint pain;
  • sleep problems (insomnia);
  • mild rash or itching; or
  • skin irritation where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Velcade (Bortezomib) »

What is Patient Information Overview?

A concise overview of the drug for the patient or caregiver from First DataBank.

Velcade Overview - Patient Information: Side Effects

SIDE EFFECTS: Dizziness, lightheadedness, nausea, vomiting, loss of appetite, diarrhea, constipation, tiredness, weakness, blurred vision, or pain/redness at injection site may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication can lower your body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

Tell your doctor right away if you have any serious side effects, including: easy bruising or bleeding, tingling/numbness/pain/burning feeling of the hands or feet (peripheral neuropathy), fainting, stomach pain, black stools, coffee-ground vomit, trouble breathing, swelling or pain in the lower legs, fast/irregular heartbeat, severe headache, vision problems, mental/mood changes (e.g., rarely, thoughts of suicide), swelling of the hands/ankles/feet, change in the amount of urine, yellowing skin/eyes, dark urine.

Get medical help right away if any of these rare but very serious side effects occur: chest pain, weakness on one side of the body, slurred speech, seizures.

An allergic reaction to this drug is unlikely, but get medical help right away if it occurs. Symptoms of an allergic reaction include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the entire patient information overview for Velcade (Bortezomib)»

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Velcade FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

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

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 9 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 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

System Organ Class
Preferred Term
VELCADE, Melphalan and Prednisone (n=340) Melphalan and Prednisone (n=337)
Total n (%) Toxicity 3 Grade, n (%) > 4 Total n (%) Toxicity 3 Grade, n (%) > 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 Neuropathya 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
aRepresents High Level Term Peripheral Neuropathies NEC

Relapsed Multiple Myeloma Randomized Study of VELCADE versus 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. 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 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 (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 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 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 versus Dexamethasone (N=663)

Preferred Term VELCADE
N=331
Dexamethasone
N=332
All Grade 3 Grade 4 All Grade 3 Grade 4
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 neuropathiesa 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
aRepresents High Level Term Peripheral Neuropathies NEC

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 11 reflect exposure to either VELCADE subcutaneous (n=147) or VELCADE intravenous (n=74) [see Clinical Studies].

Table 11: Most Commonly Reported Adverse Reactions ( ≥ 10%), with Grade 3 and ≥ 4 Intensity in theRelapsed Multiple Myeloma Study (N=221) of VELCADE Subcutaneous versus Intravenous

System Organ Class
Preferred Term
Subcutaneous
(N=147)
Intravenous (N=74)
Total n (%) Toxicity 3 Grade, n (%) ≥ 4 Total n (%) Toxicity
3
Grade, n (%) ≥ 4
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 neuropathiesa 55 (37) 8 (5) 1 (1) 37 (50) 10 (14) 1 (1)
Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least 1 dose of study medication
aRepresents High Level Term Peripheral Neuropathies NEC

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 (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.

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

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

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

System Organ Class
Preferred Term
VcR-CAP
n=240
R-CHOP
n=242
All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥ 4 n (%) All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥ 4 n (%)
Blood and lymphatic system disorders
  Neutropenia 209 (87) 32 (13) 168 (70) 172 (71) 31 (13) 125 (52)
  Leukopenia 116 (48) 34 (14) 69 (29) 87 (36) 39 (16) 27 (11)
  Anemia 106 (44) 27 (11) 4 (2) 71 (29) 23 (10) 4 (2)
  Thrombocytopenia 172 (72) 59 (25) 76 (32) 42 (17) 9 (4) 3 (1)
  Febrile neutropenia 41 (17) 24 (10) 12 (5) 33 (14) 17 (7) 15 (6)
  Lymphopenia 68 (28) 25 (10) 36 (15) 28 (12) 15 (6) 2 (1)
Nervous system disorders
  Peripheral neuropathya 71 (30) 17 (7) 1 ( < 1) 65 (27) 10 (4) 0
  Hypoesthesia 14 (6) 3 (1) 0 13 (5) 0 0
  Paresthesia 14 (6) 2 (1) 0 11 (5) 0 0
  Neuralgia 25 (10) 9 (4) 0 1 ( < 1) 0 0
General disorders and administration site conditions
  Fatigue 43 (18) 11 (5) 1 ( < 1) 38 (16) 5 (2) 0
  Pyrexia 48 (20) 7 (3) 0 23 (10) 5 (2) 0
  Asthenia 29 (12) 4 (2) 1 ( < 1) 18 (7) 1 ( < 1) 0
  Edema peripheral 16 (7) 1 ( < 1) 0 13 (5) 0 0
Gastrointestinal disorders
  Nausea 54 (23) 1 ( < 1) 0 28 (12) 0 0
  Constipation 42 (18) 1 ( < 1) 0 22 (9) 2 (1) 0
  Stomatitis 20 (8) 2 (1) 0 19 (8) 0 1 ( < 1)
  Diarrhea 59 (25) 11 (5) 0 11 (5) 3 (1) 1 ( < 1)
  Vomiting 24 (10) 1 ( < 1) 0 8 (3) 0 0
  Abdominal distension 13 (5) 0 0 4 (2) 0 0
Infections and infestations
  Pneumonia 20 (8) 8 (3) 5 (2) 11 (5) 5 (2) 3 (1)
Skin and subcutaneous tissue disorders
  Alopecia 31 (13) 1 ( < 1) 1 ( < 1) 33 (14) 4 (2) 0
Metabolism and nutrition disorders
  Hyperglycemia 10 (4) 1 ( < 1) 0 17 (7) 10 (4) 0
  Decreased appetite 36 (15) 2 (1) 0 15 (6) 1 ( < 1) 0
Vascular disorders
  Hypertension 15 (6) 1 ( < 1) 0 3 (1) 0 0
Psychiatric disorders
  Insomnia 16 (7) 1 ( < 1) 0 8 (3) 0 0
Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone.
aRepresents High Level Term Peripheral Neuropathies NEC

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

The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (3 patients in the VcR-CAP arm and 1 patient 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%; 3 patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia ( < 1%; 2 patients).

Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed 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 (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, 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.

Table 13: Most Commonly Reported ( ≥ 10% Overall) Adverse Reactionsin Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studiesusing the 1.3 mg/m² Dose (N=1163)

Preferred Term All Patients
N=1163
Multiple Myeloma
N=1008
Mantle Cell Lymphoma
N=155
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 neuropathiesa 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)
aRepresents High Level Term Peripheral Neuropathies NEC

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 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 [see WARNINGS AND PRECAUTIONS]. 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%).

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%).

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%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).

Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%).

Two deaths considered to be 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.

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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