Bortezomib - Bortezomib injection, Powder, Lyophilized, For Solution
(Bortezomib)Bortezomib - Bortezomib injection, Powder, Lyophilized, For Solution Prescribing Information
Bortezomib for injection is a proteasome inhibitor indicated for:
- treatment of adult patients with multiple myeloma ()
1.1 Multiple MyelomaBortezomib for injection is indicated for the treatment of adult patients with multiple myeloma.
- treatment of adult patients with mantle cell lymphoma ()
1.2 Mantle Cell LymphomaBortezomib for injection is indicated for the treatment of adult patients with mantle cell lymphoma.
- For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. (,
2.1 Important Dosing GuidelinesBortezomib for injection is for intravenous or subcutaneous use only. Do not administer bortezomib for injection by any other route.
Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered.The recommended starting dose of bortezomib for injection is 1.3 mg/m2. Bortezomib for injection is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL
[see Dosage and Administration (2.10)].Bortezomib for injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib for injection and who have relapsed at least six months after completing prior bortezomib for injection treatment. Treatment may be started at the last tolerated dose
[see Dosage and Administration (2.6)].When administered intravenously, administer bortezomib for injection as a 3 to 5 second bolus intravenous injection.
)2.10 Reconstitution/Preparation for Intravenous and Subcutaneous AdministrationUse proper aseptic technique. Reconstitute
only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL).
Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered[see Dosage and Administration (2.9)].For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration
(Table 7):Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration Route of Administration Bortezomib
(mg/vial)Diluent
(0.9% Sodium Chloride)Final Bortezomib Concentration
(mg/mL)Intravenous 3.5 mg 3.5 mL 1 mg/mL Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted bortezomib for injection to be administered:
- Intravenous Administration [1 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 1 mg/mL - Subcutaneous Administration [2.5 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 2.5 mg/mL
Stickers that indicate the route of administration are provided with each bortezomib for injection vial. These stickers should be placed directly on the syringe of bortezomib for injection once bortezomib for injection is prepared to help alert practitioners of the correct route of administration for bortezomib for injection.
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.
StabilityUnopened vials of bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted bortezomib for injection within eight hours of preparation. When reconstituted as directed, bortezomib for injection may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. 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.
- The recommended starting dose of bortezomib for injection is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. (, 2.4,
2.2 Dosage in Previously Untreated Multiple MyelomaBortezomib for injection 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, bortezomib for injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, bortezomib for injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of bortezomib for injection.Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib for Injection (Cycles 1 to 4)Week123456Bortezomib for Injection
(1.3 mg/m2)Day 1 -- -- Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan (9 mg/m2)
Prednisone (60 mg/m2)Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period Once Weekly Bortezomib for Injection (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)Week123456Bortezomib for Injection
(1.3 mg/m2)Day 1 -- -- Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m2)
Prednisone (60 mg/m2)Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period )2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell LymphomaBortezomib for injection (1.3 mg/m2/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, bortezomib for injection 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 bortezomib for injection.Patients with multiple myeloma who have previously responded to treatment with bortezomib for injection (either alone or in combination) and who have relapsed at least six months after their prior bortezomib for injection therapy may be started on bortezomib for injection at the last tolerated dose. Retreated patients are administered bortezomib for injection 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 bortezomib for injection. Bortezomib for injection may be administered either as a single agent or in combination with dexamethasone
[see Clinical Studies (14.1)].Bortezomib for injection 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)]. Once the symptoms of the toxicity have resolved, bortezomib for injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).For dose modifications guidelines for peripheral neuropathy, see section 2.7.
- Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. ()
2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell LymphomaBortezomib for injection (1.3 mg/m2/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, bortezomib for injection 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 bortezomib for injection.Patients with multiple myeloma who have previously responded to treatment with bortezomib for injection (either alone or in combination) and who have relapsed at least six months after their prior bortezomib for injection therapy may be started on bortezomib for injection at the last tolerated dose. Retreated patients are administered bortezomib for injection 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 bortezomib for injection. Bortezomib for injection may be administered either as a single agent or in combination with dexamethasone
[see Clinical Studies (14.1)].Bortezomib for injection 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)]. Once the symptoms of the toxicity have resolved, bortezomib for injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).For dose modifications guidelines for peripheral neuropathy, see section 2.7.
- Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. ()
2.8 Dosage in Patients with Hepatic ImpairmentDo not adjust the starting dose for patients with mild hepatic impairment.
Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m2per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m2or further dose reduction to 0.5 mg/m2based on patient tolerance
(see Table 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].Table 6: Recommended Starting Dose Modification for Bortezomib for Injection in Patients with Hepatic ImpairmentBilirubin LevelSGOT(AST)LevelsModification of Starting DoseMild Less than or equal to 1x ULN More than ULN None More than 1x to 1.5x ULN Any None Moderate More than 1.5x to 3x ULN Any Reduce bortezomib for injection to 0.7 mg/m2in the first cycle. Consider dose escalation to 1 mg/m2or further dose reduction to 0.5 mg/m2in subsequent cycles based on patient tolerability. Severe More than 3x ULN Any Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.
- Dose must be individualized to prevent overdose. ()
2.10 Reconstitution/Preparation for Intravenous and Subcutaneous AdministrationUse proper aseptic technique. Reconstitute
only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL).
Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered[see Dosage and Administration (2.9)].For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration
(Table 7):Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration Route of Administration Bortezomib
(mg/vial)Diluent
(0.9% Sodium Chloride)Final Bortezomib Concentration
(mg/mL)Intravenous 3.5 mg 3.5 mL 1 mg/mL Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted bortezomib for injection to be administered:
- Intravenous Administration [1 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 1 mg/mL - Subcutaneous Administration [2.5 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 2.5 mg/mL
Stickers that indicate the route of administration are provided with each bortezomib for injection vial. These stickers should be placed directly on the syringe of bortezomib for injection once bortezomib for injection is prepared to help alert practitioners of the correct route of administration for bortezomib for injection.
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.
StabilityUnopened vials of bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted bortezomib for injection within eight hours of preparation. When reconstituted as directed, bortezomib for injection may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. 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.
For injection: Each single-dose vial of bortezomib for injection contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white cake or powder for reconstitution and withdrawal of the appropriate individual patient dose
Use proper aseptic technique. Reconstitute
Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL).
For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration
| Route of Administration | Bortezomib (mg/vial) | Diluent (0.9% Sodium Chloride) | Final Bortezomib Concentration (mg/mL) |
|---|---|---|---|
| Intravenous | 3.5 mg | 3.5 mL | 1 mg/mL |
| Subcutaneous | 3.5 mg | 1.4 mL | 2.5 mg/mL |
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted bortezomib for injection to be administered:
- Intravenous Administration [1 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 1 mg/mL - Subcutaneous Administration [2.5 mg/mL concentration]
Bortezomib for Injection dose (mg/m2) x patient BSA (m2) =Total bortezomib for injection volume (mL) to be administered 2.5 mg/mL
Stickers that indicate the route of administration are provided with each bortezomib for injection vial. These stickers should be placed directly on the syringe of bortezomib for injection once bortezomib for injection is prepared to help alert practitioners of the correct route of administration for bortezomib for injection.
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.
Unopened vials of bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted bortezomib for injection within eight hours of preparation. When reconstituted as directed, bortezomib for injection may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. 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.
Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. (
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving bortezomib for injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Bortezomib for injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions
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.
The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.
Bortezomib, 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 * | 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 |
* Represents High Level Term Peripheral Neuropathies NEC
The safety data described below and in
Among the 331 bortezomib-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 bortezomib-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 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 bortezomib 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 bortezomib 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 bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib-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 bortezomib-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.
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥10% in the bortezomib arm are included.
Bortezomib ( 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* | 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 |
* Represents High Level Term Peripheral Neuropathies NEC
In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study
The safety and efficacy of bortezomib 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 bortezomib subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in
Subcutaneous | Intravenous | |||||
(N=147) | (N=74) | |||||
Body System | Total | Toxicity Grade, n (%) | Total | Toxicity Grade, n (%) | ||
Adverse Reaction | n (%) | 3 | ≥4 | n (%) | 3 | ≥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 neuropathies* | 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 one dose of study medication
* Represents 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 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).
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.
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%).
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 (%) |
Blood and L ymphatic S ystem D isorders | ||||||
| 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 S ystem D isorders | ||||||
| Peripheral neuropathy * | 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 D isorders and A dministration S ite C onditions | ||||||
| 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 D isorders | ||||||
| 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 I nfestations | ||||||
| Pneumonia | 20 (8) | 8 (3) | 5 (2) | 11 (5) | 5 (2) | 3 (1) |
Skin and S ubcutaneous T issue D isorders | ||||||
| Alopecia | 31 (13) | 1 (<1) | 1 (<1) | 33 (14) | 4 (2) | 0 |
Metabolism and N utrition D isorders | ||||||
| Hyperglycemia | 10 (4) | 1 (<1) | 0 | 17 (7) | 10 (4) | 0 |
| Decreased appetite | 36 (15) | 2 (1) | 0 | 15 (6) | 1 (<1) | 0 |
Vascular D isorders | ||||||
| Hypertension | 15 (6) | 1 (<1) | 0 | 3 (1) | 0 | 0 |
Psychiatric D isorders | ||||||
| Insomnia | 16 (7) | 1 (<1) | 0 | 8 (3) | 0 | 0 |
Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
* Represents 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 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).
Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m2/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 bortezomib subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib 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 bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage.
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.
The most common adverse reactions are shown in
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* | 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) |
* Represents High Level Term Peripheral Neuropathies NEC
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%).
Across the studies, bortezomib-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. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients
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 bortezomib 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 bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-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 bortezomib.
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. 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.
Neutrophil counts decreased during the bortezomib 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 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 (>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 bortezomib 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.
Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (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 bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, 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%).
A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in
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 bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis.
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.
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.
The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.
Bortezomib, 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 * | 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 |
* Represents High Level Term Peripheral Neuropathies NEC
The safety data described below and in
Among the 331 bortezomib-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 bortezomib-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 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 bortezomib 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 bortezomib 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 bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib-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 bortezomib-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.
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥10% in the bortezomib arm are included.
Bortezomib ( 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* | 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 |
* Represents High Level Term Peripheral Neuropathies NEC
In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study
The safety and efficacy of bortezomib 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 bortezomib subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in
Subcutaneous | Intravenous | |||||
(N=147) | (N=74) | |||||
Body System | Total | Toxicity Grade, n (%) | Total | Toxicity Grade, n (%) | ||
Adverse Reaction | n (%) | 3 | ≥4 | n (%) | 3 | ≥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 neuropathies* | 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 one dose of study medication
* Represents 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 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).
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.
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%).
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 (%) |
Blood and L ymphatic S ystem D isorders | ||||||
| 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 S ystem D isorders | ||||||
| Peripheral neuropathy * | 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 D isorders and A dministration S ite C onditions | ||||||
| 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 D isorders | ||||||
| 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 I nfestations | ||||||
| Pneumonia | 20 (8) | 8 (3) | 5 (2) | 11 (5) | 5 (2) | 3 (1) |
Skin and S ubcutaneous T issue D isorders | ||||||
| Alopecia | 31 (13) | 1 (<1) | 1 (<1) | 33 (14) | 4 (2) | 0 |
Metabolism and N utrition D isorders | ||||||
| Hyperglycemia | 10 (4) | 1 (<1) | 0 | 17 (7) | 10 (4) | 0 |
| Decreased appetite | 36 (15) | 2 (1) | 0 | 15 (6) | 1 (<1) | 0 |
Vascular D isorders | ||||||
| Hypertension | 15 (6) | 1 (<1) | 0 | 3 (1) | 0 | 0 |
Psychiatric D isorders | ||||||
| Insomnia | 16 (7) | 1 (<1) | 0 | 8 (3) | 0 | 0 |
Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
* Represents 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 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).
Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m2/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 bortezomib subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib 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 bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage.
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.
The most common adverse reactions are shown in
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* | 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) |
* Represents High Level Term Peripheral Neuropathies NEC
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%).
Across the studies, bortezomib-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. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients
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 bortezomib 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 bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-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 bortezomib.
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. 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.
Neutrophil counts decreased during the bortezomib 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 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 (>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 bortezomib 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.
Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (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 bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, 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%).
A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in
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 bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis.
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.
Bortezomib for injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib for injection.
- Peripheral Neuropathy: Manage with dose modification or discontinuation. () Patients with pre-existing severe neuropathy should be treated with bortezomib for injection only after careful risk-benefit assessment. (
2.7 Dose Modifications for Peripheral NeuropathyStarting bortezomib for injection 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 bortezomib for injection only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during bortezomib for injection 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 bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, see
Table 5.Table 5: Recommended Dose Modification for Bortezomib for Injection-Related Neuropathic Pain and/or Peripheral Sensory or Motor NeuropathySeverity of Peripheral Neuropathy Signs and Symptoms*Modification of Dose and RegimenGrade 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)†) Reduce bortezomib for injection to 1 mg/m2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL‡) Withhold bortezomib for injection therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of bortezomib for injection at 0.7 mg/m2once per week. Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue bortezomib for injection * Grading based on NCI Common Terminology Criteria CTCAE v4.0
†Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
‡Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden
,2.7 Dose Modifications for Peripheral NeuropathyStarting bortezomib for injection 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 bortezomib for injection only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during bortezomib for injection 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 bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, see
Table 5.Table 5: Recommended Dose Modification for Bortezomib for Injection-Related Neuropathic Pain and/or Peripheral Sensory or Motor NeuropathySeverity of Peripheral Neuropathy Signs and Symptoms*Modification of Dose and RegimenGrade 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)†) Reduce bortezomib for injection to 1 mg/m2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL‡) Withhold bortezomib for injection therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of bortezomib for injection at 0.7 mg/m2once per week. Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue bortezomib for injection * Grading based on NCI Common Terminology Criteria CTCAE v4.0
†Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
‡Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden
5.1 Peripheral NeuropathyBortezomib for injection 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 bortezomib for injection. 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 bortezomib subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group
[see Adverse Reactions (6.1)]. Starting bortezomib for injection subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during bortezomib for injection therapy may require a decrease in the dose and/or a less dose-intense schedule
[see Dosage and Administration- Embryo-Fetal Toxicity: Bortezomib for injection 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. (
)5.11 Embryo-Fetal ToxicityBased on the mechanism of action and findings in animals, bortezomib can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2based on body surface area caused postimplantation loss and a decreased number of live fetuses
[see Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with bortezomib for injection and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with bortezomib for injection and for four months following treatment. If bortezomib for injection is used during pregnancy or if the patient becomes pregnant during bortezomib for injection treatment, the patient should be apprised of the potential risk to the fetus
[see Use in Specific Populations (8.1,8.3), Nonclinical Toxicology (13.1)]. - Embryo-Fetal Toxicity: Bortezomib for injection 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. (