Bortezomib
Bortezomib 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[ seeDosage 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[seeDosage 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 AdministrationRoute of AdministrationBortezomib (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/mLDose 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.Stability
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 25ºC (77ºF). 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. (,
2.2 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 1to 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 MyelomaTwice WeeklyBortezomib 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 WeeklyBortezomib 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 ,2.4 Dosage in Previously Untreated Mantle Cell LymphomaBortezomib for injection (1.3 mg/m2) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (BR-CAP) for 6, three week treatment cycles as shown in
Table 3. Bortezomib for injection is administered first followed by rituximab. Bortezomib for injection is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21. For patients with a response first documented at Cycle 6, two additional BR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of bortezomib for injection.Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell LymphomaTwice Weekly Bortezomib for Injection (6, ThreeWeek Cycles)*Week123Bortezomib for Injection (1.3mg/m2)
Day
1
--
--
Day
4
--
Day
8
Day
11
rest periodRituximab (375 mg/m2) Cyclophosphamide (750 mg/m2) Doxorubicin (50 mg/m2)
Day 1
--
--
--
--
rest periodPrednisone (100 mg/m2)
Day 1
Day 2
Day 3
Day 4
Day 5
--
--
rest period* Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6.
)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
[seeWarnings 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
[seeWarnings 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 1 x 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 to1 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 AdministrationRoute of AdministrationBortezomib (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/mLDose 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.Stability
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 25ºC (77ºF). 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 white to off white lyophilized 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 25ºC (77ºF). 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 treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Bortezomib 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
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 BR-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 (BR-CAP 8% vs R-CHOP 5%).
BR-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 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 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 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; BR-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 BR-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 BR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥3 bleeding events resolved without sequelae in the BR-CAP arm.
Adverse reactions leading to discontinuation occurred in 8% of patients in BR-CAP group and 6% of patients in R-CHOP group. In the BR-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 tenday 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 (> 38ºC) 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 to11%) 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 is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib.
- Peripheral Neuropathy: Manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with bortezomib only after careful risk-benefit assessment. ( 2.7, )
5.1 Peripheral NeuropathyBortezomib 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. 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 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 therapy may require a decrease in the dose and/or a less dose-intense schedule
[see Dosage and Administration (2.7)].In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the Phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. - Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ()
5.2 HypotensionThe incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%
[see Adverse Reactions (6.1)].These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. - Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ()
5.3 Cardiac ToxicityAcute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction
[see Adverse Reactions (6.1)].Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of bortezomib vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the bortezomib group. In the dexamethasone group the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. - Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting bortezomib therapy. ()
5.4 Pulmonary ToxicityAcute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving bortezomib. Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m2per day) by continuous infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with bortezomib administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, consider interrupting bortezomib until a prompt and comprehensive diagnostic evaluation is conducted.
- Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue bortezomib if suspected. ()
5.5 Posterior Reversible Encephalopathy Syndrome (PRES)Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue bortezomib. The safety of reinitiating bortezomib therapy in patients previously experiencing PRES is not known.
- Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. )
5.6 Gastrointestinal ToxicityBortezomib treatment can cause nausea, diarrhea, constipation, and vomiting
[see Adverse Reactions (6.1)]sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt bortezomib for severe symptoms. - Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ()
5.7 Thrombocytopenia/NeutropeniaBortezomib is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.
Monitor complete blood counts (CBC) frequently during treatment with bortezomib. Measure platelet counts prior to each dose of bortezomib. Adjust dose/schedule for thrombocytopenia[seeDosage and Administration (2.6)].Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines.
In the single agent, relapsed multiple myeloma study of bortezomib vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown inTable 8. The incidence of bleeding (≥Grade 3) was 2% on the bortezomib arm and was <1% in the dexamethasone arm.
Table 8: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib vs DexamethasonePretreatment Platelet Count*Number of Patients (N=331)‡Number (%) of Patients with Platelet Count <10,000/µLNumber (%) of Patients with Platelet Count 10,000 to 25,000/µL≥ 75,000/µL 309 8 (3%) 36 (12%) ≥ 50,000/µL to <75,000/ µL 14 2 (14%) 11 (79%) ≥ 10,000/µL to <50,000/ µL 7 1 (14%) 5 (71%) * A baseline platelet count of 50,000/µL was required for study eligibility
‡Data were missing at baseline for one patient
In the combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin and prednisone (BR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in
Table 12. The incidence of bleeding events (≥Grade 3) was 1.7% in the BR-CAP arm (four patients) and was 1.2% in the R-CHOP arm (three patients).
Platelet transfusions were given to 23% of the patients in the BR-CAP arm and 3% of the patients in the R-CHOP arm.
The incidence of neutropenia (≥Grade 4) was 70% in the BR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the BR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the BR-CAP arm and 61% in the R-CHOP arm. - Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. ()
5.8 Tumor Lysis SyndromeTumor lysis syndrome has been reported with bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
- Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt bortezomib therapy to assess reversibility. ()
5.9 Hepatic ToxicityCases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt bortezomib therapy to assess reversibility. There is limited rechallenge information in these patients.
- Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue bortezomib if suspected. ()
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 and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with bortezomib and for four months following treatment. If bortezomib is used during pregnancy or if the patient becomes pregnant during bortezomib 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 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 and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with bortezomib and for four months following treatment. If bortezomib is used during pregnancy or if the patient becomes pregnant during bortezomib 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)].