BORTEZOMIB- bortezomib injection, powder, lyophilized, for solution
Dr.Reddy’s Laboratories Inc
1 INDICATIONS AND USAGE
1.1 Multiple Myeloma
Bortezomib for injection is indicated for the treatment of adult patients with multiple myeloma.
1.2 Mantle Cell Lymphoma
Bortezomib for injection is indicated for the treatment of adult patients with mantle cell lymphoma who have received at least 1 prior therapy.
2 DOSAGE AND ADMINISTRATION
2.1 Important Dosing Guidelines
Bortezomib for injection is for intravenous use only. Do not administer Bortezomib for injection by any other route.
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 [see Dosage and Administration (2.8)].
Bortezomib for injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib and who have relapsed at least six months after completing prior bortezomib treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.4)].
Administer Bortezomib for injection as a 3 to 5 second bolus intravenous injection.
2.2 Dosage in Previously Untreated Multiple Myeloma
Bortezomib 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)|
|Bortezomib 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)
|Bortezomib 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|
2.3 Dose Modification Guidelines for Bortezomib for injection When Given in Combination with Melphalan and Prednisone
Prior to initiating any cycle of therapy with Bortezomib for injection in combination with melphalan and prednisone:
• Platelet count should be at least 70 x 109 /L and the absolute neutrophil count (ANC) should be at least 1 x 109 /L
• Nonhematological toxicities should have resolved to Grade 1 or baseline
Table 2:Dose Modifications During Cycles of Combination Bortezomib for injection, Melphalan and Prednisone Therapy
|Toxicity||Dose modification or delay|
|Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle||Consider reduction of the melphalan dose by 25% in the next cycle.|
|If platelet count is not above 30 × 109 /L or ANC is not above 0.75 x 109 /L on a Bortezomib for injection dosing day (other than Day 1)||Withhold Bortezomib for injection dose|
|If several Bortezomib for injection doses in consecutive cycles are withheld due to toxicity||Reduce Bortezomib for injection dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2 , or from 1 mg/m2 to 0.7 mg/m2)|
|Grade 3 or higher nonhematological toxicities||Withhold Bortezomib for injection therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Bortezomib for injection may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2 , or from 1 mg/m2 to 0.7 mg/m2). For Bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib for injection as outlined in Table 5.|
For information concerning melphalan and prednisone, see manufacturer’s prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.5) ].
2.4 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
Bortezomib 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 (14.1)]. At least 72 hours should elapse between consecutive doses of bortezomib.
Patients with multiple myeloma who have previously responded to treatment with bortezomib (either alone or in combination) and who have relapsed at least six months after their prior bortezomib therapy may be started on bortezomib 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. 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 2.5.
2.5 Dose Modifications for Peripheral Neuropathy
Patients with preexisting 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 3.
Table 3: Recommended Dose Modification for Bortezomib related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy
|Severity of Peripheral Neuropathy Signs and Symptoms*||Modification of Dose and Regimen|
|Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function||No action|
|Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**)||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/m2 once per week.|
|Grade 4 (life-threatening consequences; urgent intervention indicated)||Discontinue Bortezomib for injection|
*Grading based on NCI Common Terminology Criteria CTCAE v4
**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
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