Bortezomib

BORTEZOMIB- bortezomib injection
FOSUN PHARMA USA INC

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

Bortezomib Injection is indicated for the treatment of adult patients with multiple myeloma.

1.2 Mantle Cell Lymphoma

Bortezomib Injection is indicated for the treatment of adult patients with mantle cell lymphoma.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing Guidelines

Bortezomib Injection is a ready-to-use sterile solution for intravenous use only. Do not administer Bortezomib Injection by any other route.

The recommended starting dose of Bortezomib Injection is 1.3 mg/m ². Bortezomib Injection is administered intravenously at a concentration of 1 mg/mL or 2.5 mg/mL [see Dosage and Administration (2.9 and 2.10)].

Bortezomib 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 (2.6)].

Administer Bortezomib Injection as a 3 to 5 second bolus intravenous injection.

2.2 Dosage in Previously Untreated Multiple Myleoma

Bortezomib 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 Injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib Injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib Injection.

2.3 Dose Modification Guidelines for Bortezomib Injection When Given in Combination with Melphalan and Prednisone

Prior to initiating any cycle of therapy with Bortezomib Injection in combination with melphalan and prednisone:

• Platelet count should be at least 70 × 10 ⁹ /L and the absolute neutrophil count (ANC) should be at least 1 × 10 ⁹ /L
• Nonhematological toxicities should have resolved to Grade 1 or baseline

For information concerning melphalan and prednisone, see manufacturer’s prescribing information.

Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.7)].

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

Bortezomib Injection (1.3 mg/m ²) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 3. Bortezomib Injection is administered first followed by rituximab. Bortezomib 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 VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of Bortezomib Injection.

2.5 Dose Modification Guidelines for Bortezomib Injection When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone

Prior to the first day of each cycle (other than Cycle 1):

• Platelet count should be at least 100 × 10 ⁹ /L and absolute neutrophil count (ANC) should be at least 1.5 × 100 ⁹ /L
• Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L) Nonhematologic toxicity should have recovered to Grade 1 or baseline

Interrupt Bortezomib Injection treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy [see Table 5, Warnings and Precautions (5)]. For dose adjustments, see Table 4 below.

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer’s prescribing information.

2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

Bortezomib Injection (1.3 mg/m ² /dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, Bortezomib 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 Injection.

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 Injection at the last tolerated dose. Retreated patients are administered Bortezomib 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 Injection. Bortezomib Injection may be administered either as a single agent or in combination with dexamethasone [see Clinical Studies (14.1)].

Bortezomib 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 Injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/m ² /dose reduced to 1 mg/m ² /dose; 1 mg/m ² /dose reduced to 0.7 mg/m ² /dose).

For dose modifications guidelines for peripheral neuropathy see section 2.7.

2.7 Dose Modifications for Peripheral Neuropathy

Patients with preexisting severe neuropathy should be treated with Bortezomib Injection only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during Bortezomib 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 Injection-related neuropathic pain and/or peripheral neuropathy see Table 5.

2.8 Dosage in Patients with Hepatic Impairment

Do 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/m ² per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m ² or further dose reduction to 0.5 mg/m ² based on patient tolerance (see Table 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].