BORTEZOMIB

BORTEZOMIB — bortezomib injection, powder, lyophilized, for solution
Zydus Pharmaceuticals USA 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.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing Guidelines

Bortezomib is for intravenous or subcutaneous use only. Do not administer bortezomib 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 is 1.3 mg/m². Bortezomib 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 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)].

When administered intravenously, administer bortezomib as a 3 to 5 second bolus intravenous injection.

2.2 Dosage in Previously Untreated Multiple Myeloma

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

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma

Twice Weekly Bortezomib (Cycles 1 to 4)
Week	1				2		3	4		5		6
Bortezomib (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 (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)
Week	1				2		3	4		5		6
Bortezomib (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 When Given in Combination with Melphalan and Prednisone

Prior to initiating any cycle of therapy with bortezomib 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, 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 x 109 /L or ANC is not above 0.75 x 109 /L on a bortezomib dosing day (other than Day 1)	Withhold bortezomib dose
If several bortezomib doses in consecutive cycles are withheld due to toxicity	Reduce bortezomib dose by one 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 therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, bortezomib 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-related neuropathic pain and/or peripheral neuropathy, hold or modify bortezomib 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 (2.7)].