Bortezomib (Page 2 of 10)

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

Bortezomib 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 Lymphoma

Twice Weekly Bortezomib for Injection (6, Three Week Cycles)*
Week	1					2		3
Bortezomib for Injection (1.3mg/m2)	Day1	—	—	Day4	—	Day8	Day11	rest period
Rituximab (375 mg/m2) Cyclophosphamide (750 mg/m2) Doxorubicin (50 mg/m2)	Day 1	—	—			—	—	rest period
Prednisone (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.

2.5 Dose Modification Guidelines for Bortezomib for 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 x 10⁹ /L and absolute neutrophil count (ANC) should be at least 1.5 x 10⁹ /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 for 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.Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination Bortezomib for Injection, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy

Toxicity	Dose Modification or Delay
Hematological Toxicity
Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 109 /L	Withhold bortezomib for injection therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 109 /L and a platelet count at or above 25 × 109 /L. If, after bortezomib for injection has been withheld, the toxicity does not resolve, discontinue bortezomib for injection. If toxicity resolves such that the patient has an ANC at or above 0.75 × 109 /L and a platelet count at or above 25 × 109 /L, bortezomib for injection dose should be reduced 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 the toxicity have resolved to Grade 2 or better. 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 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 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.

2.7 Dose Modifications for Peripheral Neuropathy

Starting 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 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 v4.0

^† 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