BORTEZOMIB (Page 3 of 11)

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
*
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

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

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/m2 per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 based 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 Impairment

Bilirubin Level

SGOT (AST)Levels

Modification of Starting Dose

Mild

Less than or equal to 1x ULN

More than ULN

None

More than 1x to 1.5x ULN

Any

None

Moderate

More than 1.5x to3x ULN

Any

Reduce Bortezomib for Injection to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in 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.

2.9 Administration Precautions

The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.10)].

When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

If local injection site reactions occur following Bortezomib for Injection administration subcutaneously, a less concentrated Bortezomib for Injection solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see Dosage and Administration (2.10)]. Alternatively, consider use of the intravenous route of administration [see Dosage and Administration (2.10)].

Bortezomib for Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

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