bortezomib injection 1 MG and 2.5 MG VIAL Dosage and Administration

2.1 Important Dosing Guidelines

Bortezomib for Injection is for intravenous or subcutaneous use only. Do not administer Bortezomib for Injection 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 for Injection is 1.3 mg/m2. Bortezomib for Injection 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 for Injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezomib for Injection and who have relapsed at least six months after completing prior Bortezomib for Injection treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6)].

When administered intravenously, 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.

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:

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Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1 × 109/L

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Non-hematological 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 (1.3 mg/m2) 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 is administered first followed by rituximab. Bortezomib 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.

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

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

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Platelet count should be at least 100 × 109/L and absolute neutrophil count (ANC) should be at least 1.5 × 109/L

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Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)

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Nonhematologic toxicity should have recovered to Grade 1 or baseline

Interrupt bortezomib 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 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 non-hematological 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.

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)].

2.9 Administration Precautions

The drug quantity contained in one vial (1 mg or 2.5 mg) may exceed the usual dose required. Use caution when calculating the dose to prevent overdose [see Dosage and Administration (2.10)].

When administered subcutaneously, rotate sites for each injection (thigh or abdomen). Give new injections 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

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique. Reconstitute only with 0.9% Sodium Chloride Injection, USP. The reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% Sodium Chloride Injection, USP are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered [see Dosage and Administration (2.9)].

For each 1 mg or 2.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP based on route of administration (Table 7):

Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezomib for Injection to be administered:

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Intravenous Administration [1 mg/mL concentration]

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Subcutaneous Administration [2.5 mg/mL concentration]

Stickers that indicate the route of administration are provided with each Bortezomib for Injection vial. These stickers should be placed directly on the syringe of Bortezomib for Injection once Bortezomib for Injection is prepared to help alert practitioners of the correct route of administration for Bortezomib for Injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.