Boruzu Dosage

Important Dosing Guidelines

BORUZU is for intravenous or subcutaneous use only. Do not administer BORUZU by any other route.

Because each route of administration has a different final concentration, use caution when calculating the volume to be administered.

The recommended starting dose of BORUZU is 1.3 mg/m2. BORUZU is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL.

BORUZU retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with BORUZU and who have relapsed at least six months after completing prior BORUZU treatment. Treatment may be started at the last tolerated dose.

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

Dosage in Previously Untreated Multiple Myeloma

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

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

Dosage Modification Guidelines for BORUZU When Given in Combination with Melphalan and Prednisone

Prior to initiating any cycle of therapy with BORUZU 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: Dosage Modifications During Cycles of Combination BORUZU, Melphalan and Prednisone Therapy

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

Dose modifications guidelines for peripheral neuropathy are provided.

Dosage in Previously Untreated Mantle Cell Lymphoma

BORUZU (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. BORUZU is administered first followed by rituximab. BORUZU 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 BORUZU.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma

Dosage Modification Guidelines for BORUZU 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 BORUZU treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy. For dose adjustments, see Table 4 below.

Table 4: Dosage Modifications on Days 4, 8, and 11 During Cycles of Combination BORUZU, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy

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

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

BORUZU (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, BORUZU 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). At least 72 hours should elapse between consecutive doses of BORUZU.

Patients with multiple myeloma who have previously responded to treatment with BORUZU (either alone or in combination) and who have relapsed at least six months after their prior BORUZU therapy may be started on BORUZU at the last tolerated dose. Retreated patients are administered BORUZU 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 BORUZU. BORUZU may be administered either as a single agent or in combination with dexamethasone.

BORUZU therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below. Once the symptoms of the toxicity have resolved, BORUZU 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 dosage modifications guidelines for peripheral neuropathy see section 2.7.

Dosage Modifications for Peripheral Neuropathy

Starting BORUZU 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 BORUZU only after careful risk-benefit assessment.

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

Table 5: Recommended Dosage Modification for BORUZU-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

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).

Table 6: Recommended Starting Dose Modification for BORUZU in Patients with Hepatic Impairment

Administration Precautions

The drug quantity contained in one vial may exceed the usual dose required. Use caution in calculating the dose to prevent overdose.

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 BORUZU administration subcutaneously, a less concentrated BORUZU (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, consider use of the

intravenous route of administration.

BORUZU is a hazardous drug. Follow applicable special handling and disposal procedures.1

Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique.

Instructions for Intravenous Administration

Dilute each vial with 2.1 mL of 0.9% Sodium Chloride Injection only to obtain a final concentration of 1 mg/mL (see Table 7). The diluted solution should be clear and colorless.

Table 7: Dilution Volume and Final Concentration for Intravenous Administration

Instructions for Subcutaneous Administration

No dilution is required for subcutaneous route of administration.

The concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the diluted concentration of bortezomib for intravenous administration (1 mg/mL). Use caution when calculating the volume to be administered because each route of administration has a different final concentration.

Stickers that indicate the route of administration are provided with each BORUZU vial. Place the sticker directly on the syringe of BORUZU once the required volume of BORUZU has been withdrawn from the vial to help to alert practitioners of the correct route of administration for BORUZU.

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 diluted product should not be used. Discard any unused portion.

Stability

BORUZU contains no antimicrobial preservative. The diluted product may be stored in the original vial and/or syringe at room temperature (20°C to 25°C [68°F to 77°F]) for up to 8 hours prior to use when exposed to normal indoor lighting.