INDICATIONS & USAGE SECTION

Highlight: Bortezomib for injection is a proteasome inhibitor indicated for:

• treatment of adult patients with multiple myeloma (1.1)
• treatment of adult patients with mantle cell lymphoma (1.2)

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.

DOSAGE & ADMINISTRATION SECTION

Highlight: * For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. (2.1, 2.10)

• The recommended starting dose of bortezomib for injection is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. (2.2, 2.4, 2.6)
• Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. (2.6)
• Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (2.8)
• Dose must be individualized to prevent overdose (2.10).

2 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.

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

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:

• Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1 × 109/L
• Nonhematological toxicities should have resolved to Grade 1 or baseline

Table 2: Dose Modifications during Cycles of Combination Bortezomib for Injection, Melphalan and Prednisone Therapy

Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.7)].

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 (VcR-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 VcR-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

• 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.

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 2 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.

Table 5: Recommended Dose Modification for Bortezomib for Injection- Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

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

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.

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous

Administration

Use proper aseptic technique. Reconstituteonly with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution. Different volumes of 0.9% sodium chloride 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 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 7):

Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration

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:

*Intravenous Administration [1 mg/mL concentration]

*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.

Stability

Unopened vials of bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.

Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted bortezomib for injection within eight hours of preparation. When reconstituted as directed, bortezomib for injection may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose. (3)

3 DOSAGE FORMS AND STRENGTHS

For injection: Each single-dose vial of bortezomib for injection contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration (2.10)].

---

CONTRAINDICATIONS SECTION

Highlight: * Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. (4)

• Contraindicated for intrathecal administration. (4)

4 CONTRAINDICATIONS

Bortezomib for injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1)].

Bortezomib for injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib for injection.

---

OVERDOSAGE SECTION

10 OVERDOSAGE

There is no known specific antidote for bortezomib overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given.

Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour postadministration, with progression to death in 12 to 14 hours following drug administration.

---

SPL UNCLASSIFIED SECTION

Revised: March 2024

Rev: 6

REFERENCES SECTION

15 REFERENCES

1. "OSHA Hazardous Drugs" (refer to antineoplastic weblinks including OSHA Technical Manual). OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

---