BORTEZOMIB-TEVA POWDER FOR SOLUTION FOR INJECTION 3.5MG/VIAL

TEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD.

TEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD.

Therapeutic

Prescription Only

INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION

**Dosage and Method of Administration** Bortezomib injection may be administered: - Intravenously (at a concentration of 1 mg/ml) as a 3 to 5 second bolus injection or - Subcutaneously (at a concentration of 2.5 mg/ml) Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. At least 72 hours should elapse between consecutive doses of Bortezomib injection. **BORTEZOMIB INJECTION IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY. Intrathecal administration has resulted in death.** **Monotherapy** **Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma** Recommended Dosage The recommended dose of Bortezomib injection is 1.3 mg/m2/dose administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12–21). For extended therapy of more than 8 cycles, Bortezomib injection may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) (see _Clinical Trials_ section for a description of dose administration during the trials – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). At least 72 hours should elapse between consecutive doses of Bortezomib injection. Dose Modification and Re-initiation of Therapy Bortezomib 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 _Special Warnings And Special Precautions For Use_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). Once the symptoms of the toxicity have resolved, Bortezomib injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/ m2/dose reduced to 1.0 mg/m2/dose; 1.0 mg/m2/dose reduced to 0.7 mg/m2/dose). **Table 1** contains the recommended dose modification for the management of patients who experience Bortezomib injection - related neuropathic pain and/or peripheral neuropathy. Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been reported. Patients with pre-existing severe neuropathy should be treated with Bortezomib injection only after careful risk-benefit assessment.  Administration Bortezomib injection is administered intravenously or subcutaneously. When administered intravenously, Bortezomib injection is administered as a 3–5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection. For subcutaneous administration, the reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections. If local injection site reactions occur following Bortezomib injection subcutaneously, a less concentrated Bortezomib injection (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously, or changed to IV injection. **Combination Therapy** **Previously Untreated Multiple Myeloma** Recommended Dosage in Combination with Melphalan and Prednisone Bortezomib injection is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in **Table 2**. In Cycles 1–4, Bortezomib injection is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5–9, Bortezomib injection is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib injection.  Dose Management Guidelines for Combination Therapy with Melphalan and Prednisone Dose modification and re-initiation of therapy when Bortezomib injection is administered in combination with melphalan and prednisone Prior to initiating a new cycle of therapy: - Platelet count should be ≥70 x 109/L and the absolute neutrophil count ANC should be ≥ 1.0 x 109/L - Non-hematological toxicities should have resolved to Grade 1 or baseline  For additional information concerning melphalan and prednisone, see manufacturer’s prescribing information. **Previously Untreated Mantle Cell Lymphoma Patients Not Eligible for Haematopoietic Stem Cell Transplantation** Recommended Dosage in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone For Bortezomib injection dosage, see Monotherapy. Six Bortezomib injection cycles are administered. For patients with a response first documented at Cycle 6, two additional Bortezomib injection cycles are recommended. The following medicinal products are administered on Day 1 of each Bortezomib injection 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, and doxorubicin at 50 mg/m2. Prednisone is administered orally at 100 mg/m2 on Days 1, 2, 3, 4 and 5 of each treatment cycle. Dose Adjustments during Treatment for Patients with Previously Untreated Mantle Cell Lymphoma Prior to the first day of each cycle (other than Cycle 1): - Platelet count should be ≥ 100 x 109/L and absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L - Hemoglobin should be ≥ 8 g/dL (≥ 4.96 mmol/L) - Non-hematologic toxicity should have recovered to Grade 1 or baseline Bortezomib injection treatment must be withheld at the onset of any Grade 3 non-hematological or Grade 3 hematological toxicities, excluding neuropathy. For dose adjustments, see **Table 4** below.  For dosing instructions for rituximab, cyclophosphamide, doxorubicin, or prednisone, see manufacturer’s prescribing information. **Special Populations** **Patients with Renal Impairment** The pharmacokinetics of Bortezomib injection are not influenced by the degree of renal impairment. Therefore, dosing adjustments of Bortezomib injection are not necessary for patients with renal insufficiency. Since dialysis may reduce Bortezomib injection concentrations, the drug should be administered after the dialysis procedure (see _Pharmacokinetic Properties_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Patients with Hepatic Impairment** Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib injection dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib injection at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0mg/m2 or further dose reduction to 0.5mg/m2 may be considered based on patient tolerance (see **Table 5**).