Biomib Dosage/Direction for Use

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents. Bortezomib has a narrow therapeutic index and should be used with caution.
For the treatment of adult patients with progressive multiple myeloma who have received at least one prior therapy: General Dosing Recommendations: The recommended dosage of bortezomib is 1.3 mg/m² body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
As monotherapy: It is recommended that patients should receive two cycles of bortezomib after a complete response is confirmed. It is also recommended that patients responding to treatment but who do not achieve a complete remission should receive a total of eight cycles of bortezomib therapy.
Dose adjustments during treatment and re-initiation of treatment for bortezomib monotherapy: Treatment with bortezomib must be withheld at the onset of any Grade 3 non-hematological or any Grade 4 hematological toxicities, excluding neuropathy. Once the symptoms of the toxicity have resolved, bortezomib treatment may be re-initiated at a 25% reduced dose (i.e., 1.3 mg/m² reduced to 1 mg/m²; 1 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib therapy must be considered, unless the benefit of treatment clearly outweighs the risk.
Neuropathic pain and/or peripheral neuropathy: Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy should be managed accordingly (see Table 1). Patients with pre-existing severe neuropathy should only be treated with bortezomib after careful risk-benefit assessment. (See Table 1.)

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In combination with pegylated liposomal doxorubicin: Follow general dosing recommendation as previously mentioned.
The recommended dose of pegylated liposomal doxorubicin is 30 mg/m² to be administered as a one-hour intravenous infusion following bortezomib injection on day 4 of the treatment cycle.
Up to eight cycles of this combination therapy can be administered as long as patients have not progressed and can tolerate the treatment. Patients achieving a complete response can continue with the combination therapy for at least two cycles after the first evidence of complete response, even if this requires treatment for more than eight cycles. Patients whose paraprotein levels continue to decrease after eight cycles can still receive this combination therapy for as long as the patient can tolerate and respond with the treatment.
In combination with dexamethasone: Follow general dosing recommendation as previously mentioned.
Dexamethasone 20 mg is administered orally at days 1, 2, 4, 5, 8, 9, 11 and 12 of the bortezomib treatment cycle. Patients achieving a response or a stable disease after four cycles of this combination therapy may continue to be administered with the same combination for a maximum of four additional cycles.
Dose adjustments for combination therapy for patients with progressive multiple myeloma: For dosage adjustments of bortezomib in combination therapy, follow dose modification guidelines of bortezomib as monotherapy.
For the treatment of adult patients with progressive multiple myeloma who are unsuitable for hematopoietic stem cell transplantation: In combination with melphalan and prednisone: Bortezomib is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone (See Table 2). A six-week period is considered a treatment cycle. In Cycles 1 to 4, bortezomib is administered twice weekly (i.e., on days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of bortezomib.
Melphalan and prednisone should both be administered orally on days 1, 2, 3, and 4 of the first week of each bortezomib treatment cycle. Nine treatment cycles of this combination therapy are administered. (See Table 2.)

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Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisone: Prior to initiating a treatment cycle: Platelet counts should be ≥70 x 109/L and the absolute neutrophils count should be ≥1 x 109/L; Non-hematological toxicities should have resolved to Grade I or baseline. (See Table 3.)

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For previously untreated multiple myeloma patients eligible for hematopoietic stem cell transplantation (induction therapy): In combination therapy with dexamethasone: The recommended dosage of bortezomib is 1.3 mg/m2 body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone 40 mg is administered orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib treatment cycle. Four treatment cycles of this combination therapy are administered (See Table 4).
In combination therapy with dexamethasone and thalidomide: The recommended dosage of bortezomib is 1.3 mg/m2 body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a followed by a 17-day rest period (days 12 to 28) in a 28-day treatment cycle. This four-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone 40 mg is orally administered on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib treatment cycle.
Thalidomide 50 mg is orally administered daily on days 1 to 14 and if tolerated, the dose is increased to 100 mg on days 15 to 28. Thereafter, the dose may be further increased to 200 mg daily from cycle 2 (see Table 5). Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response should receive two additional cycles. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed. (See Tables 4 & 5.)

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Dosage adjustments for transplant eligible patients: For dosage adjustments of bortezomib, dose modification guidelines described for monotherapy should be followed. In addition, when bortezomib is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the Summary of Product Characteristics.
For patients with previously untreated mantle cell lymphoma (MCL): Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone: The recommended dosage of bortezomib is 1.3 mg/m² body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
It is recommended to administer six bortezomib treatment cycles. For patients with a response first documented at cycle 6, two additional bortezomib treatment cycles may be given.
Prednisone is administered orally at 100 mg/m² on days 1, 2, 3, 4 and 5 of each bortezomib treatment cycle. The following medicinal products are administered on day 1 of each three-week treatment cycle as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at 50 mg/m².
Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma: Prior to initiating a new treatment cycle: Platelet counts should be ≥100,000 cells/mcL and the ANC should be ≥1,500 cells/mcL; Platelet counts should be ≥75,000 cells/mcL in patients with bone marrow filtration or splenic sequestration; Hemoglobin ≥8 g/dL; Non-hematological toxicities should have resolved to Grade 1 or baseline.
Bortezomib treatment must be withheld at the onset of any ≥Grade 3 bortezomib-related non-hematological toxicities (excluding neuropathy) or ≥Grade 3 hematological toxicities. Granulocyte colony stimulating factors may be given for hematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered if cycle administration is repeatedly delayed. Platelet transfusion should be considered as treatment of thrombocytopenia when clinically appropriate. (See Table 6.)

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In addition, when bortezomib is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.
Method of Administration: Bortezomib is available for intravenous or subcutaneous administration. It should not be administered by other routes. Intrathecal administration has resulted in death.
Intravenous injection: Bortezomib reconstituted solution is administered as three- to five-second bolus intravenous injection through a peripheral or central intravenous catheter, followed by a flush with 0.9% sodium chloride solution for injection. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous injection: Bortezomib reconstituted solution is administered either at the right or left thigh or right or left side of the abdomen. The solution should be injected subcutaneously at a 45° to 90° angle. Injection sites should be rotated for consecutive injections. If local injection site reactions occur, either a less concentrated solution (i.e., bortezomib 3.5 mg to be reconstituted to 1 mg/mL instead of 2.5 mg/mL) may be subcutaneously administered, or a switch to intravenous injection is recommended.
Instructions for Reconstitution: Since bortezomib is a cytotoxic agent, the handling and preparation of this product shall be performed with caution. Moreover, aseptic technique must be strictly observed, as this product does not contain preservatives. The use of gloves and other appropriate protective clothing is recommended to prevent possible skin contact.
Bortezomib should only be reconstituted by a healthcare professional. Prior to administration, the reconstituted solution must be visually inspected for particulate matter and discoloration. If any discoloration or particulate matter is observed, the reconstituted solution must be discarded.
For intravenous injection: Reconstitute the bortezomib 8 mL vial with 3.5 mL of 0.9% sodium chloride solution for injection. The dissolution of the lyophilized powder is completed in less than two minutes.
After reconstitution, 1 mL of solution for intravenous injection contains 1 mg bortezomib.
For subcutaneous injection: Reconstitute the bortezomib 8 ml vial with 1.4 mL of 0.9% sodium chloride solution for injection. The dissolution of the lyophilized powder is completed in less than two minutes.
After reconstitution, 1 mL of solution for subcutaneous injection contains 2.5 mg bortezomib.
Special Populations: Hepatic Impairment: Dose adjustments are not required in patients with mild hepatic impairment. Patients with moderate or severe hepatic impairment, however, should be administered with a reduced starting dose of bortezomib on 0.7 mg/m² per injection during the first treatment cycle. A subsequent dose escalation to 1 mg/m² or further dose reduction to 0.5 mg/m² may be considered, depending on the tolerability of the patient. (See Table 7.)

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Renal Impairment: Dose adjustments for patients with mild to moderate renal impairment are not necessary (CLCr >20 mL/min/1.73 m²). However, it is unknown if the pharmacodynamics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CLCr <20 mL/min/1.73 min²). Bortezomib should be administered after dialysis since it may reduce bortezomib concentrations (see Precautions).
Elderly: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma.
Since there are no studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation, no dose recommendations can be made in this population.
In a study, 42.9% and 10.4% of previously untreated mantle cell lymphoma patients exposed to bortezomib were in the range 65 to 74 years and ≥75 years of age, respectively. Both bortezomib-rituximab-cyclophosphamide-doxorubicin-prednisone regimen and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are less tolerated by patients aged ≥75 years of age with mantle cell lymphoma.