Zomod 1/Zomod 3.5 Dosage/Direction for Use

Treatment must be initiated and administered under the supervision of a physician experienced in the treatment of cancer patients, however Bortezomib may be administered by a healthcare professional experienced in the use of chemotherapeutic agents. Bortezomib must be reconstituted by a healthcare professional (see Special precautions for disposal and other handling under Cautions for Usage).
Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy): Monotherapy: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. It is recommended that patients receive 2 cycles of Bortezomib following a confirmation of a complete response. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of Bortezomib therapy. At least 72 hours should elapse between consecutive doses of Bortezomib.
Dose adjustments during treatment and re-initiation of treatment for monotherapy: Bortezomib treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed as follows (see also Precautions). Once the symptoms of the toxicity have resolved, Bortezomib treatment may be re-initiated at a 25% reduced dose (1.3 mg/m² reduced to 1.0 mg/m²; 1.0 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 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 are to be managed as presented in Table 9. Patients with pre-existing severe neuropathy may be treated with Bortezomib only after careful risk/benefit assessment. (See Table 9.)

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Combination therapy with pegylated liposomal doxorubicin: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib.
Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the Bortezomib treatment cycle as a 1 hour intravenous infusion administered after the Bortezomib injection. Up to 8 cycles of this combination therapy can be administered as long as patients have not progressed and tolerate treatment. Patients achieving a complete response can continue treatment for at least 2 cycles after the first evidence of complete response, even if this requires treatment for more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue for as long as treatment is tolerated and they continue to respond.
Combination with dexamethasone: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib.
Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib treatment cycle.
Patients achieving a response or a stable disease after 4 cycles of this combination therapy can continue to receive the same combination for a maximum of 4 additional cycles.
Dose adjustments for combination therapy for patients with progressive multiple myeloma: For Bortezomib dosage adjustments for combination therapy follow dose modification guidelines described under monotherapy as previously mentioned.
Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation: Combination therapy with melphalan and prednisone: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both in combination with oral melphalan and oral prednisone as shown in Table 10. A 6-week period is considered a treatment cycle. In Cycles 1-4, Bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, 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 given 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 10.)

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Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisone: Prior to initiating a new cycle of therapy: Platelet counts should be ≥70 x 10⁹/L and the absolute neutrophils count should be ≥1.0 x 10⁹/L.
Non-haematological toxicities should have resolved to Grade 1 or baseline. (See Table 11.)

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Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy): Combination therapy with dexamethasone: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib.
Dexamethasone is administered orally at 40 mg 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.
Combination therapy with dexamethasone and thalidomide: Bortezomib 1 mg is administered via intravenous injection, and Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection, both at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see Table 12).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. (See Table 12.)

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Dosage adjustments for transplant eligible patients: 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.
Zomod 1: For Bortezomib dosage adjustments, dose modification guidelines described for monotherapy should be followed.
Zomod 3.5: For Bortezomib dosage adjustmentss for neuropathy refer to Table 8.
Special populations: Elderly: 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 haematopoietic stem cell transplantation. Therefore no dose recommendations can be made in this population.
Zomod 1: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mental cell lymphoma.
In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients exposed to bortezomib were in the range 65-74 years and ≥75 years of age, respectively. In patients aged ≥75 years, both regimens, BzR-CAP as well as R-CHOP, were less tolerated (see Adverse Reactions).
Zomod 3.5: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age.
Hepatic impairment: Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib at a reduced dose of 0.7 mg/m² per injection during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerability (see Table 13 and Precautions and Pharmacology: Pharmacokinetics under Actions). (See Table 13.)

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Renal impairment: The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance [CrCL] >20 mL/min/1.73 m²); therefore, dose adjustments are not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CrCL <20 mL/min/1.73 m²). Since dialysis may reduce bortezomib concentrations, Bortezomib should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of bortezomib in children below 18 years of age have not been established (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions). Currently available data are described in Pharmacology: Pharmacodynamics under Actions but no recommendation on a posology can be made.
Zomod 1: For additional information concerning pegylated liposomal doxorubicin, see the corresponding Summary of Product Characteristics.
For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.
Posology for patients with previously untreated mantle cell lymphoma (MCL): Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (BzR-CAP): Bortezomib is administered via intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11, followed by a 10-day rest period on days 12-21. This 3-week period is considered a treatment cycle. Six bortezomib cycles are recommended, although for patients with a response first documented at cycle 6, two additional bortezomib cycles may be given. At least 72 hours should elapse between consecutive doses of Bortezomib.
The following medicinal products are administered on day 1 of each bortezomib 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 bortezomib treatment cycle.
Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma: Prior to initiating a new cycle of therapy: Platelet counts should be ≥100,000 cells/μL and the absolute neutrophils count (ANC) should be ≥1,500 cells/μL; Platelet counts should be ≥75,000 cells/μL in patients with bone marrow infiltration 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 (see also Precautions). For dose adjustments, see Table 14 as follows.
Granulocyte colony stimulating factors may be administered for hematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration. Platelet transfusion for the treatment of thrombocytopenia should be considered when clinically appropriate. (See Table 14.)

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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 should not be given by other routes. Intrathecal administration has resulted in death.
Zomod 1: Bortezomib 1 mg powder for solution for injection is available for intravenous administration only.
Intravenous injection: Bortezomib is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/mL (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of Bortezomib.
When Bortezomib is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.
Zomod 3.5: Bortezomib 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.
Intravenous injection: Bortezomib 3.5 mg reconstituted solution is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/mL (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of Bortezomib.
Subcutaneous injection: Bortezomib 3.5 mg reconstituted solution is administered subcutaneously through the thighs (right or left) or abdomen (right or left). The solution should be injected subcutaneously, at a 4590° angle. Injection sites should be rotated for successive injections.
If local injection site reactions occur following Bortezomib subcutaneous injection, either a less concentrated Bortezomib solution (Bortezomib 3.5 mg to be reconstituted to 1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously or a switch to intravenous injection is recommended.