Velcade Dosage/Direction for Use

Important Dosing Guidelines: VELCADE is for intravenous or subcutaneous use only. Do not administer VELCADE 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 VELCADE is 1.3 mg/m². VELCADE may be administered intravenously at a concentration of 1 mg/ml, or subcutaneously at a concentration of 2.5 mg/ml.
VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least 6 months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose.
When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection.
Dosage in Previously Untreated Multiple Myeloma: VELCADE 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, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE. (See Table 1.)

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Dose Modification Guidelines for VELCADE when given in Combination with Melphalan and Prednisone: Prior to initiating any cycle of therapy with VELCADE 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 1.0 x 10⁹/L; Nonhematological toxicities should have resolved to Grade 1 or baseline. (See Table 2.)

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For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided.
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy): Combination therapy with dexamethasone: VELCADE 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 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 VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Four treatment cycles of this combination therapy are administered.
Combination therapy with dexamethasone and thalidomide: VELCADE 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 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 VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE 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 3).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. (See Table 3.)

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Dosage adjustments for transplant eligible patients: For VELCADE dosage adjustments, as described under "Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma" and "Dose Modifications for Peripheral Neuropathy" should be followed.
In addition, when VELCADE 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 local package inserts.
Dosage in Previously Untreated Mantle Cell Lymphoma: VELCADE (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 4. VELCADE is administered first followed by rituximab. VELCADE 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 VELCADE. (See Table 4.)

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Dose Modification Guidelines for VELCADE 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); Non-hematologic toxicity should have recovered to Grade 1 or baseline.
Interrupt VELCADE treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy (see Table 6 and Precautions). For dose adjustments, see Table 5 as follows. (See Table 5.)

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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: VELCADE (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, VELCADE 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 VELCADE.
Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least six months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose. Retreated patients are administered VELCADE 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 VELCADE. VELCADE may be administered either as a single agent or in combination with dexamethasone.
VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows (see Precautions). Once the symptoms of the toxicity have resolved, VELCADE 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 Dose Modifications for Peripheral Neuropathy as follows.
Dose Modifications for Peripheral Neuropathy: Starting VELCADE 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 VELCADE only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during VELCADE 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 VELCADE-related neuropathic pain and/or peripheral neuropathy (see Table 6).

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Special Populations: Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended VELCADE dose. For patients with moderate or severe hepatic impairment, see Table 7 as follows, (also, see Pharmacology: Pharmacokinetics under Actions): (see Table 7.)

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Administration: VELCADE is administered intravenously or subcutaneously. When administered intravenously, VELCADE 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 VELCADE injection subcutaneously, a less concentrated VELCADE solution (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously, or changed to IV injection.