Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: JANSSEN-CILAG INTERNATIONAL NV Turnhoutseweg 30 B-2340 Beerse Belgium
VELCADE as monotherapy is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.
VELCADE in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant.
Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents. VELCADE must be reconstituted by a healthcare professional.
VELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.
VELCADE 1 mg powder for solution for injection is available for intravenous administration only.
VELCADE should not be given by other routes.Intrathecal administration has resulted in death.
The recommended starting dose of bortezomib is 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. At least 72 hours should elapse between consecutive doses of VELCADE.
It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELCADE beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy.
Currently there are limited data concerning re-treatment with VELCADE.
VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4). Once the symptoms of the toxicity have resolved, VELCADE 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 VELCADE must be considered unless the benefit of treatment clearly outweighs the risk.
Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1 (see section 4.4). Patients with pre-existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.
Table 1 – Recommended posology modifications for bortezomib-related neuropathy:*
| Severity of neuropathy | Posology modification |
|---|---|
| Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) with no pain or loss of function | None |
| Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**) | Reduce VELCADE to 1.0 mg/m² or Change VELCADE treatment schedule to 1.3 mg/m² once per week |
| Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL ***) | Withhold VELCADE treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate VELCADE treatment and reduce dose to 0.7 mg/m² once per week. |
| Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathy | Discontinue VELCADE |
* Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience. Grading based on NCI Common Toxicity Criteria CTCAE v 4.0.
** Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc;
*** Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal products, and not bedridden.
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 VELCADE 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 2 and sections 4.4 and 5.2).
*Table 2 – Recommended starting dose modification for VELCADE in patients with hepatic impairment:*
| Grade of hepatic impairment* | Bilirubin level | SGOT (AST) levels | Modification of starting dose |
|---|---|---|---|
| Mild | ≤ 1.0x ULN | > ULN | None |
| > 1.0x−1.5x ULN | Any | None | |
| Moderate | > 1.5x−3x ULN | Any | Reduce VELCADE to 0.7 mg/m² in the first treatment cycle. Consider dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² in subsequent cycles based on patient tolerability. |
| Severe | > 3x ULN | Any |
Abbreviations: SGOT = serum glutamic oxaloacetic transaminase;
AST = aspartate aminotransferase; ULN = upper limit of the normal range.
* Based on NCI Organ Dysfunction Working Group classification for categorising hepatic impairment (mild, moderate, severe).
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, VELCADE should be administered after the dialysis procedure (see section 5.2).
There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age.
Paediatric population
The safety and efficacy of VELCADE in children below age 18 have not been established (see sections 5.1 and 5.2).
VELCADE is administered in combination with oral melphalan and oral prednisone for nine treatment cycles as shown in Table 3. A 6-week period is considered a treatment cycle. In Cycles 1-4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, VELCADE is administered once weekly on days 1, 8, 22 and 29. Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
*Table 3 – Recommended posology for VELCADE in combination with melphalan and prednisone for patients with previously untreated multiple myeloma:*
| Twice weekly VELCADE (cycles 1-4) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week | 1 | 2 | 3 | 4 | 5 | 6 | ||||||
| Vc (1.3 mg/m²) | Day 1 | -- | -- | Day 4 | Day 8 | Day 11 | rest period | Day 22 | Day 25 | Day 29 | Day 32 | rest period |
| M (9 mg/m²) P (60 mg/m²) | Day 1 | Day 2 | Day 3 | Day 4 | -- | -- | rest period | -- | -- | -- | -- | rest period |
| Once weekly VELCADE (cycles 5-9) | ||||||||||||
| Week | 1 | 2 | 3 | 4 | 5 | 6 | ||||||
| Vc (1.3 mg/m²) | Day 1 | -- | -- | -- | Day 8 | rest period | Day 22 | Day 29 | rest period | |||
| M (9 mg/m²) P (60 mg/m²) | Day 1 | Day 2 | Day 3 | Day 4 | -- | rest period | -- | -- | rest period | |||
Vc = VELCADE; M = melphalan, P = prednisone
Dose adjustments during treatment and re-initiation of treatment for combination therapy
Prior to initiating a new cycle of therapy:
Table 4 – Posology modifications during subsequent cycles¨
| Toxicity | Posology modification or delay |
|---|---|
| Haematological toxicity during a cycle | |
| If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle | Consider reduction of the melphalan dose by 25% in the next cycle. |
| If platelet counts ≤30 × 109/l or ANC ≤0.75 × 109/l on a VELCADE dosing day (other than Day 1) | VELCADE therapy should be withheld |
| If several VELCADE doses in a cycle are withheld (≥ 3 doses during twice weekly administration or ≥ 2 doses during weekly administration) | VELCADE dose should be reduced by 1 dose level (from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²) |
| Grade ≥ 3 non-haematological toxicities | VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELCADE as outlined in Table 1. |
For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.
VELCADE 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 VELCADE.
VELCADE 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 45-90° angle. Injection sites should be rotated for successive injections.
If local injection site reactions occur following VELCADE subcutaneous injection, either a less concentrated VELCADE solution (VELCADE 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.
In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical cardiovascular safety pharmacology studies, see section 5.3.
There is no known specific antidote for bortezomib overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2 and 4.4).
Unopened vial: 3 years.
Reconstituted solution: The reconstituted solution should be used immediately after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours at 25 °C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.
Do not store above 30°C.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Type 1 glass 10 ml-vial with a grey bromobutyl stopper and an aluminium seal, with a royal blue cap containing 3.5 mg bortezomib.
The vial is contained in a transparent blister pack consisting of a tray with a lid. Each pack contains 1 single-use vial.
Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of VELCADE. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of VELCADE, since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mg is for intravenous use only, while VELCADE 3.5 mg is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
VELCADE must be reconstituted by a healthcare professional.
Each 10 ml vial of VELCADE must be reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Each 10 ml vial of VELCADE should be reconstituted with 1.4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
VELCADE is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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