Bortezomib
Visa No.: 400114969924
Product: Bortezomib Stada 2.5mg/ml
API: Bortezomib
Product Category: Oncology
Version approved leaflet: 698/QĐ-QLD_15/10/2024_122
INDICATIONS
Bortezomib STADA is indicated for the treatment of multiple myeloma in adult patients:
As monotherapy, or In combination with pegylated liposomal doxorubicin or dexamethasone, in patients who have received at least one prior therapy and who are not candidates for, or have already undergone, hematopoietic stem cell transplantation.
In combination with melphalan and prednisone, for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with stem cell transplantation.
Bortezomib STADA in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are not eligible for stem cell transplantation.
DOSAGE AND ADMINISTRATION
Administration and Supervision Treatment with bortezomib must be initiated under the supervision of a physician experienced in the management of oncology patients. However, administration may be conducted by a healthcare professional experienced in the use of chemotherapeutic agents. Bortezomib must be prepared by a healthcare professional.
Dosage
Treatment of Progressive Multiple Myeloma (Patients who have received at least one prior therapy)
Monotherapy
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously (after reconstitution). The recommended dose is 1.3 mg/m² body surface area, administered twice weekly for 2 weeks, on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
A 3-week period is considered one treatment cycle. Patients are recommended to receive 2 additional cycles of bortezomib after confirmation of a complete response.
Patients who respond but do not achieve complete remission are recommended to receive a total of up to 8 cycles of bortezomib. Successive doses of bortezomib must be separated by at least 72 hours.
Dose Adjustment During Treatment and Re-Initiation (Monotherapy)
Treatment with bortezomib must be withheld at the onset of: Any Grade 3 non-hematologic toxicity, or Any Grade 4 hematologic toxicity, excluding peripheral neuropathy. Once toxicity has resolved, treatment may be restarted at a 25% reduced dose: From 1.3 mg/m² to 1.0 mg/m², or From 1.0 mg/m² to 0.7 mg/m².
If toxicity does not resolve or recurs at the lowest dose, discontinuation of bortezomib should be considered, unless the potential benefit clearly outweighs the risk.
Peripheral Neuropathy and/or Neuropathic Pain
Patients with a history of bortezomib-related peripheral neuropathy and/or neuropathic pain should be managed according to Table 1 above. Patients with pre-existing severe neuropathy should only be treated with bortezomib after careful assessment of the benefit–risk balance.
Table 1: Dose Adjustment for Bortezomib-Related Peripheral Neuropathy
| Severity of peripheral neuropathy | Dose adjustment |
| Grade 1 (no symptoms; loss of deep tendon reflexes or paresthesia) | No dose modification |
| Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental activities of daily living**) | Reduce bortezomib dose to 1.0 mg/m² or change dosing frequency to 1.3 mg/m² once weekly |
| Grade 2 with pain or Grade 3 (severe symptoms; limiting self-care activities of daily living***) | Withhold bortezomib until symptoms improve, then restart at 0.7 mg/m² once weekly |
| Grade 4 (life-threatening consequences; urgent intervention required) | Discontinue bortezomib |
* Based on dose adjustments applied in Phase II and III multiple myeloma studies and post-marketing experience. Toxicity grading is based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
** Instrumental activities of daily living include preparing meals, shopping for groceries or clothing, using the telephone, and managing finances.
*** Self-care activities of daily living include bathing, dressing, eating, using the toilet, taking medications, and not being bedridden.
Combination Treatment with Pegylated Liposomal Doxorubicin
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously after reconstitution. The recommended dose is 1.3 mg/m² body surface area, administered twice weekly for 2 weeks, on Days 1, 4, 8, and 11 of a 21-day treatment cycle. A 3-week period is considered one treatment cycle. Successive doses of bortezomib should be separated by at least 72 hours.
Pegylated liposomal doxorubicin is administered at a dose of 30 mg/m² on Day 4 of the bortezomib treatment cycle, by intravenous infusion over 1 hour, after administration of bortezomib.
This combination regimen may be administered for up to 8 cycles, provided the patient does not experience disease progression and tolerates treatment well. Patients who achieve a complete response may continue treatment for at least 2 additional cycles after the first evidence of complete response, even if this results in treatment beyond 8 cycles. Patients whose paraprotein levels continue to decrease after 8 cycles may also continue treatment, provided that treatment is well tolerated and response is maintained.
For further information regarding pegylated liposomal doxorubicin, refer to the prescribing information for that medicinal product.
Combination Therapy with Dexamethasone
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously after reconstitution at a recommended dose of 1.3 mg/m² body surface area, twice weekly for 2 weeks, on Days 1, 4, 8, and 11 of a 21-day treatment cycle. A 3-week period is considered one treatment cycle. Successive doses of bortezomib should be separated by at least 72 hours.
Dexamethasone is administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib treatment cycle.
Patients who achieve a response or stable disease after 4 cycles of this combination therapy may continue the same regimen for up to 4 additional cycles.
For further information regarding dexamethasone, refer to the prescribing information for that medicinal product..
Dose Adjustment for Combination Therapy in Progressive Multiple Myeloma
Dose adjustments of bortezomib when used in combination therapy should follow the dose-modification recommendations described for monotherapy above.
Dosage for Previously Untreated Multiple Myeloma(Patients Not Eligible for Hematopoietic Stem Cell Transplantation)
Combination treatment with melphalan and prednisone
Bortezomib STADA 2.5 mg/mL solution for injection, after reconstitution, is administered by subcutaneous or intravenous injection, in combination with oral melphalan and prednisone as specified in Table 2. A 6-week period is considered one treatment cycle. In cycles 1 to 4, bortezomib is administered twice weekly 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.
Subsequent doses of bortezomib should be separated by at least 72 hours. Melphalan and prednisone should be administered orally on Days 1, 2, 3, and 4 of the first week of each bortezomib treatment cycle.
A total of 9 treatment cycles are indicated for this combination therapy.
Table 2. Recommended dosage of bortezomib in combination with melphalan and prednisone
Bortezomib Administered Twice Weekly (Cycles 1 to 4)
| Week | 1 | 2 | 3 | 4 | 5 | 6 | ||||||
Bo (1,3mg/m2) | Day 1 | - | - | Day 4 | Day 8 | Day 11 | Rest | Day 22 | Day 25 | Day 29 | Day 32 | Rest |
M (9 mg/m2) P (60 mg/m2) | Day 1 | Day 2 | Day 3 | Day 4 | - | - | Rest | - | - | - | - | |
Bortezomib Administered Once Weekly (Cycles 5 to 9)
| Week | 1 | 2 | 3 | 4 | 5 | 6 | |||
Bo (1,3mg/m2) | Day 1 | - | - | - | Day 8 | Rest | Day 22 | Day 29 | Rest |
M (9 mg/m2) P (60 mg/m2) | Day 1 | Day 2 | Day 3 | Day 4 | - | Rest | - | - | |
Bo = bortezomib; M = melphalan; P = prednisone
Dose Adjustment During Treatment & Re-Initiation for Combination Therapy with Melphalan Prednisone
Before starting a new treatment cycle:
- Platelet count should be ≥ 70 × 10⁹/L, and Absolute neutrophil count (ANC) should be ≥ 1.0 × 10⁹/L.
- Non-hematologic toxicities should have resolved to Grade 1 or baseline.
Table 3: Dose adjustment in subsequent cycles during treatment with bortezomib in combination with melphalan and prednisone
For further information regarding melphalan and prednisone, please refer to the prescribing information for those medicinal products.
Dosage for Previously Untreated Multiple Myeloma
(Patients Eligible for Hematopoietic Stem Cell Transplantation – First-Line Treatment)
Combination Therapy with Dexamethasone
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously after reconstitution at a recommended dose of 1.3 mg/m² body surface area, twice weekly for 2 weeks, on Days 1, 4, 8, and 11 of a 21-day treatfeement cycle.
A 3-week period is considered one treatment cycle. Successive doses of bortezomib should be separated by at least 72 hours. Dexamethasone is administered orally at a dose of 40 mg on Days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
A total of 4 treatment cycles is indicated for this combination regimen.
Combination Therapy with Dexamethasone and Thalidomide
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously after reconstitution at a recommended dose of 1.3 mg/m² body surface area, twice weekly for 2 weeks, on Days 1, 4, 8, and 11 of a 28-day treatment cycle.
A 4-week period is considered one treatment cycle. Successive doses of bortezomib should be separated by at least 72 hours. Dexamethasone is administered orally at a dose of 40 mg on Days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Thalidomide is administered orally at a dose of 50 mg on Days 1 to 14. If tolerated, the dose may be increased to 100 mg on Days 15 to 28, and may subsequently be increased to up to 200 mg daily from Cycle 2 onwards (see Table 4).
A total of 4 treatment cycles is indicated for this combination regimen. Patients who achieve at least a partial response should continue treatment for an additional 2 cycles (see Table 4).
Table 4. Dosage for Combination Treatment with Bortezomib in Patients with Previously Untreated Multiple Myeloma Eligible for Hematopoietic Stem Cell Transplantation
Bo = bortezomib; Dx = dexamethasone; T = thalidomide
a The thalidomide dose may be increased to 100 mg from Week 3 of Cycle 1 only if the 50 mg dose is tolerated, and further increased to 200 mg from Cycle 2 onwards if the 100 mg dose is tolerated.
b Treatment may be continued for up to 6 cycles in patients who achieve at least a partial response after 4 cycles.
Dose adjustment applies to patients eligible for hematopoietic stem cell transplantation.
Dose adjustment of bortezomib should follow the dose-modification guidelines described for monotherapy. In addition, when bortezomib is used in combination with other cytotoxic chemotherapy agents, appropriate dose reductions of those agents should be considered in the event of treatment-related toxicities, in accordance with the recommendations in their respective prescribing information.
Dosage for Previously Untreated Mantle Cell Lymphoma (MCL)
Combination Therapy with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (BoR-CAP)
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously after reconstitution at a recommended dose of 1.3 mg/m² body surface area, twice weekly for 2 weeks, on Days 1, 4, 8, and 11, followed by a 10-day rest period on Days 12 to 21.
A 3-week period is considered one treatment cycle.
Treatment is recommended for 6 cycles. If the patient achieves a first response at Cycle 6, 2 additional cycles of bortezomib should be administered.
Successive doses of bortezomib must be separated by at least 72 hours.
The following medicinal products are administered by intravenous infusion on Day 1 of each 3-week bortezomib treatment cycle: Rituximab: 375 mg/m². Cyclophosphamide: 750 mg/m² .Doxorubicin: 50 mg/m²
Prednisone is administered orally at a dose of 100 mg/m² on Days 1, 2, 3, 4, and 5 of each bortezomib treatment cycle.
Dose Adjustment During Treatment for Previously Untreated Mantle Cell Lymphoma
Before starting a new treatment cycle:
• Platelet count should be ≥ 100,000 cells/µL, and Absolute neutrophil count (ANC) should be ≥ 1,500 cells/µL
• Platelet count should be ≥ 75,000 cells/µL in patients with bone marrow infiltration or hypersplenism
• Haemoglobin should be ≥ 8 g/dL
• Non-hematologic toxicities should have resolved to Grade 1 or baseline
Treatment with bortezomib should be withheld at the onset of:Any bortezomib-related non- hematologic toxicity ≥ Grade 3, or Any hematologic toxicity ≥ Grade 3. For dose adjustment, refer to Table 5 below.
Granulocyte colony-stimulating factors (G-CSF) may be used to manage hematologic toxicity in accordance with standard institutional practice. Prophylactic use of G-CSF should be considered if bortezomib administration is repeatedly delayed during treatment cycles. Platelet transfusion should be considered for the management of thrombocytopenia when clinically indicated.
Table 5: Dose Adjustment During Treatment for Previously Untreated Mantle Cell Lymphoma
| Toxicity | Dose adjustment or delay |
| Hematologic toxicity | |
| – ≥ Grade 3 neutropenia with fever≥ Grade 4 neutropenia lasting ≥ 7 days, or platelet count < 10,000 cells/µL | Withhold bortezomib for up to 2 weeks until the patient has ANC ≥ 750 cells/µL and platelet count ≥ 25,000 cells/µL. - • If, after withholding bortezomib, the toxicity does not resolve, discontinue treatment. - • If toxicity resolves (ANC ≥ 750 cells/µL and platelet count ≥ 25,000 cells/µL), bortezomib may be reinitiated at a reduced dose of 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m². |
- Platelet count < 25,000 cells/µL or ANC < 750 cells/µL on the day of dosing (except for Day 1 of the cycle) | Withhold bortezomib. |
| Non-hematologic toxicity ≥ Grade 3 related to bortezomib | Withhold treatment with bortezomib until the toxicity has resolved to Grade 2 or better. Treatment may then be resumed at a reduced dose by one dose level (from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²). For bortezomib-related neuropathic pain and/or peripheral neuropathy, withhold treatment and/or adjust the bortezomib dose as described in Table 1. |
In addition, when bortezomib is used in combination with other cytotoxic chemotherapy agents, appropriate dose reductions of those agents should be considered in the event of treatment-related toxicities, in accordance with the recommendations in their respective prescribing information.
Special Populations
Elderly Patients
No evidence to suggest that dose adjustment is required in patients over 65 years of age with multiple myeloma or mantle cell lymphoma. No studies have been conducted 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. Therefore, no dose recommendation can be made for this population.
In a study of previously untreated mantle cell lymphoma, 42.9% and 10.4% of patients receiving bortezomib were aged 65–74 years and ≥ 75 years, respectively. In patients aged ≥ 75 years, both treatment regimens, BoR-CAP and R-CHOP, were less well tolerated. (BoR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)
Hepatic Impairment
Patients with mild hepatic impairment do not require dose adjustment and should be treated with the recommended dose Patients with moderate or severe hepatic impairment should start treatment with a reduced bortezomib dose of 0.7 mg/m² per injection during the first treatment cycle.
Subsequent dose escalation to 1.0 mg/m², or further dose reduction to 0.5 mg/m², may be considered based on the patient’s tolerability.
Table 6. Recommended Initial Dose Adjustment of Bortezomib in Patients with Hepatic Impairment
| Degree of hepatic impairment* | Total bilirubin | SGOT (AST) | Initial dose adjustment |
| Mild | ≤ 1,0 x ULN | > ULN | None |
> 1,0 x – 1,5 x U LN | Any | None | |
| Moderate | > 1,5 x – 3 x UL N | Any | Reduce the bortezomib dose to 0.7 mg/m² per cycle during the first treatment cycle. A subsequent dose increase to 1.0 mg/m² or further dose reduction to 0.5 mg/m² in subsequent cycles may be considered based on patient tolerability. |
| Servere | > 3 x ULN | Any |
Abbreviations
SGOT = serum glutamic oxaloacetic transaminase, AST = aspartate aminotransferase, ULN = upper limit of normal
* Based on the National Cancer Institute (NCI) organ dysfunction classification for hepatic impairment (mild, moderate, severe).
Renal impairment
The pharmacokinetics of bortezomib are not affected in patients with mild to moderate renal impairment ( [CrCL] > 20 mL/min/1.73 m²); therefore, dose adjustment is not required in these patients.
It is not known whether the pharmacokinetics of bortezomib are affected in patients with severe renal impairment not undergoing dialysis (CrCL < 20 mL/min/1.73 m²). As dialysis may reduce bortezomib concentrations, bortezomib should be administered after dialysis.
Pediatric population
The safety and efficacy of bortezomib in children under 18 years of age have not been established.
No dosage recommendation can be made for this population.
Method of administration
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously or intravenously (after reconstitution).
Bortezomib must not be administered by any other route. Intrathecal administration will result in death.
Intravenous injection
Bortezomib STADA 2.5 mg/mL solution for injection is first diluted to a concentration of 1 mg/mL.
The diluted solution is administered as a rapid intravenous injection over 3–5 seconds via a central or peripheral venous catheter, followed by flushing with sodium chloride 9 mg/mL (0.9%) solution for injection. Successive doses of bortezomib should be separated by at least 72 hours.
Subcutaneous injection
Bortezomib STADA 2.5 mg/mL solution for injection is administered subcutaneously into the thigh (left or right) or abdomen (left or right). The solution should be injected at an angle of 45–90°, and injection sites should be rotated for subsequent administrations.
If local injection-site reactions occur following subcutaneous administration, bortezomib may be administered subcutaneously at a lower concentration (1 mg/mL instead of 2.5 mg/mL), or a switch to intravenous administration may be considered.
When bortezomib is used in combination with other medicinal products, refer to the prescribing information of those products for their method of administration.
Special precautions for handling before and after administration
Handling before use
Pregnant staff should not handle this medicinal product.
General precautions:
Bortezomib is a cytotoxic agent; therefore, caution is required during handling and preparation.
The use of gloves and protective clothing is recommended to prevent skin contact.
Strict aseptic technique must be observed during handling of Bortezomib STADA, as the product does not contain preservatives.
Cases of fatal outcomes have been reported due to inadvertent intrathecal administration of bortezomib. Bortezomib STADA 2.5 mg/mL solution for injection is intended for subcutaneous or intravenous use only (after dilution) and must not be administered intrathecally.
Instructions for preparation and use
Bortezomib STADA must be prepared by healthcare professionals.
Intravenous administration
Each vial of Bortezomib STADA should be carefully reconstituted with 2.1 mL of sodium chloride 9 mg/mL (0.9%) solution for injection using an appropriately sized syringe, without removing the vial stopper.
After reconstitution, each mL of solution contains 1 mg of bortezomib. The reconstituted solution is clear and colorless to pale yellow, with a final pH of 4–7. The solution should be visually inspected for particulate matter and discoloration prior to administration. If any discoloration or particulate matter is observed, the solution must be discarded.
Subcutaneous administration
Each vial of Bortezomib STADA is ready for subcutaneous injection. Each mL of solution contains 2.5 mg of bortezomib. The solution is clear and colorless to pale yellow, with a pH of 4.0–5.5. The solution should be visually inspected for particulate matter and discoloration prior to administration. If any discoloration or particulate matter is observed, the solution must be discarded.
Handling after use
Bortezomib STADA is for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.
CONTRAINDICATIONS
Hypersensitivity to bortezomib, boron, or any of the excipients of the medicinal product.
Acute diffuse infiltrative lung disease and pericardial disease.
When bortezomib is used in combination with other medicinal products, refer to the prescribing information of those products for additional contraindications.
WARNINGS AND PRECAUTIONS
This medicinal product is for prescription use only.
Read the instructions for use carefully before use.
If further information is required, consult a physician or pharmacist.
Keep out of the reach of children.
