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BORTEBIN (Bortezomib 3.5 mg powder for solution for injection)

BORTEBIN (Bortezomib 3.5 mg powder for solution for injection)

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX32.

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signaling cascades within the cell, ultimately resulting in cancer cell death.

Bortezomib is highly selective for the proteasome. At 10 μM concentrations, Bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and Bortezomib was shown to dissociate from the proteasome with a t½ of 20 minutes, thus demonstrating that proteasome inhibition by Bortezomib is reversible.

Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, Bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.

Experiments have demonstrated that Bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumor growth in vivo in many preclinical tumor models, including multiple myeloma.

Data from in vitro, ex-vivo, and animal models with Bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with Bortezomib.

BORTEBIN Therapeutic indications

BORTEBIN as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone 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 haematopoietic stem cell transplantation.

BORTEBIN 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 haematopoietic stem cell transplantation.

BORTEBIN in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

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BORTEBIN in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.

BORTEBIN Posology and method of administration

BORTEBIN treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients, however BORTEBIN may be administered by a healthcare professional experienced in use of chemotherapeutic agents. BORTEBIN must be reconstituted by a healthcare professional.

Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy)

Monotherapy:

Bortezomib 3.5 mg powder for solution for injection is administered via intravenous orsubcutaneous injection at the recommended dose of 1.3 mg/m2 body surface area twice weeklyfor 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 below (see also section

4.4). 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 1. Patients with pre-existing severe neuropathy may be treated with Bortezomib 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 functionNONE
Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**)Reduce Bortezomib to 1.0 mg/m2 or Change Bortezomib treatment schedule to 1.3 mg/m2  once per week
Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL***)Withhold Bortezomib treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate Bortezomib treatment and reduce dose to 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathyDiscontinue Bortezomib

* 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.

Combination therapy with pegylated liposomal doxorubicin

Bortezomib 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 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.

For additional information concerning pegylated liposomal doxorubicin, see the corresponding Summary of Product Characteristics.

Combination with dexamethasone

Bortezomib 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 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.

For additional information concerning dexamethasone, see the corresponding Summary of Product Characteristics.

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 above.

Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation

Combination therapy with melphalan and prednisone

Bortezomib 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone. 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.

Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy)

Combination therapy with dexamethasone

Bortezomib 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 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 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 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.

Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles.

For Bortezomib dosage adjustments, 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.

Posology for patients with previously untreated mantle cell lymphoma (MCL)

Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)

Bortezomib 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, 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.

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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
  • Haemoglobin ≥ 8 g/dL
  • Non-haematological toxicities should have resolved to Grade 1 or baseline.

Bortezomib treatment must be withheld at the onset of any ≥ Grade 3 Bortezomib -related nonhaematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities. For dose adjustments.

Granulocyte colony stimulating factors may be administered for haematologic 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.

BORTEBIN Method of administration

Bortezomib 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.

Bortezomib 1 mg powder for solution for injection is available for intravenous administration only.

Bortezomib should not be given by other routes. Intrathecal administration has resulted in death.

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 sodiumchloride 9 mg/ml (0.9%) solution for injection. At least 72 hours should elapse betweenconsecutive 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 45-90° 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.

When Bortezomib is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.

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