Bertred Injection

BERTRED 3,5 for injection is indicated for:

Multiple Myeloma

• as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone 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;
• in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high dose chemotherapy with haematopoietic 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 haematopoietic stem cell transplantation.

Mantle Cell Lymphoma

• treatment of relapsed or refractory mantle cell lymphoma for patients who have received at least 1 prior line of therapy, one of which should have included an anthracycline (or mitoxantrone) and/or rituximab as part of their chemotherapy regimen.
• treatment for newly diagnosed mantle cell lymphoma (MCL) in adults, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone who are unsuitable for haematopoietic stem cell transplantation.

Posology

BERTRED 3,5 lyophilised powder for solution for injection is available for:

• intravenous administration at a concentration of 1 mg /mL (as a 3 to 5 second bolus injection) or
• subcutaneous administration at a concentration of 2,5 mg/mL. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

BERTRED 3,5 IS FOR INTRAVENOUS AND SUBCUTANEOUS USE ONLY and should not be given by other routes. Intrathecal administration has resulted in death. See section 6.6 for Reconstitution instructions.

BERTRED 3,5 re-treatment may be considered for multiple myeloma patients who had previously responded to treatment with BERTRED 3,5 (see below).

Monotherapy

Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

Recommended dosage

• The recommended starting dose of BERTRED 3,5 is 1,3 mg/mu00b2 body surface area (BSA) administered twice weekly for two weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21).
• This 3-week period is considered a treatment cycle.
• It is recommended that patients receive 2 cycles of BERTRED 3,5 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 therapy.
• At least 72 hours should elapse between consecutive doses of BERTRED 3,5.

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Hypersensitivity to bortezomib, boron or to any of the excipients of BERTRED 3,5.

Acute diffuse infiltrative pulmonary disease or pericardial disease.

Herpes zoster virus reactivation: Medical practitioners should consider the need for antiviral prophylaxis in patients being treated with BERTED 3,5. In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was very common in patients treated with bortezomib, Melphalan and Prednisone.

Hepatitis B Virus (HBV) reactivation and infection: When rituximab is used in combination with BERTRED 3,5, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with BERTRED 3,5. Antiviral prophylaxis should be considered. Refer to the Professional Information of rituximab for more information.

Progressive multifocal leukoencephalopathy (PML): Cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue BERTRED 3,5 if PML is diagnosed.

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Bortezomib as in BERTRED 3,5 is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4 in vitro. Based on the limited contribution (7 %) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of BERTRED 3,5.

Co-administration of bortezomib and ketoconazole, a potent CYP3A4 inhibitor, increased the mean AUC of bortezomib by 35 %. Patients receiving potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, chloramphenicol, clarithromycin) together with BERTRED 3,5, should be monitored closely.

Concomitant use of bortezomib with rifampicin, a potent CYP3A4 inducer, showed a mean bortezomib AUC reduction of 45 %. Therefore, the concomitant use of BERTRED 3,5 with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbitone and St. John's Wort (Hypericum perforatum)) is not recommended, as efficacy may be reduced.

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Women of childbearing potential / Contraception in males and females

Female patients and female sexual partners of male patients receiving genotoxic anticancer medicines, should be advised to use highly effective contraception, until the end of relevant systemic exposure to the genotoxic compound including potential genotoxic metabolites for 40 days (i.e., five half-lives (5*8 days) after the last dose) plus 6 months (which covers the growth and maturation phase of folliculogenesis). Male patients should be advised to use highly effective contraception, until the end of relevant systemic exposure to the genotoxic compound including potential genotoxic metabolites for 40 days (i.e., five half-lives (5*8 days) after the last dose) plus 90 days (i.e., 60 to 75 days for sperm production plus 10 to 14 days for the transport to epididymis).

Pregnancy

Safety in pregnancy has not been established. If BERTRED 3,5 is used during pregnancy, alone or in combination with other medicines, or if the patient becomes pregnant while receiving BERTRED 3,5, the patient needs to be informed of the potential hazards to the foetus.

Breastfeeding

Safety in lactation has not been established. It is not known whether BERTRED 3,5 is excreted in human milk. Because of the potential for serious undesirable effects in breast-fed infants from BERTRED 3,5, women are advised against breastfeeding while receiving BERTRED 3,5.

BERTRED 3,5 may have a moderate influence on the ability to drive and use machines. BERTRED 3,5 may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension or blurred vision. Therefore, patients must be cautious when driving, or using machines and should be advised not to drive or operate machinery if they experience these symptoms (see section 4.8).

Summary of the safety profile

Serious adverse reactions less frequently reported during treatment with bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy. The most frequently reported adverse reactions during treatment with bortezomib are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

Adverse reactions reported with bortezomib are listed below by system organ class and frequency grouping.

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Overdosage was associated with acute onset of symptomatic hypotension and thrombocytopenia and the patient subsequently died. It is recommended that in the event of overdosage, patients should undergo careful haemodynamic monitoring, and hypotension should be treated aggressively with intravenous hydration and other clinically appropriate measures.