Spalbend 25 & 100 25 mg, 100 mg Tablet

SPALBEND is indicated in patients with the following conditions:

• First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
• First-line treatment of indolent CD 20 positive non-Hodgkinu2019s lymphoma in combination with rituximab.
• Indolent non-Hodgkinu2019s lymphomas as monotherapy in patients, who have progressed during or within 6 months following treatment with rituximab or a rituximab containing regimen.
• Front line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis precluding the use of thalidomide or bortezomib containing treatment.

Posology

Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity. Treatment should not be started if leukocyte and/or platelet values dropped to < 3 x 109/L or < 75 x 109/L, respectively (see section 4.3).

Monotherapy for chronic lymphocytic leukaemia

100 mg/m2 body surface area SPALBEND on days 1 and 2; every 4 weeks.

Combination treatment for first-line indolent non-Hodgkinu2019s lymphoma

90 mg/m2 body surface area SPALBEND on days 1 and 2 in combination with 375 mg/m2 body surface area rituximab as a slow i.v. infusion on day 1; every 4 weeks.

Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab

120 mg/m2 body surface area SPALBEND on days 1 and 2; every 3 weeks.

Multiple myeloma

120 - 150 mg/m2 body surface area SPALBEND on days 1 and 2, 60 mg/m2 body surface area prednisone IV or per orally on days 1 to 4; every 4 weeks.

Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to u2264 3 x 109/L or u2264 75 x 109/L, respectively. Treatment can be continued after leukocyte values have increased to > 4 x 109/L and platelet values to > 100 x 109/L. The leukocyte and platelet Nadir is reached, after 14 - 20 days with regeneration after 3 - 5 weeks. During therapy free intervals strict monitoring of the blood count is recommended (see section 4.4).

In case of non-haematological toxicity dose reductions have to be based on the worst CTC grades in the preceding cycle. A 50 % dose reduction is recommended in case of CTC grade 3 toxicity. An interruption of treatment is recommended in case of CTC grade 4 toxicity. If a patient requires a dose modification the individually calculated reduced dose must be given on day 1 and 2 of the respective treatment cycle. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hepatic impairment

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment (serum bilirubin 3.0 mg/dl) (see section 4.3).

Renal impairment

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with a creatinine clearance of > 10 ml/min. Experience in patients with severe renal impairment is limited.

Paediatric population:

The safety and efficacy of bendamustine hydrochloride in children have not yet been established. Current available data is not sufficient to make a recommendation on posology.

Elderly patients

There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).

Method of administration

For intravenous infusion over 30-60 min (see section 6.6). Infusion must be administered under the supervision of a healthcare professional qualified and experienced in the use of chemotherapeutic medicines.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Pregnancy and lactation
• Severe hepatic impairment [serum bilirubin > 34,2 u03bcmol/ L (2,0 mg/dL)]
• Jaundice
• Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3 x 109/L or < 75 x 109/L, respectively)
• Major surgery less than 30 days before start of treatment
• Infections, especially involving leukocytopenia
• Yellow fever vaccination or any other live (attenuated) vaccination
• Congenital QT prolongation
• Concomitant medicines causing QT prolongation

Myelosuppression

Patients treated with SPALBEND experience myelosuppression. Treatment-related myelosuppression, leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least weekly. Prior to the initiation of the next cycle of therapy, the following parameters are recommended: Leukocyte and/or platelet values > 4 x 109/L or > 100 x 109/L, respectively.

Infections

The CD4/CD8 ratio may be reduced. A reduction of the lymphocyte count was seen. In immunosuppressed patients, the risk of infection (e.g., with herpes zoster) may be increased. Cases of tuberculosis have been less frequently reported compared to other infections. Latent or dormant tuberculosis may become active. Infection, including pneumonia and sepsis, has been reported. Infection has been associated with hospitalisation, septic shock and death. Patients with neutropenia and/or lymphopenia following treatment with SPALBEND are more susceptible to infections including tuberculosis. Patients with myelosuppression following SPALBEND treatment should be advised to contact a medical practitioner if they have symptoms or signs of infection, including fever or respiratory symptoms. The presence of tuberculosis should be excluded before treatment with SPALBEND is commenced.

Skin reactions

A number of skin reactions have been reported. These events have included rash, toxic skin reactions and bullous exanthema. Some of these events occurred when SPALBEND was given in combination with other anticancer medicines. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, SPALBEND should be withheld or discontinued. For severe skin reactions where a relationship to SPALBEND is suspected, treatment should be discontinued.

Patients with cardiac disorders

During treatment with SPALBEND the concentration of potassium in the blood must be closely monitored. When serum potassium levels are < 3,5 mEq/L (3,5 mmol/L), an ECG recording must be performed, and potassium supplement must be given.

QTcf was prolonged by more than 30 msecs in 4 of 9 patients studied.

Nausea, vomiting

An antiemetic should be given for the symptomatic treatment of nausea and vomiting.

Tumour lysis syndrome

Tumour lysis syndrome associated with bendamustine, as contained in SPALBEND, treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of SPALBEND and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate fluid volume status and close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of allopurinol during the first one to two weeks of SPALBEND therapy can be considered. However, there have been cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported when SPALBEND and allopurinol are administered concomitantly.

Anaphylaxis

Infusion reactions to bendamustine, as contained in SPALBEND, have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. Severe anaphylactic and anaphylactoid reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion reactions. In patients who experienced Grade 3 or worse allergic-type reactions, SPALBEND should be discontinued.

Contraception

SPALBEND is teratogenic and mutagenic. Women should not become pregnant during treatment. Male patients should not father a child during and up to 6 months after treatment. They should seek advice about sperm conservation prior to treatment with SPALBEND because of possible irreversible infertility.

Extravasation

An extravasal injection should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit. There have been reports of necrosis after accidental extra-vascular administration and toxic epidermal necrosis, tumour lysis syndrome, and anaphylaxis.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received bendamustine hydrochloride. Some cases resulted in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with bendamustine hydrochloride. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B tests (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with bendamustine hydrochloride should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

Secondary tumours

There are reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma.

Non-melanoma skin cancer

In clinical studies, an increased risk for non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) has been observed in patients treated with bendamustine containing therapies. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

No in-vivo interaction studies have been performed.

When SPALBEND is combined with myelosuppressive medicines, the effect of SPALBEND and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing the patientu2019s performance status or impairing bone marrow function can increase the toxicity of SPALBEND.

Combination of SPALBEND with ciclosporin or tacrolimus may result in excessive immunosuppression with risk of lymph proliferation.

Cytostatics can reduce antibody formation following live-virus vaccination and increase the risk of infection which may lead to fatal outcome. This risk is increased in patients who are already immunosuppressed by their underlying disease.

Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see section 5.2). Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine exist.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are no adequate data from the use of SPALBEND in pregnant women. In nonclinical studies SPALBEND was embryo-/foetolethal, teratogenic and genotoxic. Therefore, SPALBEND is contraindicated during pregnancy (see section 4.3).

Women of childbearing potential/contraception

Women of childbearing potential must use effective methods of contraception both before and during SPALBEND therapy. Men being treated with SPALBEND are advised not to father a child during and for up to 6 months following cessation of treatment. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with SPALBEND.

Breastfeeding

It is not known whether SPALBEND passes into the breast milk. Treatment with SPALBEND is therefore contraindicated during breastfeeding (see section 4.3). Mothers on SPALBEND must not breastfeed their babies.

SPALBEND has major influence on the ability to drive and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with bendamustine hydrochloride as contained in SPALBEND (see section 4.8). Patients should be instructed that if they experience these symptoms, they should avoid potentially hazardous tasks such as driving and using machines.

Summary of the safety profile

The most frequent side effects with SPALBEND are haematological adverse reactions (leucopenia, thrombocytopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).

Adverse reactions in patients treated with bendamustine hydrochloride.

MedDRA system organ class

NOS = Not otherwise specified

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

After application of a 30 min infusion of bendamustine once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/mu00b2. Cardiac events of CTC grade 2 which were compatible with ischaemic ECG changes occurred which were regarded as dose limiting. In a subsequent study with a 30 min infusion of bendamustine at day 1 and 2 every 3 weeks the MTD was found to be 180 mg/m2. The dose limiting toxicity was grade 4, thrombocytopenia. Cardiac toxicity was not dose limiting with this schedule.

Counter measures

There is no specific antidote. Bone marrow transplantation and transfusions (platelets, concentrated erythrocytes) may be made, or haematological growth factors may be given as effective countermeasures to control haematological side effects. Bendamustine and its metabolites are dialysable to a small extent.