Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord Healthcare Limited, Sage House, 319 Pinner Road, North Harrow, Middlesex HA1 4HF, United Kingdom
First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
Indolent non-Hodgkin’s 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.
100 mg/m² body surface area bendamustine hydrochloride on days 1 and 2; every 4 weeks up to 6 times.
120 mg/m² body surface area bendamustine hydrochloride on days 1 and 2; every 3 weeks for at least 6 times.
120-150 mg/m² body surface area bendamustine hydrochloride on days 1 and 2, 60 mg/m² body surface area prednisone i.v. or per os on days 1 to 4; every 4 weeks for at least 3 times.
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment (serum bilirubin <1.2 mg/dl). A 30% dose reduction is recommended in patients with moderate hepatic impairment (serum bilirubin 1.2-3.0 mg/dl).
No data is available in patients with severe hepatic impairment (serum bilirubin values of >3.0 mg/dl) (see section 4.3).
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.
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.
There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).
For intravenous infusion over 30-60 min (see section 6.6).
Infusion must be administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.
Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity. Treatment should not be started if leukocyte and/or platelet values have dropped to <3,000/µl or <75,000/µl, respectively (see section 4.3).
Treatment should be terminated or delayed if leukocyte and/or platelet values have dropped to <3,000/µl or <75,000/µl, respectively. Treatment can be continued after leukocyte values have increased to >4,000/µl and platelet values to >100,000/µl.
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."
After application of a 30 min infusion of Bendamustine once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/m². 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.
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 hydrochloride and its metabolites are dialyzable to a small extent.
Shelf life: 3 years.
The powder should be reconstituted immediately after opening of the vial.
The reconstituted concentrate should be diluted immediately with 0.9% sodium chloride solution.
After reconstitution and dilution, chemical and physical stability has been demonstrated for 3.5 hours at 25°C and 2 days at 2°C to 8°C in polyethylene bags.
From a microbiological point of view, the solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
This medicinal product does not require any special temperature storage conditions. Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted or diluted medicinal product, see section 6.3.
Type I amber glass vials of 10 ml or 50 ml with bromobutyl rubber stopper and an aluminium flip-off cap.
10 ml-vials contain 25 mg bendamustine hydrochloride and are supplied in packs of 5, 10 and 20 vials.
50 ml-vials contain 100 mg bendamustine hydrochloride and are supplied in pack of 1 and 5 vials.
Not all pack sizes may be marketed.
When handling Bendamustine, inhalation, skin contact or contact with mucous membranes should be avoided (wear gloves and protective clothes!). Contaminated body parts should be carefully rinsed with water and soap, the eye should be rinsed with physiological saline solution. If possible it is recommended to work on special safety workbenches (laminar flow) with liquid impermeable, absorbent disposable foil. Pregnant personnel should be excluded from handling cytostatics.
The powder for concentrate for solution for infusion has to be reconstituted with water for injection, diluted with sodium chloride 9 mg/ml (0.9%) solution for injection and then administered by intravenous infusion. Aseptic technique is to be used.
1. Reconstitution:
Reconstitute each vial of Bendamustine hydrochloride 2.5 mg/mL powder for concentrate for solution for infusion containing 25 mg bendamustine hydrochloride in 10 ml water for injection by shaking;
Reconstitute each vial of Bendamustine hydrochloride 2.5 mg/mL powder for concentrate for solution for infusion containing 100 mg bendamustine hydrochloride in 40 ml water for injection by shaking.
The reconstituted concentrate contains 2.5 mg bendamustine hydrochloride per ml and appears as a clear colourless solution.
2. Dilution:
As soon as a clear solution is obtained (usually after 5-10 minutes) dilute the total recommended dose of Bendamustine hydrochloride 2.5 mg/mL powder for concentrate for solution for infusion immediately with 0.9% NaCl solution to produce a final volume of about 500 ml.
Bendamustine hydrochloride 2.5 mg/mL powder for concentrate for solution for infusion must be diluted with 0.9% NaCl solution and not with any other injectable solution.
3. Administration:
The solution is administered by intravenous infusion over 30-60 min.
The vials are for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
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