部分中文盐酸苯达莫司汀（Levact）处方资料（仅供参考）
盐酸苯达莫司汀（Bendamustine　Hydrochloride）是一种双功能基烷化剂，具有抗肿瘤和杀细胞作用。本品的抗肿瘤和杀细胞作用主要归功于DNA单链和双联通过烷化作用交联，这打乱了DNA的功能和DNA的合成，也会使DNA和蛋白之间，以及蛋白和蛋白之间产生交联，从而发挥抗肿瘤作用。本品作为单用或联合化疗，对何杰金氏淋巴瘤和非何杰金氏淋巴瘤的治疗反应率分别为61％～97％和41％～48％。
主要应用于单独或与其它抗肿瘤药物联合用药来治疗下列恶性肿瘤：何杰金病；非何杰金淋巴瘤；浆细胞瘤（多发性骨髓瘤）；慢性淋巴细胞白血病（CLL）；乳腺癌。
本品用于何杰金病、非何杰金淋巴瘤、多发性骨髓瘤、CLL和乳腺癌。其剂量血癌为50～60mg／m²／d，3～5天或每3～4周为100～120mg／m²；实体瘤每4周为120～150mg／m²，每日1次，30～60min静脉滴注。盐酸苯达莫司汀作为单用或联合化疗，对何杰金病和非何杰金淋巴瘤的治疗反应率分别为61％～97％和41％～48　％。对多发性骨髓瘤病人，苯达莫司汀／泼尼松治疗的完全反应率较高（32％），美法仑／泼尼松疗法反应更持久。在环磷酰胺、长春新碱、泼尼松治疗方案中，苯达莫司汀取代环磷酰胺，对发展中低度毒性非何杰金淋巴瘤有相似的反应率。在环磷酰胺、甲氨蝶呤、氟尿嘧啶治疗方案中，苯达莫司汀取代环磷酰胺，使转移性乳腺癌病人的缓解期从6.2个月延长至15.2个月。
盐酸苯达莫司汀作为新一代抗癌药物，对多种癌症具有明显的治疗作用。临床应用表明，本品单独治疗或联合用药治疗非何杰金淋巴瘤、多发性骨髓瘤、CLL和乳腺癌等，疗效确切，明显降低复发率与死亡率，而且不良反应小，安全性好。
适应症：
1.慢性淋巴细胞白血病（CLL）。不同于苯丁酸氮芥的一线疗法的疗效尚未确立。
2.在利妥昔单抗（rituximab，美罗华）或含利妥昔单抗方案治疗过程中，或者治疗6个月内，病情仍然进展的惰性B细胞非霍奇金淋巴瘤（NHL）患者。用法用量：
作用机理
本品是一种双功能基烷化剂，可以导致DNA单链和双链通过烷化作用交联，打乱DNA 的功能和DNA的合成，使DNA和蛋白之间，以及蛋白和蛋白之间产生交联，从而发挥抗肿瘤作用。
剂量及用药
该药储存温度不应超过30℃，避光保存，使用前临时配制。
配制流程：该药每100mg须先溶于20ml无菌注射用水，充分振摇直到完全溶解成澄清、无色或淡黄色溶液，溶解时间一般不超过5分钟，溶解后浓度为5mg/ml。在溶解后30分钟之内，根据需要抽取适量苯达莫司汀水溶液，转移至500ml氯化钠注射液（0.9%）或葡萄糖氯化钠注射液（2.5%/0.45%）中，并确保苯达莫司汀在注射液中的最终浓度在0.2～0.6mg/ml之间。配制好的注射液可在2～8℃冷藏保存24小时，或在室温及自然光下保存3小时。
苯达莫司汀治疗CLL时，以28天为一个治疗周期，一般需要6个治疗周期。在每个治疗周期的第一天和第二天给药，推荐剂量为100mg/m2。该药经静脉滴注给药，每次给药时间不应少于30分钟。
苯达莫司汀治疗NHL时，以21天为一个治疗周期，一般需要8个治疗周期。在每个治疗周期的第一天和第二天给药，推荐剂量为120mg/m2。每次给药时间不应少于60分钟。
特点
①疗效确切，能明显降低复发率与死亡率，且不良反应小，安全性好，起效迅速，作用持久；
②本品在31至84岁人群中的药代动力学指标（AUC和Cmax）显示：65周岁以上或以下患者之间没有明显区别；
③在儿童患者上的有效性虽尚未建立。但通过白血病儿童患者的I、II期临床试验评估，其安全性与成人体内基本相似；
④随着深入临床研究，未来可能扩大到儿童用药；
⑤R-CHOP方案（环磷酰胺、多柔比星、长春新碱、泼尼松加利妥昔单抗）是目前晚期惰性淋巴瘤和套细胞淋巴瘤老年患者的一线标准治疗。苯达莫司汀单药治疗利妥昔单抗耐药的B细胞惰性淋巴瘤可提高疗效,且耐受性良好。研究发现苯达莫司汀联合利妥昔单抗较之传统R-CHOP更有效且毒性更小，耐受性更好。《柳叶刀》杂志的一项研究，苯达莫司汀联合利妥昔单抗治疗方案可以替代标准治疗，用于新诊断的惰性非霍奇金淋巴瘤(NHL)和套细胞淋巴瘤(MCL)患者。
包装规格：[注：本来德国上市包装]
25mg *5支/盒
25mg*10支/盒
25mg*20支
100mg/60mlx5支/盒
生产厂家：Mundipharma GmbH
Levact®(Bendamustine)
Levact 25mg and 100mg powder for concentrate for solution for infusion is indicated for: 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.
Levact®2.5mg/ml powder for concentrate for solution for infusion
1. Name of the medicinal product
Levact 2.5 mg/ml powder for concentrate for solution for infusion
2. Qualitative and quantitative composition
One vial contains 25 mg bendamustine hydrochloride.
One vial contains 100 mg bendamustine hydrochloride.
1 ml of the concentrate contains 2.5 mg bendamustine hydrochloride when reconstituted according to section 6.6.
For a full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder for concentrate for solution for infusion
White, microcrystalline powder
4. Clinical particulars
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
For intravenous infusion over 30 - 60 minutes (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).
Monotherapy for chronic lymphocytic leukaemia
100 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 4 weeks.
Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab
120 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 3 weeks.
Multiple myeloma
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.
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 preparation and administration instructions 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 < 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).
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 patients
There is no experience in children and adolescents with Levact.
Elderly patients
There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
During breast feeding
Severe hepatic impairment (serum bilirubin > 3.0 mg/dl)
Jaundice
Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3,000/µl or < 75,000/µl, respectively)
Major surgery less than 30 days before start of treatment
Infections, especially involving leukocytopenia
Yellow fever vaccination
4.4 Special warnings and precautions for use
Myelosuppression
Patients treated with bendamustine hydrochloride may experience myelosuppression. In the event of 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 > 4,000/µl or > 100,000/µl, respectively.
Infections
Infection, including pneumonia and sepsis, has been reported. In rare cases, infection has been associated with hospitalization, septic shock and death. Patients with neutropenia and/or lymphopenia following treatment with bendamustine hydrochloride are more susceptible to infections. Patients with myelosuppression following bendamustine hydrochloride treatment should be advised to contact a physician if they have symptoms or signs of infection, including fever or respiratory symptoms.
Skin reactions
A number of skin reactions have been reported. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when bendamustine hydrochloride was given in combination with other anticancer agents, so the precise relationship is uncertain. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, Levact should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine hydrochloride is suspected, treatment should be discontinued.
Patients with cardiac disorders
During treatment with bendamustine hydrochloride the concentration of potassium in the blood must be closely monitored and potassium supplement must be given when K+ <3.5 mEq/l, and ECG measurement must be performed.
Nausea, vomiting
An antiemetic may be given for the symptomatic treatment of nausea and vomiting.
Tumour lysis syndrome
Tumour lysis syndrome associated with Levact treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of Levact and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate 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 Levact therapy can be considered but not necessarily as standard. However, there have been a few cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported when bendamustine and allopurinol were administered concomitantly.
Anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances 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.
Patients who experienced Grade 3 or worse allergic-type reactions were typically not re-challenged.
Contraception
Bendamustine hydrochloride 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 bendamustine hydrochloride 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.
4.5 Interaction with other medicinal products and other forms of interaction
No in-vivo interaction studies have been performed.
When Levact is combined with myelosuppressive agents, the effect of Levact and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing the patient's performance status or impairing bone marrow function can increase the toxicity of Levact.
Combination of Levact with cyclosporine or tacrolimus may result in excessive immunosuppression with risk of lymphoproliferation.
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 subjects who are already immunosuppressed by their underlying disease.
Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see section 5.2). Therefore, the potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine exists.
4.6 Pregnancy and lactation
Pregnancy
There are insufficient data from the use of Levact in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic (see section 5.3). During pregnancy Levact should not be used unless clearly necessary. The mother should be informed about the risk to the foetus. If treatment with Levact is absolutely necessary during pregnancy or if pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered.
Women of childbearing potential/contraception
Women of childbearing potential must use effective methods of contraception both before and during Levact therapy.
Men being treated with Levact 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 Levact.
Breast feeding
It is not known whether bendamustine passes into the breast milk, therefore, Levact is contraindicated during breast feeding (see section 4.3). Breast feeding must be discontinued during treatment with Levact.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, ataxia, peripheral neuropathy and somnolence have been reported during treatment with Levact (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.
4.8 Undesirable effects
The most common adverse reactions with bendamustine hydrochloride are hematological adverse reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).
The table below reflects the data obtained with bendamustine hydrochloride in clinical trials.
Tabl1: Adverse reactions in patients treated with bendamustine hydrochloride.
NOS = Not otherwise specified
A small number of cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported in patients using bendamustine in combination with allopurinol or in combination with allopurinol and rituximab.
The CD4/CD8 ratio may be reduced. A reduction of the lymphocyte count was seen. In immuno-suppressed patients, the risk of infection (e.g. with herpes zoster) may be increased.
There have been isolated reports of necrosis after accidental extra-vascular administration and toxic epidermal necrolysis, tumour lysis syndrome and anaphylaxis.
There are reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma. The association with Levact therapy has not been determined.
4.9 Overdose
After application of a 30 min infusion of Levact 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 Levact 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 hydrochloride and its metabolites are dialyzable to a small extent.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents,
ATC code: L01AA09
Bendamustine hydrochloride is an alkylating antitumour agent with unique activity. The antineoplastic and cytocidal effect of bendamustine hydrochloride is based essentially on a cross-linking of DNA single and double strands by alkylation. As a result, DNA matrix functions and DNA synthesis and repair are impaired. The antitumour effect of bendamustine hydrochloride has been demonstrated by several in vitro studies in different human tumour cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian carcinoma and different leukaemia) and in vivo in different experimental tumour models with tumours of mouse, rat and human origin (melanoma, breast cancer, sarcoma, lymphoma, leukaemia and small cell lung cancer).
Bendamustine hydrochloride showed an activity profile in human tumour cell lines different to that of other alkylating agents. The active substance revealed no or very low cross-resistance in human tumour cell lines with different resistance mechanisms at least in part due to a comparatively persistent DNA interaction. Additionally, it was shown in clinical studies that there is no complete cross-resistance of bendamustine with anthracyclines, alkylating agents or rituximab. However, the number of assessed patients is small.
Chronic lymphocytic leukaemia
The indication for use in chronic lymphocytic leukaemia is supported by a single open label study comparing bendamustine with chlorambucil. In the prospective, multi-centre, randomised study, 319 previously untreated patients with chronic lymphocytic leukaemia stage Binet B or C requiring therapy were included. The first line therapy with bendamustine hydrochloride 100 mg/m2 i.v. on days 1 and 2 (BEN) was compared to treatment with chlorambucil 0.8 mg/kg days 1 and 15 (CLB) for 6 cycles in both arms. Patients received allopurinol in order to prevent tumour lysis syndrome.
Patients with BEN had a significantly longer median progression free survival than patients with CLB treatment (21.5 versus 8.3 months, p < 0.0001 in the latest follow-up). Overall survival was not statistically significantly different (median not reached). The median duration of remission was 19 months with BEN and 6 months with CLB treatment (p < 0.0001). The safety eva luation in both treatment arms did not reveal any unexpected undesirable effects in nature and frequency. The dose of BEN was reduced in 34% of the patients. Treatment with BEN was discontinued in 3.9% of patients due to allergic reactions.
Indolent non-Hodgkin's lymphomas
The indication for indolent non-Hodgkin's lymphomas relied on two uncontrolled phase II trials.
In the pivotal prospective, multi-centre, open study 100 patients with indolent B-cell non-Hodgkin´s lymphomas refractory to rituximab mono- or combination therapy were treated with BEN single agent. Patients had received a median of 3 previous chemotherapy or biological therapy courses. The median number of previous rituximab-containing courses was 2. The patients had had no response or there had been progression within 6 months after rituximab treatment. The dose of BEN was 120 mg/m2 i.v. on days 1 and 2 planned for at least 6 cycles. Duration of treatment depended on response (6 cycles planned). The overall response rate was 75% including 17% complete (CR and CRu) and 58% partial response as assessed by independent review committee. The median duration of remission was 40 weeks. BEN was generally well tolerated when given in this dose and schedule.
The indication is further supported by another prospective, multi-centre, open study including 77 patients. The patient population was more heterogeneous including: indolent or transformed B-cell non-Hodgkin's lymphomas refractory to rituximab mono- or combination therapy. The patients had no response or there had been progression within 6 months or had had an untoward reaction to prior rituximab treatment. Patients had received a median of 3 previous chemotherapy or biological therapy courses. The median number of previous rituximab-containing courses had been 2. The overall response rate was 76% with a median duration of response of 5 months (29 [95% CI 22.1, 43.1] weeks).
Multiple myeloma
In a prospective, multi-centre, randomised, open study 131 patients with advanced multiple myeloma (Durie-Salmon stage II with progression or stage III) were included. The first line therapy with bendamustine hydrochloride in combination with prednisone (BP) was compared to treatment with melphalan and prednisone (MP). Neither transplant-eligibility nor the presence of specific co-morbidities played a role for inclusion into the trial. The dose was bendamustine hydrochloride 150 mg/m2 i.v. on days 1 and 2 or melphalan 15 mg/m2 i.v. on day 1 each in combination with prednisone. Duration of treatment depended on response and averaged 6.8 cycles in the BP and 8.7 cycles in the MP group.
Patients with BP treatment had a longer median progression free survival than patients with MP (15 [95% CI 12-21] versus 12 [95% CI 10-14] months) (p=0.0566). The median time to treatment failure was 14 months with BP and 9 months with MP treatment. The duration of remission was 18 months with BP and 12 months with MP treatment. The difference in overall survival was not significantly different (35 months BP versus 33 months MP). Tolerability in both treatment arms was in line with the known safety profile of the respective medicinal products with significantly more dose reductions in the BP arm.
5.2 Pharmacokinetic properties
Distribution
The elimination half-life t1/2ß after 30 min i.v. infusion of 120 mg/m2 area to 12 subjects was 28.2 minutes.
Following 30 min i.v. infusion the central volume of distribution was 19.3 l. Under steady-state conditions following i.v. bolus injection the volume of distribution was 15.8-20.5 l.
More than 95% of the substance is bound to plasma proteins (primarily albumin).
Metabolism
A major route of clearance of bendamustine is the hydrolysis to monohydroxy- and dihydroxy-bendamustine. Formation of N-desmethyl-bendamustine and gamma-hydroxy-bendamustine by hepatic metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Another major route of bendamustine metabolism involves conjugation with glutathione.
In-vitro bendamustine does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 or CYP 3A4.
Elimination
The mean total clearance after 30 min i.v. infusion of 120 mg/m2 body surface area to 12 subjects was 639.4 ml/minute. About 20% of the administered dose was recovered in urine within 24 hours. Amounts excreted in urine were in the order monohydroxy-bendamustine > bendamustine > dihydroxy-bendamustine > oxidised metabolite > N-desmethyl bendamustine. In the bile, primarily polar metabolites are eliminated.
Hepatic impairment
In patients with 30 - 70% tumour infestation of the liver and mild hepatic impairment (serum bilirubin < 1.2 mg/dl) the pharmacokinetic behaviour was not changed. There was no significant difference to patients with normal liver and kidney function with respect to Cmax, tmax, AUC, t1/2ß , volume of distribution and clearance. AUC and total body clearance of bendamustine correlate inversely with serum bilirubin.
Renal impairment
In patients with creatinine clearance > 10 ml/min including dialysis dependent patients, no significant difference to patients with normal liver and kidney function was observed with respect to Cmax, tmax, AUC, t1/2ß, volume of distribution and clearance.
Elderly subjects
Subjects up to 84 years of age were included in pharmacokinetic studies. Higher age does not influence the pharmacokinetics of bendamustine.
5.3 Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Histological investigations in dogs showed macroscopic visible hyperaemia of the mucosa and haemorrhagia in the gastrointestinal tract. Microscopic investigations showed extensive changes of the lymphatic tissue indicating an immunosuppression and tubular changes of kidneys and testis, as well as atrophic, necrotic changes of the prostate epithelium.
Animal studies showed that bendamustine is embryotoxic and teratogenic.
Bendamustine induces aberrations of the chromosomes and is mutagenic in vivo as well as in vitro. In long-term studies in female mice bendamustine is carcinogenic.
6. Pharmaceutical particulars
6.1 List of excipients
Mannitol
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 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.
Solution for infusion
After reconstitution and dilution, chemical and physical stability has been demonstrated for 3.5 hours at 25 °C/ 60% RH 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.
6.4 Special precautions for storage
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.
6.5 Nature and contents of container
Type I brown glass vials of 25/26 ml or 60 ml with rubber stopper and an aluminium flip-off cap.
25/26 ml-vials contain 25 mg bendamustine hydrochloride and are supplied in packs of 5, 10 and 20 vials.
60 ml-vials contain 100 mg bendamustine hydrochloride and are supplied in packs of 5 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
When handling Levact, 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 eyes 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 Levact containing 25 mg bendamustine hydrochloride in 10 ml water for injection by shaking;
Reconstitute each vial of Levact 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 Levact immediately with 0.9% NaCl solution to produce a final volume of about 500 ml.
Levact 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.
7. Marketing authorisation holder
Astellas Pharma GmbH
Postfach 50 01 66
80971 München
Germany
Phone: +49 (0)89 45 44 01
Fax: +49 (0)89 45 44 13 29
8. Marketing authorisation number(s)
PL 14427/0026
9. Date of first authorisation/renewal of the authorisation
3rd August 2010
10. Date of revision of the text
17th November 2014