One 25-mg vial contains 25 mg bendamustine hydrochloride.
One 100-mg vial contains 100 mg bendamustine hydrochloride.
1 mL of the concentrate contains 2.5 mg bendamustine hydrochloride when reconstituted according to Instructions for Use and Handling under Cautions for Usage.
Bendamustine hydrochloride is a white, microcrystalline powder for reconstitution and dilution for solution for intravenous infusion.
Excipients/Inactive Ingredients: Mannitol.
Pharmacotherapeutic Group: Antineoplastic agents, alkylating agents. ATC Code: L01AA09.
Pharmacology: Pharmacodynamics: Bendamustine is an alkylating antitumor agent with unique activity containing a purine-like benzimidazole ring. The antineoplastic and cytocidal effect of bendamustine 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. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.
The antitumor effect of bendamustine hydrochloride has been demonstrated by several in vitro studies in different human tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovary carcinoma and different leukemia) and in vivo in different experimental tumor models with tumors of mouse, rat and human origin (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer). Bendamustine hydrochloride showed an activity profile in human tumor cell lines different to that of other alkylating agents. The active substance revealed no or very low cross-resistance in human tumor 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 Leukemia: The indication for use in chronic lymphocytic leukemia is supported by a single open-label study comparing bendamustine with chlorambucil. In the prospective, multicenter, randomized study, 319 previously untreated patients with chronic lymphocytic leukemia 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 tumor lysis syndrome.
Patients with BEN have 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 is 19 months with BEN and 6 months with CLB treatment (p<0.0001). The safety evaluation in both treatment arms did not reveal any unexpected adverse reactions 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, multicenter, 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 received a median of 3 previous chemotherapy or biologic therapy courses. The median number of previous rituximab-containing courses was 2. The patients had no response or progress 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, multicenter, 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 progress within 6 months or had an untoward reaction to prior rituximab treatment. Patients received a median of 3 previous chemotherapy or biological therapy courses. The median number of previous rituximab-containing courses was 2. The overall response rate was 76% with a median duration of response of 5 months [29 (95% CI 22.1, 43.1) weeks]. Bendamustine in combination with rituximab (BR) was investigated in a trial with the title "A Multicenter Phase II Study to Investigate the Safety and Activity of SDX-105 (Bendamustine) in Combination with Rituximab in Patients with Relapsed Indolent or Mantle Cell Non-Hodgkin's Lymphoma (NHL)". Patients received a dose of 375 mg/m2 of rituximab 7 days before the first 28-day cycle of bendamustine and rituximab. Subsequently, rituximab was given on the first day of a cycle at a single dose of 375 mg/m2, followed on the second and third day of a cycle by bendamustine at a dose of 90 mg/m2 per day of treatment. Four 28-day cycles were planned. Sixty-seven patients were enrolled in the trial and 66 received at least one dose of bendamustine and rituximab. The results of this study show the combination therapy of bendamustine and rituximab to be an efficacious treatment for patients with relapsed indolent or mantle cell NHL leading to an overall response rate of 92% and a CR rate of 41%. The responses obtained were durable with a median duration of response of 91 weeks and a median progression-free survival of 100 weeks. A high rate of durable response was also observed in both patients with prior rituximab treatment and those refractory to their last alkylator treatment.
Multiple Myeloma: In a prospective, multicenter, randomized, open study 131 patients with advanced multiple myeloma (Durie-Salmon stage II with progress 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 in the BP and 8.7 cycles in the MP group.
Patients with BP treatment have 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 is 14 months with BP and 9 months with MP treatment. The duration of remission is 18 months with BP and 12 months with MP treatment. The difference in overall survival is 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.
Pharmacokinetics: Distribution: The elimination half-life t½β 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 CYP1A2, CYP2C9/10, CYP2D6, CYP2E1 and CYP3A4.
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 > oxidized metabolite > N-desmethyl bendamustine. In the bile, primarily polar metabolites are eliminated.
Hepatic Impairment: In patients with 30-70% tumor infestation of the liver and mild hepatic impairment (serum bilirubin <1.2 mg/dL) the pharmacokinetic behavior was not changed. There was no significant difference to patients with normal liver and kidney function with respect to Cmax, tmax, AUC, t½β, 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, t½β, 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.
Toxicology: Non-Clinical Information: 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 hyperemia of the mucosa and hemorrhagia 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.
CLL: First-line treatment of chronic lymphocytic leukemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
NHL: Indolent non-Hodgkin's lymphomas in patients, who have progressed following treatment with rituximab or a rituximab containing regimen.
MM: 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.
CLL: 100 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2 of 4-week cycles.
NHL: 120 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2 of 3-week cycles.
MM: 120-150 mg/m2 body surface are bendamustine hydrochloride on days 1 and 2, combined with 60 mg/m2 body surface area prednisone i.v. or per os on days 1 to 4; of week 4-week cycles.
Treatment should be terminated or delayed if leukocyte and/or platelet values drop to 3000/μL or <75000/μL, respectively. Treatment can be continued after leukocyte values have increased to >4000/μL and platelet values to >100000/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 Precautions).
In case of non-hematological toxicity, dose reductions have to be based on the worst common toxicity criteria (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 Instructions for Use and Handling under Cautions for Usage.
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 are available in patients with severe hepatic impairment (serum bilirubin values of >3.0 mg/dL) (see Contraindications).
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.
Children: As there are limited data, the safety and efficacy of bendamustine in pediatric patients has not been established.
Elderly: There is no evidence that dose adjustments are necessary in elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Administration: For intravenous infusion over 30-60 minutes.
After application of a 30-minute infusion of bendamustine once every 3 weeks, the maximum tolerated dose (MTD) was 280 mg/m2. Cardiac events of CTC grade 2 occurred, which were compatible with ischemic ECG changes that were regarded as dose-limiting.
In a subsequent study with a 30-minute 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 hematological growth factors may be given as effective counter measures to control hematological side effects. Bendamustine hydrochloride and its metabolites are dialyzable to a small extent.
Hypersensitivity to the active substance or to any of the excipients.
During breastfeeding. 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 <3000/μL or <75000/μL, respectively). Major surgery less than 30 days before start of treatment. Infections, especially involving leukocytopenia. Yellow fever vaccination.
Use in Lactation: It is not known whether bendamustine passes into the breast milk, therefore, Ribomustin is contraindicated during breastfeeding. Breastfeeding must be discontinued during treatment with Ribomustin.
Myelosuppression: Patients treated with bendamustine hydrochloride may experience myelosuppression (bone marrow failure). In the event of treatment-related myelosuppression, leukocytes, platelets, hemoglobin, and neutrophils should be monitored and re-evaluated prior to initiation of the next cycle of therapy. Prior to the initiation of the next cycle of therapy, the following parameters are recommended: Leukocyte and/or platelet values >4000/μL or >100000/μL, respectively.
Treatment-related myelosuppression may require dose adjustment and/or dose delays. Ribomustin should not be used during severe bone marrow suppression and severe blood count alterations. See Dosage and Administration.
Infections: Infection, including pneumonia and sepsis, has been reported. In rare cases, infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Patients with myelosuppression following Ribomustin treatment should be advised to contact a physician if they have symptoms or signs of infection, including fever or respiratory symptoms.
Cytomegalovirus and herpes virus reactivation have been reported and may occur.
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 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; therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, Ribomustin should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine hydrochloride is suspected, treatment should be discontinued. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some fatal, have been reported when bendamustine was administered concomitantly with allopurinol and other medications known to cause these syndromes.
Patients with Cardiac Disorders: During treatment with bendamustine hydrochloride the concentration of potassium in the blood should be closely monitored. Potassium supplementation should be given when K+ <3.5 mEq/L, and ECG measurement must be performed.
Fatal cases of myocardial infarction and cardiac failure have been reported with bendamustine treatment. Patients with concurrent or history of cardiac disease should be observed closely.
Nausea, Vomiting: An antiemetic may be given for the symptomatic treatment of nausea and vomiting.
Tumor Lysis Syndrome: Tumor lysis syndrome associated with Ribomustin treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of Ribomustin and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate volume status, close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of allopurinol during the first one to two weeks of Ribomustin therapy can be considered but not necessarily as standard.
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 administration of 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. The patient should seek advice about sperm conservation prior to treatment with Ribomustin 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, such as the use of corticosteroids, are not of clear benefit.
Other Malignancies: There are reports of secondary tumors, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with bendamustine therapy has not been determined.
Hepatitis B Reactivation: Hepatitis B reactivation including fatal outcome have been reported and hepatitis due to reactivation of hepatitis B virus may occur. Patients should undergo appropriate measures for hepatitis B infection prior to administration of Ribomustin and liver function and hepatitis B markers should be regularly monitored and appropriate medication and/or prophylaxis should be used to prevent HBV reactivation.
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 Ribomustin (see Adverse Reactions). Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.
Impairment of Fertility: Men being treated with bendamustine 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 Ribomustin.
Use in Pregnancy: There are insufficient data from the use of Ribomustin in pregnant women.
In non-clinical studies bendamustine was embryo-/fetolethal, teratogenic and genotoxic (see Pharmacology: Toxicology: Non-Clinical Information under Actions). Women of childbearing potential must use effective methods of contraception both before, during, and one month following Ribomustin therapy.
During pregnancy Ribomustin should not be used unless the benefit outweighs the risk. The mother should be informed about the risk to the fetus. If treatment with Ribomustin 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 counseling should be considered.
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 as follows reflects the data obtained with bendamustine hydrochloride in clinical trials. (See table.)
Click on icon to see table/diagram/image
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. In addition, a few cases of hepatitis B reactivation resulting in hepatic failure have been reported in patients treated with bendamustine. Pancytopenia, headache, dizziness have also been reported in patients treated with bendamustine.
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.
There have been isolated reports of necrosis after accidental extravascular administration and toxic epidermal necrosis, tumor lysis syndrome, and anaphylaxis. There are reports of secondary tumors, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma.
The association with Ribomustin therapy has not been determined.
No in vivo interaction studies have been performed.
When Ribomustin is combined with myelosuppressive agents, the effect of Ribomustin 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 Ribomustin.
Combination of Ribomustin 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. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see Pharmacology: Pharmacokinetics under Actions). Therefore, potential for interaction with CYP1A2 inhibitors (such as fluvoxamine, ciprofloxacin, acyclovir, cimetidine) exists.
Incompatibilities: This medicinal product should not be mixed with other medicinal products except those mentioned in Instructions for Use and Handling and Disposal as follows.
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.
Instructions for Use and Handling: When handling Ribomustin, 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, absorbing 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.
Reconstitution: Reconstitute each vial of Ribomustin containing 25 mg bendamustine hydrochloride in 10 mL water for injection by shaking.
Reconstitute each vial of Ribomustin 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 colorless solution.
Dilution: As soon as a clear solution is obtained (usually after 5-10 minutes) dilute the total recommended dose of Ribomustin immediately with 0.9% NaCl solution to produce a final volume of about 500 mL.
Ribomustin must be diluted with 0.9% NaCl solution and not with any other injectable solution.
Administration: The solution is administered by intravenous infusion over 30-60 min.
The vials are for single use only.
Instructions for Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Store below 30°C. Keep the vial in the outer carton in order to protect from light.
Shelf-Life: The powder should be reconstituted immediately after opening of the vial.
The reconstituted concentrate should be diluted immediately with 0.9% sodium chloride solution.
L01AA09 - bendamustine ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.
Lyophilized powd for infusion (vial) 25 mg x 1's. 100 mg x 1's.