Bendamustine Mylan

Bendamustine Mylan

bendamustine

Manufacturer:

Mylan

Distributor:

DKSH

Marketer:

Viatris
The information highlighted (if any) are the most recent updates for this brand.
Full Prescribing Info
Contents
Bendamustine hydrochloride.
Description
Each vial contains Bendamustine Hydrochloride 25 mg.
Each vial contains Bendamustine Hydrochloride 100 mg.
Excipients/Inactive Ingredients: Mannitol, Tertiary butyl alcohol, Water for Injection.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Bendamustine is a mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of Bendamustine remains unknown.
Pharmacokinetics: Absorption: Following a single IV dose of Bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of Bendamustine has not been studied.
Distribution: In vitro, the binding of Bendamustine to human serum plasma proteins ranged from 94-96% and was concentration independent from 1-50 μg/mL. Data suggest that Bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 μg/mL indicating that Bendamustine distributes freely in human red blood cells. In humans, the mean steady state volume of distribution (Vss) was approximately 25 L.
Metabolism: In vitro data indicate that Bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. In vitro, studies indicate that two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10 and 1/100 that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to Bendamustine.
In vitro studies using human liver microsomes indicate that Bendamustine does not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4/5 enzymes in primary cultures of human hepatocytes.
Elimination: No mass balance study has been undertaken in humans. Preclinical radiolabeled Bendamustine studies showed that approximately 90% of drug administered was recovered in excreta primarily in the feces.
Bendamustine clearance in humans is approximately 700 mL/minute. After a single dose of 120 mg/m2 Bendamustine IV over 1-hour the intermediate t½ of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t½ of M3 and M4 are approximately 3 hours and 30 minutes respectively. Little or no accumulation in plasma is expected for Bendamustine administered on Days 1 and 2 of a 28-day cycle.
Renal Impairment: In a population pharmacokinetic analysis of Bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of renal impairment (CrCL 40-80 mL/min, N=31) on the pharmacokinetics of Bendamustine. Bendamustine has not been studied in patients with CrCL <40 mL/min. These results are however limited, and therefore bendamustine should be used with caution in patients with mild or moderate renal impairment. Bendamustine should not be used in patients with CrCL<40 mL/min.
Hepatic Impairment: In a population pharmacokinetic analysis of Bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of mild (total bilirubin ≤ ULN, AST ≥ ULN to 2.5 × ULN, and/or ALP ≥ ULN to 5.0 × ULN, N=26) hepatic impairment on the pharmacokinetics of Bendamustine. Bendamustine has not been studied in patients with moderate or severe hepatic impairment. These results are however limited, and therefore Bendamustine should be used with caution in patients with mild hepatic impairment. Bendamustine should not be used in patients with moderate (AST or ALT 2.5 - 10 × ULN and total bilirubin 1.5 - 3 × ULN) or severe (total bilirubin > 3 ULN) hepatic impairment.
Effect of Age: The pharmacokinetics of Bendamustine (AUC and Cmax) were not significantly different between patients less than or greater than/equal to 65 years of age.
Effect of Gender: The pharmacokinetics of Bendamustine were similar in male and female patients.
Effect of Race: The effect of race on the safety, and/or efficacy of Bendamustine Hydrochloride for Injection has not been established.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m2/day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced.
Oral administration at 187.5 mg/m2/day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.
Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), Bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human in micronucleated polychromatic erythrocytes from 37.5 mg/m2, the lowest dose tested.
Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.
Indications/Uses
Bendamustine Hydrochloride for Injection is an alkylating drug indicated for treatment of patients with: Chronic Lymphocytic Leukemia (CLL): Bendamustine Hydrochloride for Injection is indicated for the treatment of patients with chronic lymphocytic leukemia.
Non-Hodgkin's Lymphoma (NHL): Bendamustine Hydrochloride for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin's lymphoma that has progressed during or following treatment with rituximab or a rituximab-containing regimen.
Dosage/Direction for Use
For intravenous use.
Recommended dose: Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: Bendamustine Hydrochloride for Injection administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 × 109/L, platelets ≥ 75 × 109/L], Bendamustine Hydrochloride for Injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted.
Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.
Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.
For NHL: 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: Bendamustine Hydrochloride for Injection administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 × 109/L, platelets ≥ 75 × 109/L], Bendamustine Hydrochloride for Injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted.
Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
General Dosing Considerations: Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.
Bendamustine Hydrochloride for Injection must be reconstituted and further diluted prior to infusion.
Overdosage
The intravenous LD50 of Bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.
No specific antidote for Bendamustine Hydrochloride for Injection overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.
Contraindications
Bendamustine Hydrochloride for Injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to Bendamustine.
Warnings
According to Ministry of Public Health Announcement: This drug can cause serious danger, it must be used under health care professional control only.
Special Precautions
Myelosuppression: Patients treated with Bendamustine Hydrochloride for Injection are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1×109/L and the platelet count should be ≥ 75×109/L.
Infections: Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with Bendamustine Hydrochloride for Injection are more susceptible to infections. Patients with myelosuppression following Bendamustine Hydrochloride for Injection treatment should be advised to contact a physician if they have symptoms or signs of infection.
Infusion Reactions and Anaphylaxis: Infusion reactions to Bendamustine Hydrochloride for Injection have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions.
Tumor Lysis Syndrome: Tumor lysis syndrome associated with Bendamustine Hydrochloride for Injection treatment has been reported in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of Bendamustine Hydrochloride for Injection and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of Bendamustine Hydrochloride for Injection therapy. However, there may be an increased risk of severe skin toxicity when Bendamustine Hydrochloride for Injection and allopurinol are administered concomitantly.
Skin Reactions: A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when Bendamustine Hydrochloride for Injection was given in combination with other anticancer agents, so the precise relationship to Bendamustine Hydrochloride for Injection is uncertain.
In a study of Bendamustine Hydrochloride for Injection (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when Bendamustine Hydrochloride for Injection was known to cause these syndromes. The relationship to Bendamustine Hydrochloride for Injection cannot be determined.
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, Bendamustine Hydrochloride for Injection should be withheld or discontinued.
Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with Bendamustine Hydrochloride for Injection, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with Bendamustine Hydrochloride for Injection therapy has not been determined.
Hepatitis B Virus Reactivation: Administration of Bendamustine Hydrochloride for Injection may cause hepatitis due to reactivation of hepatitis B virus. Therefore patients should be tested for hepatitis B infection and undergo appropriate measures prior to administration of Bendamustine Hydrochloride for Injection. Regular liver function tests and monitoring of hepatitis virus markers after the start of administration of Bendamustine Hydrochloride for Injection must be performed in order to be alerted to signs and/or symptoms of reactivation of hepatitis B virus.
Effects on ability to drive and use machines: Fatigue have been reported during treatment with Bendamustine Hydrochloride. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.
Use in Pregnancy: Bendamustine Hydrochloride for Injection can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of Bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weight.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Category D.
Bendamustine hydrochloride for Injection can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine from 210 mg/m2 (70 mg/kg) in mice administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated.
Repeat intraperitoneal dosing in mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m2 (25 mg/kg) and an increase in abnormalities from 112.5 mg/m2 (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m2 (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13 caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external [effect on tail, head, and herniation of external organs (exomphalos)] and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats. There are no adequate and well-controlled studies in pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Most common non-hematologic adverse reactions for CLL (frequency ≥ 15%) are pyrexia, nausea, and vomiting.
Most common non-hematologic adverse reactions for NHL (frequency ≥ 15%) are nausea, fatigue, pyrexia, constipation, anorexia, cough, headache, weight decreased, and stomatitis.
Most common hematologic abnormalities for both indications (frequency ≥ 15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.
The following serious adverse reactions have been associated with Bendamustine Hydrochloride for Injection in clinical trials and are discussed in greater detail in other sections of the label: Myelosuppression, Infections, Infusion Reactions and Anaphylaxis, Tumor Lysis Syndrome, Skin Reactions, Other Malignancies, Hepatitis B Virus Reactivation.
Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. Adverse reactions occurring less frequently but possibly related to Bendamustine Hydrochloride for Injection treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.
Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Bendamustine Hydrochloride for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling.
Skin reactions including SJS and TEN have occurred when Bendamustine Hydrochloride for Injection was administered concomitantly with allopurinol and other medications known to cause these syndromes.
Hepatitis due to reactivation of hepatitis B virus may occur.
Drug Interactions
No formal clinical assessments of pharmacokinetic drug-drug interactions between Bendamustine Hydrochloride for Injection and other drugs have been conducted.
Bendamustine's active metabolites, gamma-hydroxy Bendamustine (M3) and N-desmethyl-Bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of Bendamustine and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of Bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.
The role of active transport system in Bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in Bendamustine transport.
Based on in vitro data, Bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.
Caution For Usage
Preparation and Administration Precautions: Reconstitution/Preparation for Intravenous Administration: Bendamustine Hydrochloride for Injection is indicated for intravenous administration.
After reconstitution of the solution according to the instructions, Bendamustine Hydrochloride for Injection is administered as a short intravenous infusion over 30 - 60 minutes.
To prepare the ready-to-use solution, the contents of a vial of Bendamustine Hydrochloride for Injection are dissolved in water for Injections as follows: First dissolve the vial of Bendamustine Hydrochloride for Injection containing 25 mg of Bendamustine hydrochloride in 10 mL by shaking.
First dissolve the vial of Bendamustine hydrochloride for Injection containing 100 mg of Bendamustine hydrochloride in 40 mL by shaking.
As soon as clear solution forms (within 5 minutes) the total Bendamustine Hydrochloride for Injection dose is immediately diluted to a final volume of approximately 500 mL with 0.9% sodium chloride solution. If particulate matter is observed, the reconstituted product should not be used.
Apart from isotonic saline solution, Bendamustine Hydrochloride for Injection must not be diluted with other base infusion solutions or other injection solutions.
Admixture Stability: Unopened vial: Do not store above 30°C. Protect from light.
Keep the vial in the outer carton in order to protect from light.
Reconstituted concentration in the vial: The concentrate should be further processed immediately.
Diluted solution for infusion: The chemical and physical stability of the preparation after reconstitution to form the solution for infusion (water for injections and 0.9% Sodium Chloride solution) was confirmed for 3.5 hours at 25°C and 48 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately.
Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Storage
Do not store above 30°C. Protect from light.
Shelf-life: 24 months.
MIMS Class
Cytotoxic Chemotherapy
ATC Classification
L01AA09 - bendamustine ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.
Presentation/Packing
Powd for concentrate for infusion (vial) (white to off white, lyophilized) 100 mg x 1's.
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