Treanda存達

Treanda

bendamustine

Manufacturer:

Teva

Distributor:

DCH Auriga - Healthcare
/
Four Star
The information highlighted (if any) are the most recent updates for this brand.
Full Prescribing Info
Contents
Bendamustine HCl.
Description
TREANDA (bendamustine HCl) for Injection for intravenous use is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-dose vial. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 - 3.5.
Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2∙HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Bendamustine is a bifunctional 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.
Pharmacodynamic Effects: Based on the pharmacokinetics/pharmacodynamics analyses of data from adult NHL patients, nausea increased with increasing bendamustine Cmax.
Cardiac Electrophysiology: The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab 375 mg/m2 intravenous infusion followed by a 30-minute intravenous infusion of bendamustine 90 mg/m2/day. No mean changes greater than 20 milliseconds were detected up to one hour post-infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.
Clinical Studies: Chronic Lymphocytic Leukemia (CLL): The safety and efficacy of TREANDA were evaluated in an open-label, randomized, controlled multicenter trial comparing TREANDA to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I-IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome or transformation to prolymphocytic leukemia were excluded from the study.
The patient populations in the TREANDA and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), "B" symptoms (51% vs. 53%), lymphocyte count (mean 65.7 x 109/L vs. 65.1 x 109/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).
Patients were randomly assigned to receive either TREANDA at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.
The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for TREANDA compared to chlorambucil (see Table 1). Survival data are not mature.

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Kaplan-Meier estimates of progression-free survival comparing TREANDA with chlorambucil are shown in the figure. (See figure.)

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Non-Hodgkin's Lymphoma (NHL): The efficacy of TREANDA was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the 1st dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received TREANDA intravenously at a dose of 120 mg/m2, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.
The median age was 60 years, 65% were male and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.
Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 2. (See Table 2.)

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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: The protein binding of bendamustine ranged from 94-96% and was concentration independent from 1-50 μg/mL. The blood to plasma concentration ratios in human blood ranged from 0.84-0.86 over a concentration range of 10-100 μg/mL.
The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20-25 L.
Elimination: After a single intravenous dose of 120 mg/m2 of bendamustine over 1 hour, the intermediate half-life (t½) of the parent compound is approximately 40 minutes. The mean terminal elimination t½ of two active metabolites, γ-hydroxybendamustine (M3) and N desmethylbendamustine (M4) are approximately 3 hours and 30 minutes, respectively. Bendamustine clearance in humans is approximately 700 mL/min.
Metabolism: Bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity in vitro. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2 in vitro. M3 and M4 concentrations in plasma are 1/10th and 1/100th that of the parent compound, respectively.
Excretion: Following IV infusion of radiolabeled bendamustine hydrochloride in cancer patients, approximately 76% of the dose was recovered. Approximately 50% of the dose was recovered in the urine (3.3% unchanged) and approximately 25% of the dose was recovered in the feces. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.
Specific Populations: No clinically meaningful effects on the pharmacokinetics of bendamustine were observed based on age (31 to 84 years), sex, mild to moderate renal impairment (CLcr ≥ 30 mL/min), or hepatic impairment with total bilirubin 1.5 < ULN and AST or ALT <2.5 x ULN. The effects of severe renal impairment (CLcr < 30 mL/min), or hepatic impairment with total bilirubin 1.5-3 x ULN and AST or ALT 2.5-10 x ULN or total bilirubin > 3 x ULN on the pharmacokinetics of bendamustine is unknown.
Race / Ethnicity: Exposures in Japanese subjects (n=6) were 40% higher than that in non-Japanese subjects receiving the same dose. The clinical importance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.
Drug Interaction Studies: In vitro studies: Effect of Bendamustine on CYP Substrates: Bendamustine did not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5.
Effect of Transporters on Bendamustine Hydrochloride: Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (the lowest dose tested, approximately 0.3 times the maximum recommended human dose [MRHD]) and 75 mg/m2/day (approximately 0.6 times the MRHD) for four days, peritoneal sarcomas in female AB/Jena mice were produced. Oral administration at 187.5 mg/m2/day (the only dose tested, approximately 1.6 times the MRHD) for four days induced mammary carcinomas and pulmonary adenomas.
Bendamustine is a mutagen and clastogen. In a bacterial reverse mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2 (the lowest dose tested, approximately 0.3 times the MRHD).
Bendamustine induced morphologic abnormalities in spermatozoa in mice. Following tail vein injection of bendaumustine at 120 mg/m2 or a saline control on days 1 and 2 for a total of 3 weeks, the number of spermatozoa with morphologic abnormalities was 16% higher in the bendamustine-treated group as compared to the saline control group.
Indications/Uses
Chronic Lymphocytic Leukemia (CLL): TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.
Non-Hodgkin Lymphoma (NHL): TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.
Dosage/Direction for Use
Dosing Instructions for CLL: 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: TREANDA 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 x 109/L, platelets ≥75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted (see Precautions).
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.
Dosing Instructions for NHL: 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: TREANDA 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 x 109/L, platelets ≥75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted (see Precautions).
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.
Preparation for Intravenous Administration: TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures.
If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation, only use TREANDA for Injection, the lyophilized formulation.
Each vial for TREANDA for Injection is intended for single dose only.
Aseptically reconstitute each TREANDA for Injection vial as follows: 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP.
Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used.
Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2-0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag.
Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution.
Use Sterile Water for Injection, USP for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as previously stated. No other diluents have been shown to be compatible.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.
Overdosage
The intravenous LD50 of bendamustine HCl is 240 mg/m2 in mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.
Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.
No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.
Contraindications
TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine (see Precautions).
Special Precautions
Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Adverse Reactions). 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).
Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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 x 109/L and the platelet count should be ≥75 x 109/L. (See Dosage & Administration.)
Infections: Infection, including pneumonia, sepsis, septic shock and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports (see Adverse Reactions). Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.
Progressive Multifocal Leukoencephalopathy (PML): Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab (see Adverse Reactions). Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold TREANDA treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials (see Adverse Reactions). 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.
Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports (see Adverse Reactions). The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly (see Precautions).
Skin Reactions: Fatal and serious skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash (see Adverse Reactions). Events occurred when TREANDA was given as a single agent and in combination with other anticancer agents or allopurinol.
Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA.
Hepatotoxicity: Fatal and serious cases of liver injury have been reported with TREANDA (see Adverse Reactions). Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients (see Precautions). Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.
Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma (see Adverse Reactions).
Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with TREANDA.

Extravasation Injury: TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain (see Adverse Reactions). Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.
Embryo-Fetal Toxicity: Based on findings from animal reproduction studies and the drug's mechanism of action, TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with TREANDA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose (see Use in Pregnancy & Lactation and Pharmacology: Pharmacodynamics: Mechanism of Action under Actions).
Renal Impairment: Do not use TREANDA in patients with CLcr < 30 mL/min (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: Do not use TREANDA in patients with AST or ALT 2.5-10 x upper limit of normal (ULN) and total bilirubin 1.5-3 x ULN, or total bilirubin > 3 x ULN (see Pharmacology: Pharmacokinetics under Actions).
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). TREANDA was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient in the Phase 2 portion of the trial at a dose of 120 mg/m2. However, 2 patients with ALL achieved CR at a dose of 90 mg/m2 in the Phase 1 portion of the study. The safety profile in these patients was consistent with that seen in adults, and no new safety signals were identified.
The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.
Use in the Elderly: No overall differences in safety were observed between patients ≥ 65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receiving TREANDA based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was also longer in younger patients with CLL receiving TREANDA (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal data: Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m2 (approximately 1.8 times the MRHD) during organogenesis and 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 administration of bendamustine hydrochloride to mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m2 (approximately 0.9 times the MRHD) similar to those seen after a single intraperitoneal administration.
Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and 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.
Lactation: Risk Summary: There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with TREANDA, and for at least 1 week after the last dose.
Females and Males of Reproductive Potential: TREANDA can cause fetal harm when administered to a pregnant woman (see Pregnancy as previously mentioned).
Pregnancy Testing: Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with TREANDA.
Contraception: Females: TREANDA can cause embryo-fetal harm when administered to pregnant women (see Pregnancy as previously mentioned). Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for at least 6 months after the final dose.
Males: Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose (see Pharmacology: Nonclinical Toxicology under Actions).
Infertility: Males: Based on findings from clinical studies, TREANDA may impair male fertility. 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.
Based on findings from animal studies, TREANDA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of TREANDA on male fertility, including the reversibility of adverse effects, have not been studied (see Pharmacology: Nonclinical Toxicology under Actions).
Adverse Reactions
The following clinically significant adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the monograph: Myelosuppression; Infections; Progressive Multifocal Leukoencephalopathy; Anaphylaxis and Infusion Reactions; Tumor Lysis Syndrome; Skin Reactions; Hepatotoxicity; Other Malignancies; Extravasation Injury (see Precautions).
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Chronic Lymphocytic Leukemia: The data described as follows reflect exposure to TREANDA in 153 patients. TREANDA was studied in an actively-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% White and had treatment-naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.
Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%) and vomiting (16%).
Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.
Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.
The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).
Table 3 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥5% of patients in either treatment group in the randomized CLL clinical study. (See Table 3.)

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The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 4. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. (See Table 4.)

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In the randomized CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.
Non-Hodgkin Lymphoma: The data described as follows reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.
The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 5. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. (See Table 5.)

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Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 6. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%) and hypocalcemia (2%). (See Table 6.)

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In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.
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 TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis and skin necrosis.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of TREANDA. 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.
Blood and lymphatic systems disorders: Pancytopenia.
Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.

General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).
Immune system disorders: Anaphylaxis.
Infections and infestations: Pneumocystis jiroveci pneumonia, progressive multifocal leukoencephalopathy (PML).
Respiratory, thoracic and mediastinal disorders: Pneumonitis.
Skin and subcutaneous tissue disorders: DRESS (Drug reaction with eosinophilia and systemic symptoms), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
Drug Interactions
Effect of Other Drugs on TREANDA: CYP1A2 Inhibitors: The coadministration of TREANDA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with TREANDA (see Pharmacology: Pharmacokinetics under Actions). Consider alternative therapies that are not CYP1A2 inhibitors during treatment with TREANDA.
CYP1A2 Inducers: The coadministration of TREANDA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of TREANDA (see Pharmacology: Pharmacokinetics under Actions). Consider alternative therapies that are not CYP1A2 inducers during treatment with TREANDA.
Caution For Usage
Safe Handling and Disposal: TREANDA (bendamustine hydrochloride) is a cytotoxic drug. Follow applicable special handling and disposal procedures. Care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If gloves come in contact with TREANDA prior to dilution, remove gloves and follow disposal procedures. If a solution of TREANDA (bendamustine hydrochloride) contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA (bendamustine hydrochloride) contacts the mucous membranes, flush thoroughly with water.
Storage
TREANDA for Injection may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F). Retain in the original package until time of use to protect from light.
Admixture Stability: TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.
Once diluted with either 0.9% Sodium Chloride Injection, USP, or 0.25% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and diluted TREANDA for injection must be completed within this period.
Patient Counseling Information
Allergic (Hypersensitivity) Reactions: Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion (see Precautions).
Myelosuppression: Inform patients of the likelihood that TREANDA will cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection (see Precautions).
Progressive Multifocal Leukoencephalopathy (PML): Inform patients to immediately contact their healthcare provider if they experience confusion, memory loss, trouble thinking, difficulty talking or walking, vision loss or other neurological or cognitive symptoms (see Precautions).
Hepatotoxicity: Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising (see Precautions).

Fatigue: Advise patients that TREANDA may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect (see Adverse Reactions).
Nausea and Vomiting: Advise patients that TREANDA may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided (see Adverse Reactions).
Diarrhea: Advise patients that TREANDA may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided (see Adverse Reactions).
Rash: Advise patients that a rash or itching may occur during treatment with TREANDA. Advise patients to immediately report severe or worsening rash or itching (see Precautions).
Non-Melanoma Skin Cancer (NMSC): Advise patients to undergo regular skin cancer screenings, and to report any suspicious skin changes to their healthcare provider (see Precautions).
Embryo-Fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy (see Precautions, Use in Pregnancy & Lactation, and Pharmacology: Nonclinical Toxicology under Actions). Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for at least 6 months after the final dose (see Use in Pregnancy & Lactation). Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose (see Use in Pregnancy & Lactation, and Pharmacology: Nonclinical Toxicology under Actions).
Lactation: Advise females not to breastfeed during treatment with TREANDA and for at least 1 week after the final dose (see Use in Pregnancy & Lactation).
Infertility: Advise males of reproductive potential that TREANDA may impair fertility (see Use in Pregnancy & Lactation).
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
Form
Treanda powd for inj 100 mg/20 mL
Packing/Price
1's
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