Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Safe Handling and Disposal Bendamustine Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Care should be exercised in the handling and preparation of solutions prepared from Bendamustine Hydrochloride Injection. 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 Bendamustine Hydrochloride Injection prior to dilution, remove gloves and follow disposal procedures 1 . If a solution of Bendamustine Hydrochloride Injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If Bendamustine Hydrochloride Injection contacts the mucous membranes, flush thoroughly with water. How Supplied Bendamustine Hydrochloride Injection is supplied in individual cartons of 6 mL clear multiple-dose vials containing 100 mg of bendamustine hydrochloride as a clear and colorless to yellow solution. NDC 10019-079-01, 100 mg/4 mL (25 mg/mL). Storage Store Bendamustine Hydrochloride Injection in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light.; PRINCIPAL DISPLAY PANEL Container Label Lot: Exp: NDC 10019-079-01 Sterile Multiple-Dose Vial Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) Must dilute required dose in a 500 mL admixture prior to administration For Intravenous Infusion Only USA HA-65-02-315 C 666 Bar Code 3 10019 07901 1 Store in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light. Dosage: See Prescribing Information. Manufactured for: Baxter Healthcare Corp. DeerField, IL 60015, USA Product of Germany 2D Bar Code PEEL HERE Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) CAUTION: Concentrate Solution – 25 mg/mL Must be diluted prior to administration (see Prescribing Information for instructions) Aseptically withdraw the volume needed for the required dose based on 25 mg/mL concentration as per Table A (see Prescribing Information) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/ 0.45% Sodium Chloride Injection. Do not use if solid or particulate matter is observed Carton Label Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) Bar Code NDC 10019-079-01 Sterile Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) For Intravenous Infusion Only Must dilute required dose in a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection prior to administration. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015, USA Product of Germany Baxter Logo HA-80-03-226 USA Store in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light. Dosage: See Prescribing Information. Each mL contains 25 mg bendamustine hydrochloride (equivalent to 22.7 mg bendamustine free base), 0.1 g alcohol, USP (equivalent to 0.1 g absolute ethanol), 5 mg monothioglycerol, NF in polyethylene glycol 400, NF, sodium hydroxide, NF to adjust acidity of polyethylene glycol 400. C 377 NDC 10019-079-01 Sterile Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) For Intravenous Infusion Only Must dilute required dose in a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection prior to administration. One 4 mL Multiple-Dose Vial 2395b0105 Bar Code Hazardous Agent - Use caution during handling and preparation. Use of gloves and safety glasses is recommended to avoid exposure. See Prescribing Information for details. Bar Code (01)20310019079015 Representative NDC 10019-079-01 Container 1 of 3 Representative NDC 10019-079-01 Container 2 of 3 Representative NDC 10019-079-01 Container 3 of 3 Representative carton lbl
- 16 HOW SUPPLIED/STORAGE AND HANDLING Safe Handling and Disposal Bendamustine Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Care should be exercised in the handling and preparation of solutions prepared from Bendamustine Hydrochloride Injection. 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 Bendamustine Hydrochloride Injection prior to dilution, remove gloves and follow disposal procedures 1 . If a solution of Bendamustine Hydrochloride Injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If Bendamustine Hydrochloride Injection contacts the mucous membranes, flush thoroughly with water. How Supplied Bendamustine Hydrochloride Injection is supplied in individual cartons of 6 mL clear multiple-dose vials containing 100 mg of bendamustine hydrochloride as a clear and colorless to yellow solution. NDC 10019-079-01, 100 mg/4 mL (25 mg/mL). Storage Store Bendamustine Hydrochloride Injection in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light.
- PRINCIPAL DISPLAY PANEL Container Label Lot: Exp: NDC 10019-079-01 Sterile Multiple-Dose Vial Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) Must dilute required dose in a 500 mL admixture prior to administration For Intravenous Infusion Only USA HA-65-02-315 C 666 Bar Code 3 10019 07901 1 Store in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light. Dosage: See Prescribing Information. Manufactured for: Baxter Healthcare Corp. DeerField, IL 60015, USA Product of Germany 2D Bar Code PEEL HERE Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) CAUTION: Concentrate Solution – 25 mg/mL Must be diluted prior to administration (see Prescribing Information for instructions) Aseptically withdraw the volume needed for the required dose based on 25 mg/mL concentration as per Table A (see Prescribing Information) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/ 0.45% Sodium Chloride Injection. Do not use if solid or particulate matter is observed Carton Label Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) Bar Code NDC 10019-079-01 Sterile Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) For Intravenous Infusion Only Must dilute required dose in a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection prior to administration. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015, USA Product of Germany Baxter Logo HA-80-03-226 USA Store in refrigerator, 2° to 8°C (36° to 46°F). Retain vial in original carton until contents are used to protect from light. Dosage: See Prescribing Information. Each mL contains 25 mg bendamustine hydrochloride (equivalent to 22.7 mg bendamustine free base), 0.1 g alcohol, USP (equivalent to 0.1 g absolute ethanol), 5 mg monothioglycerol, NF in polyethylene glycol 400, NF, sodium hydroxide, NF to adjust acidity of polyethylene glycol 400. C 377 NDC 10019-079-01 Sterile Rx Only Bendamustine HCl Injection 100 mg/4 mL (25 mg/mL) For Intravenous Infusion Only Must dilute required dose in a 500 mL infusion bag of 0.9% Sodium Chloride Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection prior to administration. One 4 mL Multiple-Dose Vial 2395b0105 Bar Code Hazardous Agent - Use caution during handling and preparation. Use of gloves and safety glasses is recommended to avoid exposure. See Prescribing Information for details. Bar Code (01)20310019079015 Representative NDC 10019-079-01 Container 1 of 3 Representative NDC 10019-079-01 Container 2 of 3 Representative NDC 10019-079-01 Container 3 of 3 Representative carton lbl
Overview
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 C 16 H 21 Cl 2 N 3 O 2 ∙HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: Bendamustine Hydrochloride Injection for intravenous use is supplied as a sterile, clear, and colorless to yellow solution in a multiple-dose clear glass vial. Each milliliter contains 25 mg of bendamustine hydrochloride (equivalent to 22.7 mg bendamustine free base), 0.1 g of alcohol, USP (equivalent to 0.1 g absolute ethanol), 5 mg of monothioglycerol, NF (used as an antioxidant) and q.s. to 1 mL polyethylene glycol 400, NF. Sodium hydroxide, NF is used to adjust the acidity of polyethylene glycol 400. chemical structure
Indications & Usage
Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult patients with: • Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. ( 1.1 ) • Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. ( 1.2 ) 1.1 Chronic Lymphocytic Leukemia (CLL) Bendamustine q Hydrochloride Injection is indicated for the treatment of adult patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) Bendamustine Hydrochloride Injection is indicated for the treatment of adult 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 & Administration
For CLL : • 100 mg/m 2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. ( 2.1 ) For NHL : • 120 mg/m 2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. ( 2.2 ) 2.1 Dosing Instructions for CLL Recommended Dosage : The recommended dose is 100 mg/m 2 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: Delay Bendamustine Hydrochloride Injection administration in the event of Grade 4 hematologic toxicity or clinically significant Grade 2 or greater non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate Bendamustine Hydrochloride Injection at the discretion of the treating physician. In addition, consider dose reduction. [see Warnings and Precautions ( 5.1 )] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m 2 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/m 2 on Days 1 and 2 of each cycle. Consider dose re-escalation in subsequent cycles at the discretion of the treating physician. 2.2 Dosing Instructions for NHL Recommended Dosage : The recommended dose is 120 mg/m 2 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: Delay Bendamustine Hydrochloride Injection administration in the event of a Grade 4 hematologic toxicity or clinically significant greater or equal to 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 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate Bendamustine Hydrochloride Injection at the discretion of the treating physician. In addition, consider dose reduction. [see Warnings and Precautions ( 5.1 )] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m 2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m 2 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/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. 2.3 Preparation for Intravenous Administration Bendamustine Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Bendamustine Hydrochloride Injection is in a multiple-dose vial. Bendamustine Hydrochloride Injection is a clear and colorless to yellow solution. Store Bendamustine Hydrochloride Injection at recommended refrigerated storage conditions (2° to 8°C or 36° to 46°F). When refrigerated the contents may partially freeze. Allow the vial to reach room temperature (15° to 30°C or 59° to 86°F) prior to use. Observe the contents of the vial for any visible solid or particulate matter. Do not use the product if solid or particulate matter is observed after reaching room temperature. Intravenous Infusion Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution as per Table A below and immediately transfer to a 500 mL infusion bag of one of the following diluents: • 0.9% Sodium Chloride Injection, USP; or • 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. The resulting final concentration of Bendamustine Hydrochloride Injection in the infusion bag should be within 0.05 to 0.7 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Table A: Volume (mL) of Bendamustine Hydrochloride Injection required for dilution into 500 mL of 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP for a given dose (mg/m 2 ) and Body Surface Area (m 2 ) Body Surface Area (m 2 ) Volume of Bendamustine Hydrochloride Injection to withdraw (mL) 120 mg/m 2 100 mg/m 2 90 mg/m 2 60 mg/m 2 50 mg/m 2 25 mg/m 2 1 4.8 4 3.6 2.4 2 1 1.1 5.3 4.4 4 2.6 2.2 1.1 1.2 5.8 4.8 4.3 2.9 2.4 1.2 1.3 6.2 5.2 4.7 3.1 2.6 1.3 1.4 6.7 5.6 5 3.4 2.8 1.4 1.5 7.2 6 5.4 3.6 3 1.5 1.6 7.7 6.4 5.8 3.8 3.2 1.6 1.7 8.2 6.8 6.1 4.1 3.4 1.7 1.8 8.6 7.2 6.5 4.3 3.6 1.8 1.9 9.1 7.6 6.8 4.6 3.8 1.9 2 9.6 8 7.2 4.8 4 2 2.1 10.1 8.4 7.6 5 4.2 2.1 2.2 10.6 8.8 7.9 5.3 4.4 2.2 2.3 11 9.2 8.3 5.5 4.6 2.3 2.4 11.5 9.6 8.6 5.8 4.8 2.4 2.5 12 10 9 6 5 2.5 2.6 12.5 10.4 9.4 6.2 5.2 2.6 2.7 13 10.8 9.7 6.5 5.4 2.7 2.8 13.4 11.2 10.1 6.7 5.6 2.8 2.9 13.9 11.6 10.4 7 5.8 2.9 3 14.4 12 10.8 7.2 6 3 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. 2.4 Admixture Stability Bendamustine Hydrochloride Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. If diluted with 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2° to 8°C or 36° to 46°F) or for 3 hours when stored at room temperature (15° to 30°C or 59° to 86°F) and room light. Administration of diluted Bendamustine Hydrochloride Injection must be completed within this period of time. Bendamustine Hydrochloride Injection is supplied in a multiple-dose vial. Retain the partially used vial in original package to protect from light and store refrigerated (2° to 8°C or 36° to 46°F) if additional dose withdrawal from the same vial is intended. 2.5 Stability of Partially Used Vials (Needle Punched Vials) Bendamustine Hydrochloride Injection is supplied as a multiple-dose vial. Although it does not contain any antimicrobial preservative, Bendamustine Hydrochloride Injection is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2° to 8°C or 36° to 46°F). Each vial is not recommended for more than a total of six (6) dose withdrawals. After first use, store the partially used vial in original carton at 2° to 8°C (36° to 46°F), and then discard after 28 days.
Warnings & Precautions
• Myelosuppression: Delay or reduce dose, and restart treatment based on ANC and platelet count recovery. ( 5.1 ) • Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. ( 5.2 ) • Progressive Multifocal Leukoencephalopathy (PML): Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. ( 5.3 ) • Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Pre-medicate in subsequent cycles for milder reactions. ( 5.4 ) • Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. ( 5.5 ) • Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. ( 5.6 ) • Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment. ( 5.7 ) • Other Malignancies: Pre-malignant and malignant diseases have been reported. ( 5.8 ) • Extravasation Injury: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. ( 5.9 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. ( 5.10 , 8.1 ) 5.1 Myelosuppression Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies [see Adverse Reactions (6.1) ] . 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). Bendamustine Hydrochloride Injection causes myelosuppression. 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 10 9 /L and the platelet count should be ≥ 75 x 10 9 /L [see Dosage and Administration ( 2.1 ) and ( 2.2 )]. 5.2 Infections Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride [see Adverse Reactions (6.1) ] . Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following Bendamustine Hydrochloride Injection treatment to contact a physician immediately if they have symptoms or signs of infection. Patients treated with Bendamustine Hydrochloride Injection are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration. 5.3 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 (6.2) ] . Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold Bendamustine Hydrochloride Injection treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.4 Anaphylaxis and Infusion Reactions Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials [see Adverse Reactions (6.1) ] . 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 experience 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 Bendamustine Hydrochloride Injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in post-marketing reports [see Adverse Reactions (6.1) ] . The onset tends to be within the first treatment cycle of bendamustine hydrochloride 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 bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly. [see Warnings and Precautions ( 5.6 )]. 5.6 Skin Reactions Fatal and serious skin reactions have been reported with bendamustine hydrochloride 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 (6.1 and 6.2) ]. Events occurred when bendamustine hydrochloride 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 Bendamustine Hydrochloride Injection. 5.7 Hepatotoxicity Fatal and serious cases of liver injury have been reported with Bendamustine Hydrochloride Injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients. [see Warnings and Precautions ( 5.2 )] Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during Bendamustine Hydrochloride Injection therapy. 5.8 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, 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 (6.2) ] . Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with Bendamustine Hydrochloride Injection. 5.9 Extravasation Injury Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain [see Adverse Reactions (6.2) ] . Assure good venous access prior to starting Bendamustine Hydrochloride Injection infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Bendamustine Hydrochloride Injection. 5.10 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and the drug’s mechanism of action, Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )].
Contraindications
Bendamustine Hydrochloride Injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, alcohol, or monothioglycerol. [see Warnings and Precautions ( 5.4 )] Bendamustine Hydrochloride Injection is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, alcohol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions. ( 4 , 5.4 )
Adverse Reactions
The following clinically significant serious adverse reactions are discussed in greater detail in other sections of the prescribing information. • Myelosuppression [see Warnings and Precautions ( 5.1 )] • Infections [see Warnings and Precautions ( 5.2 )] • Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions ( 5.3 )] • Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.4 )] • Tumor Lysis Syndrome [ see Warnings and Precautions ( 5.5 )] • Skin Reactions [see Warnings and Precautions ( 5.6 )] • Hepatotoxicity [see Warnings and Precautions ( 5.7 )] • Other Malignancies [see Warnings and Precautions ( 5.8 )] • Extravasation Injury [see Warnings and Precautions ( 5.9 )] • Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue. ( 6.1 ) • Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, hyperbilirubinemia, pyrexia, nausea, vomiting. ( 6.1 ) • Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . 6.1 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. Clinical Trials Experience in CLL The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-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/m 2 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 bendamustine hydrochloride 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 bendamustine hydrochloride in the randomized CLL clinical study and in 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 bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%). Table 1 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. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) Body System Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2 . These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Laboratory Abnormality Bendamustine Hydrochloride N=150 Chlorambucil N=141 All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) 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 bendamustine hydrochloride 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. Clinical Trials Experience in NHL The data described below reflect exposure to bendamustine hydrochloride 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 bendamustine hydrochloride at a dose of 120 mg/m 2 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 3 . 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. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamustine Hydrochloride by System Organ Class and Preferred Term (N=176) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category Body System Number (%) of patientsError! Hyperlink reference not valid. Adverse Reaction All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac Disorders Tachycardia 13 (7) 0 Gastrointestinal disorders Nausea 132 (75) 7 (4) Vomiting 71 (40) 5 (3) Diarrhea 65 (37) 6 (3) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 1 (<1) Abdominal pain 22 (13) 2 (1) Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 0 Dry mouth 15 (9) 1 (<1) Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) 0 General disorders and administration site conditions Fatigue 101 (57) 19 (11) Pyrexia 59 (34) 3 (2) Chills 24 (14) 0 Edema peripheral 23 (13) 1 (<1) Asthenia 19 (11) 4 (2) Chest pain 11 (6) 1 (<1) Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) 0 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile neutropenia 11 (6) 11 (6) Oral candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorder Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4 . 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%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies Hematology Variable Percent of Patients All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. 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 post-marketing 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 bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. 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 jirovecii pneumonia, progressive multifocal leukoencephalopathy (PML) Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI) Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN).
Drug Interactions
Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with Bendamustine Hydrochloride Injection. ( 7.1 ) 7.1 Effect of Other Drugs on Bendamustine Hydrochloride Injection CYP1A2 Inhibitors The coadministration of Bendamustine Hydrochloride Injection with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with Bendamustine Hydrochloride Injection [see Clinical Pharmacology ( 12.3 )] . Consider alternative therapies that are not CYP1A2 inhibitors during treatment with Bendamustine Hydrochloride Injection. CYP1A2 Inducers The coadministration of Bendamustine Hydrochloride Injection with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of Bendamustine Hydrochloride Injection [see Clinical Pharmacology ( 12.3 )] . Consider alternative therapies that are not CYP1A2 inducers during treatment with Bendamustine Hydrochloride Injection.
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