BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR BENDEKA ® ( bendamustine hydrochloride ) injection , for intravenous use
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1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia ( CLL ) BENDEKA ® ( bendamustine hydrochloride ) injection is indicated for the treatment of patients with chronic lymphocytic leukemia . Efficacy relative to first line therapies other than chlorambucil has not been established . 1.2 Non-Hodgkin Lymphoma ( NHL ) BENDEKA ( bendamustine hydrochloride ) injection 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 .
2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage : The recommended dose is 100 mg / m 2 administered intravenously over 10 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 : BENDEKA ( bendamustine hydrochloride ) injection administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity . Once nonhematologic toxicity has recovered to less than or equal to Grade 1 and / or the blood counts have improved [ Absolute Neutrophil Count ( ANC ) greater than or equal to 1 x 10 9 / L , platelets greater than or equal to 75 x 10 9 / L ], BENDEKA ( bendamustine hydrochloride ) injection can be reinitiated at the discretion of the treating physician . In addition , dose reduction may be warranted . [ 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 . Dose re-escalation in subsequent cycles may be considered 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 10 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 : BENDEKA ( bendamustine hydrochloride ) injection administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity . Once nonhematologic toxicity has recovered to less than or equal to Grade 1 and / or the blood counts have improved [ Absolute Neutrophil Count ( ANC ) greater than or equal to 1 x 10 9 / L , platelets greater than or equal to 75 x 10 9 / L ], BENDEKA ( bendamustine hydrochloride ) 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 / 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 BENDEKA ( bendamustine hydrochloride ) injection is a cytotoxic drug . Follow applicable special handling and disposal procedures . 1 BENDEKA is in a multiple-dose vial . At room temperature , BENDEKA is a clear , and colorless to yellow ready-to-dilute solution . Store BENDEKA at recommended refrigerated storage conditions ( 2-8 ° C or 36-46 ° F ). When refrigerated , the contents may partially freeze . Allow the vial to reach room temperature ( 15-30 ° C or 59-86 ° F ) prior to use . If particulate matter is observed after achieving room temperature , the product should not be used . 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 the solution to a 50 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 ; or − 5 % Dextrose Injection , USP . The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 1.85 mg / mL – 5.6 mg / mL . After transferring , thoroughly mix the contents of the infusion bag . The admixture should be a clear , and colorless to yellow solution .
BENDEKA ® ( bendamustine hydrochloride ) injection
No other diluents have been shown to be compatible . The 5 % Dextrose Injection , USP , offers a sodium-free method of administration for patients with certain medical conditions requiring restricted sodium intake . 2.4 Admixture Stability BENDEKA ( 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 ( 2-8 ° C or 36-46 ° F ) or for 6 hours when stored at room temperature ( 15-30 ° C or 59-86 ° F ) and room light . Administration of diluted BENDEKA ( bendamustine hydrochloride ) injection must be completed within this period of time . In the event that 5 % Dextrose Injection , USP is utilized , the final admixture is stable for 24 hours when stored refrigerated ( 2-8 ° C or 36-46 ° F ) or for only 3 hours when stored at room temperature ( 15-30 ° C or 59-86 ° F ) and room light . Administration of diluted BENDEKA must be completed within this period of time . Retain the partially used vial in original package to protect from light and store refrigerated ( 2-8 ° C or 36-46 ° F ) if additional dose withdrawal from the same vial is intended . 2.5 Stability of Partially Used Vials ( Needle Punched Vials ) BENDEKA is supplied in a multiple-dose vial . Although it does not contain any antimicrobial preservative , BENDEKA is bacteriostatic . The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration ( 2-8 ° C or 36-46 ° F ). Each vial is not recommended for more than a total of six ( 6 ) dose withdrawals . After first use , the partially used vial should be stored in the refrigerator in the original carton at 2 ° -8 ° C or 36-46 ° F and then discarded after 28 days .
4 CONTRAINDICATIONS BENDEKA ( bendamustine hydrochloride ) injection is contraindicated in patients with a known hypersensitivity ( e . g ., anaphylactic and anaphylactoid reactions ) to bendamustine , polyethylene glycol 400 , propylene glycol , or monothioglycerol .
5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Bendamustine hydrochloride caused severe myelosuppression ( Grade 3-4 ) in 98 % of patients in the two NHL studies ( see Table 4 ). 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 ). BENDEKA ( 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 occurred 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 . 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 . Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections . Advise patients with myelosuppression following BENDEKA ( bendamustine hydrochloride ) injection treatment to contact a physician immediately if they have symptoms or signs of infection . Patients treated with bendamustine hydrochloride 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 Anaphylaxis and Infusion Reactions Infusion reactions to bendamustine hydrochloride 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 . Ask patients 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 . 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 BENDEKA ( 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 .