Bendamustine Hydrochloride

5 WARNINGS AND 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 , 8.3 ) 5.1 Myelosuppression Bendamustine hydrochloride caused severe myelosuppression (Grade 3 to 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 ( 2.2 )]. 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 , 6.2)] . 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 hydrochloride, 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 [see Adverse Reactions ( 6.1 )]. 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 )] .