Pharmacy & Therapeutics - May 2008 - (Page 299) Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Bendamustine HCl (Treanda for Injection) Manufacturer: Cephalon, Inc., Frazer, Pa. Indication: Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Its efficacy relative to first-line therapies other than chlorambucil (Leukeran, GlaxoSmithKline) has not been established. Drug Class: Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazol group. Uniqueness of Drug: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activating DNA-damage stress response and apoptosis (cell death), inhibiting mitotic checkpoints, and inducing mitotic catastrophe, which disrupts cell division. Unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. DNA replication stress develops in preneoplastic cells downstream of the activation of oncogenic growth-signaling pathways and contributes to onco- gene-induced senescence. Warnings and Precautions: Myelosuppression: Patients receiving bendamustine are likely to experience myelosuppression. In a randomized CLL clinical study, treated patients experienced grade 3 or 4 neutropenia (24%) and febrile neutropenia (3%); 20% needed red blood cell transfusions, and fewer than 1% needed platelet transfusions. If treatment-related myelosuppression occurs, leukocytes, platelets, hemoglobin (Hb), and neutrophils should be closely monitored. In the study, hemoglobin and the white blood cell differential counts were monitored weekly and platelet counts were monitored during each cycle. Based on data from this study, hematological nadirs should be expected in the third week of therapy and dose delays may be necessary if the recommended values have not recovered by day 28. Before the next cycle of therapy begins, the absolute neutrophil count should be one times 109/L or higher, and the platelet count should be 75 times 109/L or greater. Infection: Infections, including pneumonia and sepsis, have been reported in patients in clinical trials and in postmarketing reports. Infection has been associated with hospitalization, septic shock, and death. Patients who have myelosuppression after treatment with bendamustine are more susceptible to infections, and they should be advised to contact a physician if they have symptoms or signs of infection. Infusion reactions and anaphylaxis: Infusion reactions to bendamustine have been common 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 The author is President of Pharmaceutical and Scientific Services at Marvin M. Goldenberg, LLC, in Westfield, N.J. His e-mail address is marvinmgoldenberg@verizon.net. therapy. Patients should be monitored, and the medication should be discontinued if reactions are severe. Patients should be asked about symptoms that suggest infusion reactions after the first cycle of therapy. In the CLL study, patients who experienced grade 3 or worse allergic-type reactions were not usually re-challenged. Measures to prevent severe reactions, including antihistamines, antipyretic agents, and corticosteroids, should be considered in subsequent cycles for patients who have previously experienced grade 1 or 2 infusion reactions. Discontinuation of bendamustine should be considered in patients with grade 3 or 4 infusion reactions. Tumor lysis syndrome: Bendamustine-associated tumor lysis syndrome has been reported. The onset tends to be within the first treatment cycle. Without intervention, the syndrome can lead to acute renal failure and death. Preventive measures include maintaining adequate volume status; close monitoring of blood chemistry, particularly potassium and uric acid levels; and the use of allopurinol (Zyloprim, Prometheus) during the first one to two weeks of bendamustine therapy in patients at high risk. Skin reactions: Rash, bullous exanthema, and toxic skin reactions have been reported. Because some adverse drug events occurred when bendamustine was given along with other anticancer agents, the precise relationship of these events to bendamustine is uncertain. If skin reactions occur, they may be progressive and may increase in severity with further treatment. If skin reactions are severe or progressive, bendamustine should be withheld or discontinued. Use in pregnancy: Bendamustine can cause fetal harm when given to pregnant women. Single intraperitoneal doses administered during organogenesis caused an increase in resorption, skeletal and visceral malformations, and decreased fetal body weights in mice and rats. Dosage and Administration: Bendamustine HCl is available in a single-use vial containing 100 mg of lyophilized powder. The powder must be reconstituted and diluted further before it is infused. The dosing schedule is 100 mg/m 2 infused intravenously over 30 minutes on days one and two of a 28-day cycle, up to six cycles. For grade 2 non-hematologic toxicity or higher and for grade 4 toxicity, treatment should be delayed. For grade 3 or greater toxicity, the dose should be reduced to 50 mg/m2 on the first and second days. If grade 3 or greater toxicity recurs, the dose should be lowered to 25 mg/m2 on days one and two. For clinically significant grade 3 or greater non-hematological toxicity, the dose should be reduced to 50 mg/m2 on days one and two of each cycle. Dose re-escalation may be considered. Commentar y: CLL is a slowly progressing disease of the blood and bone marrow. The American Cancer Society estimates that more than 15,000 new cases of this rare disease will Vol. 33 No. 5 • May 2008 • P&T® 299
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