Pharmacy & Therapeutics - November 2008 - (Page 646)

References: 1. Data on ﬁle. Cephalon, Inc. 2. Hirschberg E, Gellhorn A, Gump WS. Laboratory evaluation of a new nitrogen mustard, 2-[Di-(2-chloroethyl)aminomethyl]benzimidazole, and of other 2-chloroethyl compounds. Cancer Res. 1957;17(9):904-910. 3. Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008;14:309-317. 4. Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anti-cancer Drugs. 1996;7:415-421. 5. Schwänen C, Hecker T, Hübinger G, et al. In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia. Leukemia. 2002;16:2096-2105. TREANDA® (bendamustine hydrochloride) for Injection Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA® (bendamustine hydrochloride) for Injection is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the randomized CLL clinical study, patients receiving TREANDA experienced Grade 3 or 4 neutropenia (24%), febrile neutropenia (3%), red blood cell transfusions (20%), and platelet transfusions (< 1%). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the randomized CLL clinical study hemoglobin and WBC differential counts were monitored weekly and platelet counts were monitored each cycle. Based on data from this study, hematologic nadirs should be expected in the third week of therapy and may require dose delays if recovery to the recommended values have not occurred by day 28. 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. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA 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. Patients should be asked 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 in the randomized CLL clinical study. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. 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 maintaining adequate volume status, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of allopurinol during the first one to two weeks of TREANDA therapy in patients at high risk. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled 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. 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. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label. Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were neutropenia (28%), thrombocytopenia (23%), anemia (19%), and leukopenia (18%). 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 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: Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 136 (89) 88 (58) 113 (79) 44 (31) Blood and lymphatic system disorders Neutropenia 43 (28) 36 (24) 20 (14) 13 (9) Thrombocytopenia 35 (23) 20 (13) 28 (20) 11 (8) Anemia 29 (19) 4 (3) 16 (11) 0 Leukopenia 28 (18) 23 (15) 4 (3) 2 (1) Lymphopenia 10 (7) 10 (7) 0 0 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 Table 1: Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Respiratory, thoracic and mediastinal disorders Cough 6 (4) Skin and subcutaneous tissue disorders Rash 12 (8) Pruritus 8 (5) 1 (<1) 4 (3) 0 7 (5) 7 (5) 2 (1) 1 (<1) 3 (2) 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 TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) Laboratory Abnormality All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) 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 clinical study, 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

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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