Pharmacy & Therapeutics - February 2009 - (Page 75)

DRUG FORECAST skin reactions have been reported.17,26 Patients may also experience infusion reactions, including chills, fever, and pruritus. In rare cases, severe anaphylactic and anaphylactoid reactions may occur during subsequent cycles of therapy. Bendamustine has also been associated with other serious adverse events, such as pneumonia (2%), sepsis (in fewer than 1%), and tumor lysis syndrome (2%).17,26 Laboratory abnormalities are common in patients receiving bendamustine and primarily involve hematological parameters that reflect myelosuppression. Decreased levels of hemoglobin (89%), platelets (77%), neutrophils (75%), lymphocytes (68%), and leukocytes (671%) are common. In addition, hyperbilirubinemia (34%) and increased serum creatinine (31%) have been reported.17,26 DOSAGE AND ADMINISTRATION Bendamustine is supplied as a lyophilized powder that must be reconstituted with sterile water and diluted with normal saline prior to infusion. After bendamustine is diluted, it is stable for three hours at room temperature or for 24 hours when it is refrigerated; the medication should be administered during this time frame. Bendamustine is available in singleuse 100-mg vials (bendamustine 100 mg plus mannitol 170 mg). It is recommended that a dose of 100 mg/m2 as an IV infusion be given over 30 minutes on days 1 and 2 of a 28-day cycle for up to six cycles. Coadministration of allopurinol (Zyloprim, Faro; Aloprim, Bioniche) should be considered as a preventive measure in patients at high risk for the development of tumor lysis syndrome. The use of antihistamines and corticosteroids should also be considered for patients who are susceptible to grade 1 or 2 infusion reactions.17 In the event of toxicity, dosing modifications should be made. Subsequent cycles of bendamustine should be delayed in patients who experience grade 4 hematological toxicity or grade 2 or higher nonhematological toxicity until blood counts have increased (an absolute neutrophil count of one or more times 109/L, platelets ≥ 75 or more times 109/L) or until toxicity has ben reduced to grade 1 or below. Bendamustine therapy should be reinitiated at a reduced dose of 50 mg/m2 on days 1 and 2 for subsequent cycles in patients who experienced grade 3 toxicity or higher. The dose should be further reduced to 25 mg/m2 if grade 3 toxicity or higher recurs. Re-escalation of the bendamustine dose may be considered.17 feeding unless the benefits of bendamustine therapy outweigh risks to the infant.17 COST The average wholesale price (AWP) of bendamustine is $4,320 per dose. The AWP for one treatment cycle is $8,640. By contrast, the AWP of chlorambucil is $75 per dose, or $151 per treatment cycle.27 CONCLUSION Bendamustine is a new alternative for the treatment of patients with CLL. Therapy may be useful in patients with refractor y disease or in patients who show resistance to other chemotherapeutic regimens. Myelosuppression and gastrointestinal tract–related events are commonly associated with bendamustine therapy. The drug demonstrates only partial cross-resistance with other alkylating agents and has shown superior overall response and progression-free survival rates over chlorambucil for the treatment of CLL.15 Similar overall response and progression-free survival rates have been observed between cyclophosphamide and bendamustine regimens in patients with NHL.22 With the FDA’s most recent approval of bendamustine for the treatment of rituximab-resistant, indolent B-cell NHL in late 2008, the drug is likely to be a valuable option for these patients. DRUG INTERACTIONS AND CONTRAINDICATIONS Bendamustine is metabolized by the CYP P450 1A2 enzyme. Coadministration of bendamustine with CYP 1A2 inhibitors, such as ciprofloxacin (Cipro, Bayer) or fluvoxamine (Luvox, Solvay), would increase bendamustine serum levels and decrease the concentration of its active metabolites. Conversely, inducers of CYP 1A, such as smoking, would lead to an increase the serum level of active metabolites. Bendamustine is not likely to inhibit the activity of CYP 450 enzymes or to interfere with metabolism of their substrates.17,26 Contraindications include a known hypersensitivity to mannitol or bendamustine. Patients should be closely monitored for reactions or symptoms during the first cycle of therapy. Therapy should be discontinued if severe re actions occur.17 Because studies examining the effect of renal and hepatic impairment are limited, bendamustine should be used with caution in patients with mild renal or hepatic impairment. Bendamustine is not recommended for patients with severe renal impairment (a CrCl below 40 mL/minute), with moderate hepatic impairment (AST or ALT levels 2.5 to 10 times the ULN, or with total bilirubin levels 1.3 to three times the ULN) or in patients with severe hepatic impairment (total bilirubin levels above three times the ULN). The use of bendamustine in pediatric patients has not been evaluated.15,17 REFERENCES 1. American Cancer Society. Detailed guide: leukemia–chronic lymphocytic (CLL): What are the key statistics about chronic lymphocytic leukemia? Available at: www. cancer.org. Accessed October 2008. 2. Bergmann MA, Goebeler ME, Herold M, et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: Results of a phase I/II study of the German CLL Study Group. Haematologica 2005;90(10):1357–1364. 3. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximabrefractory indolent and transformed nonHodgkin’s lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 2008;26(2):204–210. 4. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol 2005;23(15):3383–3389. 5. Knop S, Straka C, Haen M, et al. The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high- PREGNANCY Bendamustine is classified as a Pregnancy Category D medication. In studies of rodents, the administration of single intraperitoneal doses during organogenesis resulted in decreased fetal body weights and increased malformations and resorption. Women of childbearing age should consider taking precautions for birth control while receiving bendamustine. No data are available as to whether the drug is excreted in human milk, but mothers should avoid breast- Vol. 34 No. 2 • February 2009 • P&T® 75 http://www.cancer.org http://www.cancer.org

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Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

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