December 2012, Vol 4 No 1
Stakeholder’s Perspective: Pharmacy Considerations
Since the approval of bendamustine, healthcare practitioners have additional treatment options available to patients with specific hematologic malignancies. In the United States, bendamustine was approved for patients with chronic lymphocytic leukemia (CLL) or indolent B-cell non-Hodgkin lymphoma (NHL) who had progressed within 6 months of receiving rituximab-containing regimens. In Europe, bendamustine has also been approved for use in the CLL and NHL populations, and in some countries it has additional approval for use in multiple myeloma (MM) patients in combination with prednisone when other treatments such as autologous transplant or bortezomib are not appropriate options. In addition to its approved uses, bendamustine is being studied in multiple clinical trials as monotherapy or in combination in patients with relapsed or refractory Hodgkin lymphoma, MM, CLL, and as initial therapy in combination in patients with diffuse large B-cell lymphoma.1
Although bendamustine has been approved for use in the United States and Europe for only a short period, it has been under investigation for more than 40 years. Structurally, bendamustine has similarities to both alkylating agents and purine analogs, while maintaining an acceptable side effect profile. The structure contains an alkylating group, a benzimidazole ring, and butyric acid side chain. It has been suggested that the benzimidazole ring, which is unique to bendamustine, contributes to its distinct activity.2 Even though the chemical structure has many similarities to other agents, the mechanism of action of bendamustine has not yet been fully elucidated. The benzimidazole ring is thought to provide stability and accounts for the sustained toxic effects to the DNA, as well as the blunted DNA repair when compared with other alkylating agents. Despite maintaining activity in more resistant malignancies, bendamustine remains reasonably well tolerated. Hematologic side effects are common. Neutropenia, thrombocytopenia, and anemia have been reported to occur in more than 15% of patients.3 Common nonhematologic toxicities include nausea, vomiting, diarrhea, fatigue, and fever. As with other alkylating agents, secondary malignancies have been reported, but an association with this agent has yet to be determined.
Drug reconstitution and dilution is straightforward and does not require excessive manipulation or specific tubing. In the United States, bendamustine is available in 25- and 100-mg vials that must be reconstituted with sterile water for injection, resulting in a 5-mg/mL solution. This is then further diluted with 0.9% sodium chloride or 2.5% dextrose and 0.45% sodium chloride solution, with a final concentration of bendamustine between 0.2 and 0.6 mg/mL.
Bendamustine does not contain an antimicrobial preservative, so it should be used as soon as possible once it has been reconstituted and further diluted. However, the diluted admixture is stable for 3 hours at room temperature and for 24 hours when refrigerated.3 Since bendamustine is not cell cycle specific, it may be administered as short infusions. Bendamustine is infused over a 30- or 60-minute duration depending on the dose and indication. Infusion-related toxicities have been reported. Caution should be used when infusing bendamustine, as extravasations of this agent have been reported to cause pain, redness, and swelling.3
The pharmacokinetic properties of bendamustine have been well described. Despite good oral bioavailability, bendamustine has only been studied in its IV formulation. This agent is highly protein bound, with over 90% of the drug binding to serum plasma proteins. This binding is not affected by lower levels of serum albumin or advancing age.4
Bendamustine is metabolized primarily though hydrolysis in the liver into 2 minor active metabolites. The elimination half-life of the parent compound has been reported to be relatively short at 40 minutes. Few drug interactions have been associated with bendamustine. Theoretical drug interactions include concomitant use with strong CYP1A2 agents such as ciprofloxacin or fluvoxamine. These inhibitors could increase the concentrations of bendamustine while decreasing the levels of the minor metabolites. The clinical significance of these potential interactions remains unclear.
Bendamustine provides another option of therapy for patients with specific hematologic malignancies, with a unique mechanism of action, predictable pharmacokinetic profile, and tolerable toxicity profile.
- ClinicalTrials.gov. www.clinicaltrials.gov. Accessed November 5, 2012.
- 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.
- Treanda [prescribing information]. Cephalon, Inc: Frazer, PA; Revised 8/2012.
- Barman Balfour JA, Goa KL. Bendamustine. Drugs. 2001;61:631-638.
Bendamustine has an interesting history that spans more than 50 years. Bendamustine was first synthesized in the early 1960s in the former East Germany. It was first used to treat multiple myeloma and was subsequently extended to patients with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. Unfortunately, [ Read More ]
This is the first article in a 4-part series on bendamustine. This article describes the history and characterization of bendamustine. Subsequent articles will discuss the efficacy and safety of bendamustine in registration studies and describe ongoing clinical investigations of bendamustine. Bendamustine is a bifunctional chemotherapeutic agent with both alkylating and [ Read More ]