FDA APPROVALS

Eltrombopag (Promacta) for Treatment of Chronic Idiopathic Thrombocytopenic Purpura

On November 20, the FDA granted accelerated approval and orphan drug designation for eltrombopag 25-mg and 50-mg tablets (Promacta; GlaxoSmithKline), allowing their use for the treatment of chronic immune (idiopathic) thrombocytopenic purpura (ITP) in patients who have demonstrated inadequate response to corticosteroids, immunoglobulins, or splenectomy.

Approval of the thrombopoietin receptor agonist was based primarily on data from 2 pivotal short-term studies and supported by a unanimous decision from the FDA's Oncology Drugs Advisory Committee regarding the favorable nature of risk-benefit profile of eltrombopag in short-term therapy.

In the studies, patients who had completed at least 1 previous regimen of ITP therapy and who had a platelet count of less than 30 x 10⁹/L were randomly assigned to either daily placebo or eltrombopag administered for a maximal treatment period of 6 weeks, followed by 6 weeks off therapy. Treatment was discontinued if platelet counts exceeded 200 x 10⁹/L.

Results showed that eltrombopag 50 mg/day was significantly more effective vs placebo to achieve platelet count response, defined as a shift from a baseline of less than 30 x 10⁹/L to a level of 50 x 10⁹/L or more at any time during the treatment period (study 1, 59% vs 16%; study 2, 70% vs 11%; P < .001 for both).

The platelet count response to eltrombopag was similar between patients who had undergone a splenectomy and those who had not; in general, increases in platelet count were detected after 1 week of treatment and were highest after 2 weeks of therapy. Discontinuation of treatment because of increased platelet counts (> 200 x 10⁹/L) occurred in 27% of eltrombopag-treated patients and in 3% of those given placebo.

Eltrombopag therapy should be initiated at a dose of 50 mg once daily, except in patients of East Asian ancestry or in those who have moderate to severe hepatic impairment. For these patients, the recommended starting dose is 25 mg once daily.

Clinical hematologic and liver tests should be monitored regularly throughout therapy. Dosing should be adjusted to achieve and maintain a platelet count of 50 x 10⁹/L as necessary to reduce the risk for bleeding, but should not exceed 75 mg daily.

In the studies, hemorrhage was the most common serious adverse reaction, with most cases occurring after discontinuation of eltrombopag. Other serious events included liver test abnormalities and thrombotic or thromboembolic complications.

Because of these risks, eltrombopag will only be available through a restricted distribution program called Promacta CARES, which has been developed as part of a risk evaluation and mitigation strategy that will also provide patient support and education and assist with safety data collection.

Bendamustine (Treanda) Approved for Refractory Indolent B-Cell NHL

On October 31, the FDA approved a new indication for bendamustine HCl intravenous infusion (Treanda; Cephalon, Inc [under license from Astellas Deutschland GmbH]), allowing its use for the treatment of indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Bendamustine consists of an alkylating group and a benzimidazole component. Although its mechanism of action remains unclear, the agent can cause the death of cancer cells via several pathways including DNA damage (leading to apoptosis) and disruption of normal cell division (mitotic catastrophe).

Approval of the NHL indication was based on a data from a pivotal study (n = 100), showing that the overall response rate to bendamustine therapy was 74% (95% confidence interval [CI], 64.3% - 82.3%); 13% of patients achieved a complete response. Median response duration was 9.2 months (95% CI, 7.1 - 10.8 months).

In the study, the most commonly reported hematologic adverse events (incidence, > 15%) were lymphopenia, leukopenia, anemia, thrombocytopenia, and neutropenia. Nonhematologic events included nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decrease, dyspnea, rash, and stomatitis.

The recommended dose of bendamustine in NHL is 120 mg/m² infused intravenously for 60 minutes on days 1 and 2 of a 21-day cycle, for up to 8 cycles. Dose delays are recommended for grade 4 hematologic toxicity or clinically significant nonhematologic toxicities of grade 2 or higher; dose reductions to 60 mg/m² are recommended for grade 4 hematologic toxicities, or grade 3 or higher nonhematologic toxicities.

Bendamustine previously was approved by the FDA for the treatment of chronic lymphocytic leukemia.