On November 20, 2008, the U.S. Food and Drug Administration (FDA) granted accelerated approval for eltrombopag tablets (Promacta, GlaxoSmithKline Inc.) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is an orally-administered thrombopoietin receptor agonist that stimulates bone marrow megakaryocytes to produce platelets. Data supporting this indication were derived from a controlled clinical study of patients treated over a six week period and a single arm extension study treating patients for multiple months. Continuing and recently completed studies will assess the long term safety and clinical benefit of eltrombopag.
The safety and efficacy of eltrombopag were evaluated in two double-blind, placebo-controlled clinical studies of 231 adult patients with chronic ITP who had completed at least one prior ITP therapy and who had baseline platelet counts < 30,000/mcL, including patients who may have undergone splenectomy. In one study, patients were randomized to either placebo or one of three doses of eltrombopag, 30, 50 or 75 mg. In the other study, patients were randomized to either placebo or eltrombopag 50 mg. Eltrombopag and placebo tablets were administered daily for six weeks. Eltrombopag was discontinued if platelet counts exceeded 200,000/mcL. Patients were observed for six weeks following discontinuation of the study drugs.
The primary endpoint in both studies was "response rate," defined as an increase from the baseline platelet count to a count > 50,000/mcL. Eltrombopag 50 mg administration resulted in response rates of 70 and 59% in each study, compared to placebo response rates of 11 and 16% (p < 0.01 for the treatment difference in each study). Eltrombopag response rates were similar irrespective of whether a previous splenectomy had been performed. Overall, seven patients (three in the placebo and four in the eltrombopag groups) underwent hemostatic challenges, such as surgical procedures. Additional ITP medications were required in all placebo patients and none of the eltrombopag patients.
Eltrombopag was administered to 109 patients in an open label, extension study; 74 received the drug for at least three months, 53 for at least six months and three for at least one year. At baseline, the median platelet count was 18,000/mcL. Median platelet counts were 74,000, 67,000 and 95,000/mcL, at three, six and nine month follow-up time points, respectively.
Overall, 313 patients with chronic ITP were exposed to eltrombopag. The clinical studies identified risks for hepatotoxicty, worsened thrombocytopenia (compared to baseline) and hemorrhage following eltrombopag discontinuation, and a risk for cataracts. Potential risks for TPO receptor agonists include bone marrow reticulin formation and marrow fibrosis during long term therapy and a risk for thromboses due to excessive platelet increases.
The risk for hepatotoxicity is cited as a boxed warning. In the controlled clinical studies, one patient experienced grade 4 (NCI Common Terminology Criteria for Adverse Events) elevations in serum liver test values during eltrombopag therapy, worsening of underlying cardiopulmonary disease, and death. No placebo group patients experienced grade 4 liver test abnormalities. Overall, serum liver test abnormalities (predominantly grade 2 or less in severity) were reported in 10 and 8% of the eltrombopag and placebo groups, respectively.
The controlled clinical studies also noted a risk for worsened thrombocytopenia and hemorrhage following eltrombopag discontinuation. Transient platelet count decreases to levels below baseline were observed following study drug discontinuation in 10% of the eltrombopag and 6% of the placebo groups. Serious hemorrhagic events requiring the use of supportive ITP medications occurred in 3 severely thrombocytopenic patients within one month following eltrombopag discontinuation; none were reported within the placebo groups.
In the controlled clinical studies, cataracts developed or worsened in 5% of the patients who received eltrombopag 50 mg daily and 3% of the placebo-group patients. Cataracts were also observed in non-clinical rodent toxicology studies.
The most common adverse reactions that occurred more frequently in the eltrombopag groups compared to the placebo groups consisted of nausea, vomiting, mennorrhagia, myalgia, paresthesia and cataracts. These reactions occurred in 3 to 6% of the eltrombopag patients and were generally mild to moderate severity.
The recommended starting dose of eltrombopag is 50 mg once daily for most patients. For patients of East Asian ancestry or patients with moderate or severe hepatic insufficiency, the starting dose is 25 mg once daily. The eltrombopag dose is adjusted to achieve platelet counts > 50,000/mcL as necessary to reduce the risk for bleeding. Eltrombopag should not be used in an attempt to normalize platelet counts. Only prescribers enrolled in the PROMACTA CARES Program may prescribe eltrombopag.
Full prescribing information, including details of the PROMACTA CARES restricted distribution program, clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at Drugs@FDA
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Date created: November 24, 2008