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Drug Therapy New Treatments for Chronic Idiopathic Thrombocytopenic... Continued from page 22 Table 2. Adverse Events Associated with the Use of Eltrombopag Eltrombopag 50 mg (n = 106)
Placebo (n = 67)
n (%)
n (%)
Headache
9 (8)
10 (15)
Nausea
6 (6)
2 (4)
Vomiting
4 (4)
2 (3)
Diarrhea
4 (4)
3 (4)
Myalgia
3 (3)
1 (1)
Constipation
2 (2)
2 (3)
Increased ALT
2 (2)
0
Increased AST
2 (2)
0
Arthralgia
2 (2)
4 (6)
Event
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. Sources: References 8 and 9.
treatments for ITP had to be discontinued at least 2 weeks before enrollment. In the 109 patients evaluated for efficacy data, the primary end point (platelets ≥50 ¥ 109/L on day 43) was achieved in 11%, 28%, 70%, and 81% in the placebo, 30-mg, 50-mg, and 75mg groups, respectively. By day 15 of therapy, more than 80% of patients in the 50-mg and 75-mg groups had reached platelet counts ≥50 ¥ 109/L. Platelet counts rose to ≥200 ¥ 109/L in 28 patients (26%), at which time eltrombopag was discontinued. After cessation of therapy, platelet counts returned to near baseline levels within 2 weeks. The incidence of bleeding also decreased as platelet counts increased, particularly in the patients receiving the 50-mg and 75mg doses of eltrombopag.8 A phase 3 trial was conducted as a follow-up to assess the efficacy, safety, and tolerability of eltrombopag 50 mg orally once per day compared with placebo. Inclusion criteria were similar in the two studies. The 114 patients enrolled were randomized 2:1 to eltrombopag therapy for up to 6 weeks or placebo. Eltrombopag could be increased to 75 mg daily after 3 weeks if platelet counts had not reached 50 ¥ 109/L. The primary end point (platelets ≥50 ¥ 109/L after 6 weeks of therapy) was reached by more patients in the eltrombopag arm than the placebo arm (59% vs 16%, P <.0001). Of the 34 patients who received a dose increase to 75 mg, 29% met the primary end point; however, none of these patients reached platelet counts ≥200 ¥ 109/L. Prior history of splenectomy, concomitant drugs for ITP, or baseline platelet count ≤15 ¥ 109/L did not have a significant effect on response rates to eltrombopag compared with placebo. As is the goal in the treatment of ITP, a significant reduction in bleeding symptoms was seen in the treatment group compared with the
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June 2010 I VOL 3, nO 4
placebo group (39% vs 60%, P = .029). As seen in the phase 2 trial, platelet counts returned to baseline following discontinuation of eltrombopag, as did the risk for bleeding complications.9 Dosing, administration, and toxicity Eltrombopag should be started at a dose of 50 mg orally once per day on an empty stomach (1 hour before or 2 hours after a meal) and should be separated by at least 4 hours from antacids, calcium-rich food, and supplements containing polyvalent cations (iron, calcium, magnesium, aluminum, selenium, and zinc).7 Patients of East-Asian decent (Chinese, Japanese, Korean, and Taiwanese) should be started at 25 mg orally daily because of pharmacokinetic data showing this population had a 70% increased exposure compared with nonAsian subjects. Moderate to severe hepatic impairment (as determined by Child-Pugh criteria) will require dose reduction of eltrombopag to 25 mg orally once per day. The lowest dose of eltrombopag should be used to maintain a platelet count >50 ¥ 109/L. Dose adjustments and monitoring parameters can be found in Table 1. Because eltrombopag is metabolized by cytochrome P450 (CYP) 1A2, CYP2C8, and several uridine diphosphate-glucuronosyltransferases, patients receiving concomitant therapy with moderate or strong inhibitors of these metabolizers and eltrombopag should be monitored closely for signs and symptoms of excessive eltrombopag exposure. In vitro studies also show that eltrombopag is an inhibitor of the organic anion transporting polypeptide 1B1 and can increase systemic exposure to drugs that use this transport system, such as atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateflinide, repaglinide, and rifampin. Although no specific dose reductions
have been given, caution should be used with administering these drugs concomitantly.7 The most common adverse effects associated with eltrombopag use were headache, nausea, vomiting, and diarrhea. Adverse events associated with the 50-mg dose of eltrombopag combined from the two randomized studies are summarized in Table 2. The incidence of grade 3/4 adverse events during treatment in both studies was similar for patients receiving eltrombopag and placebo, 11 (7%) versus five (7%).8,9 Reticulin fiber deposition, without cytopenias, was reported in the bone marrow biopsies of seven patients. This observation prompted the manufacturer to warn prescribers to monitor patients closely by examining peripheral blood smears and to discontinue therapy if the patient develops new or worsening morphologic abnormalities or cytopenias.7 Thrombotic complications have also been observed in patients receiving eltrombopag and are likely a result of excessive increases in platelet counts. Distribution program Promacta Cares is a restricted distribution program that was designed to promote risk-benefit decisions before eltrombopag is dispensed to patients as well as to require prescribers to report baseline and periodic safety information for each patient enrolled. Before distribution of eltrombopag, each prescriber must complete a one-time enrollment form, which can be found on the Promacta Cares website.10 In addition, a completed enrollment form and patient baseline form must be sent in for each patient before the patient can receive the medication. Twice yearly, a consultant from Promacta Cares will contact the prescriber to collect safety information, verify the patient is still receiving eltrombopag, and verify whether the patient should continue therapy. To help establish long-term data regarding safety and use, registered prescribers must report any adverse events to the program. In particular, the risk for hepatotoxicity, bone marrow reticulin formation and fibrosis, worsened thrombocytopenia upon cessation of therapy leading to serious hemorrhage, thromboembolic/thrombotic complications, and increased risk or progression of hematologic malignancies are the focus of the registry program. In addition to proper counseling regarding the use and side effects of eltrombopag, a mandatory medication guide must be distributed to each patient and can be found on the Promacta Cares website.10 Conclusion With up to 10% of ITP patients
developing refractory disease, the need for agents to reduce mortality from bleeding complications in this population has encouraged many researchers to delve into new mechanisms in the pathogenesis of ITP. Second-generation thrombopoiesis-stimulating agents were developed to provide an additional mechanism of increasing platelets by stimulating the production of platelets in the bloodstream. Eltrombopag has shown substantial efficacy in maintaining platelets above 50 ¥ 109/L in patients with chronic ITP in two randomized controlled trials. Its long-term efficacy has not been established, however, as the duration of these trials was only 6 weeks. Several ongoing studies are looking at long-term use of eltrombopag in patients with chronic ITP. Preliminary data from the Eltrombopag Extended Dosing Study (EXTEND) have shown that 73% of patients with baseline platelets <30 ¥ 109/L achieved platelet counts ≥50 ¥ 109/L during a median treatment duration of 151 days, and the adverse event profile was similar to that in previous studies.11 The study also seeks to determine whether tapering of concomitant medications for ITP will maintain platelet counts while on eltrombopag, thus allowing patients to receive less corticosteroid therapy. Based on these favorable re sults, the use of eltrombopag and romiplostim is currently being studied in other disease states causing thrombocytopenia, including myelodysplastic syndrome and chemotherapy-induced thrombocytopenia.12-14 Continued re search in the use of thrombopoiesisstimulating agents may identify which patients are more likely to respond to these therapies as well as determine whether these agents should be used as frontline therapy. ● References 1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:9951008. 2. Cines DB, McMillan R. Pathogenesis of chronic thrombocytopenia purpura. Curr Opin Hematol. 2007;14:511-514. 3. Godeau B, Provan D, Bussel J. Immune thrombocytopenic purpura in adults. Curr Opin Hematol. 2007;14:535-556. 4. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623-2634. 5. Porcelijn L, Folman CC, Bossers B, et al. The diagnostic value or thrombopoietin level measurements in thrombocytopenia. Thomb Haemost. 1998;79:1101-1105. 6. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-3248. 7. Promacta (eltrombopag) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
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