Pharmacy & Therapeutics - January 2009 - (Page 29) Pharmaceutical Approval Update two placebo patients (3%) discontinued treatment because of hepatobiliary laboratory abnormalities. In the extension study, seven treated patients with hepatobiliary laboratory abnormalities were re-exposed to eltrombopag. Six of these patients again experienced liver test abnormalities (mostly grade 1), resulting in discontinuation of therapy in one patient. In the extension study, one additional patient discontinued eltrombopag because of liver test abnormalities (grade 3 or lower). ALT, AST, and bilirubin should be measured before therapy begins, every two weeks during the dose-adjustment phase, and monthly after the establishment of a stable dose. If serum liver test results are abnormal, the test is repeated within three to five days. If the abnormalities are confirmed, serum liver tests are monitored weekly until the abnormality resolves, stabilizes, or returns to baseline levels. Eltrombopag should be discontinued if ALT levels increase to more than three times the ULN, are progressive, persist for four weeks or more, and are accompanied by increased direct bilirubin or by symptoms of liver injury or evidence of hepatic decompensation. Re-initiating treatment with eltrombopag is not recommended, but if the potential benefit is considered to outweigh the risk for hepatotoxicity, the drug can be cautiously re-introduced. Serum liver tests should be measured weekly during the dose-adjustment phase. If liver tests abnormalities persist, worsen or recur, eltrombopag should be permanently discontinued. A lower starting dose is used in patients with moderate-tosevere hepatic disease. Bone marrow reticulin formation and risk of bone marrow fibrosis. Thrombopoietin receptor agonists increase the risk for development of or progression of reticulin fiber deposition in bone marrow. In the extension study, seven patients undergoing bone marrow biopsies had reticulin fiber, including two patients who also had collagen fiber deposition. The fiber deposition was not associated with cytopenias and did not necessitate discontinuation of eltrombopag. However, clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias. Before therapy begins, the peripheral blood smear should be closely examined to establish a baseline level of cellular morphological abnormalities. After a stable dose of eltrombopag has been identified, peripheral blood smears and CBCs are examined monthly to check for new or worsening morphological abnormalities, such as teardrop and nucleated red blood cells, immature white blood cells, or cytopenia. If new or worsening morphological abnormalities or cytopenia develops, treatment is discontinued, and a bone marrow biopsy, including staining for fibrosis, should be considered. Worsened thrombocytopenia and risk of hemorrhage after cessation of therapy. Discontinuing eltrombopag may result in thrombocytopenia of a greater severity than that which was present before therapy. This worsened thrombocytopenia may increase the risk of bleeding, particularly if the drug is discontinued while the patient is taking anticoagulants or antiplatelet agents. In controlled studies, transient decreases in platelet counts to levels lower than baseline were observed after treatment was discontinued in 10% of the eltrombopag patients and in 6% of the placebo patients. Serious hemorrhagic events requiring the use of supportive ITP medications occurred in three severely thrombocytopenic patients within one month after the drug was stopped; no events were reported in the placebo group. After discontination, weekly CBCs, including platelet counts for at least four weeks, are obtained. Alternative treatments for worsening thrombocytopenia should be considered. Thrombotic and thromboembolic complications. Complications can result from excessive increases in platelet counts. Excessive doses of eltrombopag, or medication errors that result in excessive doses of eltrombopag, may increase platelet counts to a level that produces thromboses or thromboembolism. In controlled studies, one such complication was reported in patients who received eltrombopag but none were observed within the placebo groups. In the extension study, seven patients experienced complications. Caution should be used for patients with known risk factors for thromboembolism, such as factor V Leiden and antiphospholipid syndrome. To minimize the risk of thrombotic or thromboembolic complications, eltrombopag should not be used in an attempt to normalize platelet counts. The doseadjustment guidelines should be followed to achieve and maintain a platelet count of 50 × 109/L or higher. Malignancies. Eltrombopag’s stimulation of the thrombopoietin receptor on the surface of hematopoietic cells may increase the risk of hematological malignancies. In clinical studies, no hematological malignancies were reported for patients receiving eltrombopag for a maximum of six weeks. One hematological malignancy (non-Hodgkin’s lymphoma) was reported in the extension study. Eltrombopag is not indicated for the treatment of thrombocytopenia resulting from etiologic factors (e.g., myelodysplasia or chemotherapy) other than chronic ITP. Cataracts. In controlled studies, cataracts developed or worsened in five patients (5%) who received 50 mg of eltrombopag daily and two placebo patients (3%). In the extension study, cataracts developed or worsened in 4% of patients who underwent an eye examination before receiving eltrombopag. Cataracts were also observed in studies of eltrombopag in rodents. A baseline ocular examination should be performed before therapy begins, and patients should be monitored during therapy for signs and symptoms of cataracts. Dosage and Administration: Only health care providers who have enrolled in the Promacta Cares Program may prescribe eltrombopag. The 25-mg tablets are round, biconvex, and orange; each tablet contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. The 50-mg tablets are round, biconvex, and blue; each tablet contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid. Eltrombopag is initiated at a dose of 50 mg once daily. For patients of East Asian ancestr y or those with moderateto-severe hepatic impairment, the dose should be reduced to 25 mg once daily. The lowest possible dose should be used to achieve and maintain a platelet count of 50 × 109/L or more to reduce the risk of bleeding. Eltrombopag should not be used in an attempt to normalize platelet counts. continued on page 50 Vol. 34 No. 1 • January 2009 • P&T® 29
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