Pharmacy & Therapeutics - January 2009 - (Page 28) Pharmaceutical Approval Update divided doses. The dose should be increased by increments of approximately 10 mg/kg every other day to a target dose of 45 mg/kg per day or 3,200 mg/day, whichever is less, in two equally divided doses. It is not known whether doses lower than the target doses are effective. Adults with Lennox–Gastaut syndrome: Treatment is initiated at a daily dose of 400 to 800 mg/day, taken in two equally divided doses. The dose should be increased by 400 to 800 mg/day every two days until a maximum daily dose of 3,200 mg/day, taken in two equally divided doses, is reached. It is not known whether doses lower than 3,200 mg are effective. Patients with renal impairment. Renally impaired patients (with a CrCl below 30 mL/minute) do not require any dose adjustments. Patients undergoing hemodialysis. Hemodialysis may reduce exposure to a limited extent (about 30%). Accordingly, adjusting the rufinamide dose during the dialysis process can be considered. Patients with hepatic disease. The use of rufinamide in patients with hepatic impairment has not been studied, and it is therefore not recommended for patients with severe hepatic impairment. Caution should be exercised in treating patients with mild-to-moderate hepatic impairment. Commentar y: Lennox–Gastaut syndrome is a difficult-totreat form of childhood-onset epilepsy. Seizures usually start between two and five years of age but may also start before age two. Seizures may be tonic, atonic, atypical absence, and myoclonic. Most affected children experience impaired intellectual functioning or information processing along with developmental delays and behavioral disturbances. Severe myoclonic epilepsy in infancy is considered a chronically debilitating condition. From 1,400 to 4,500 new cases of the syndrome are diagnosed each year in the U.S. Complete recovery is unusual, and there is no known cure. In clinical trials, rufinamide reduced the frequency and types of seizures. Patients seemed to tolerate the drug well, but it is not clear whether these results will ultimately change prognosis. Treated patients experienced a 32.7% median reduction in total seizure frequency per 28 days relative to baseline, compared with an 11.7% median decrease with placebo. There was a 42.5% median reduction in the frequency of tonic–atonic seizures per 28 days relative to the baseline in the rufinamide group, compared with a 1.4% median increase for the placebo group. A significantly higher percentage of the rufinamide patients (42.5%) responded to treatment, compared with placebo patients (16.7%), experiencing a reduction of 50% or more in the frequency of tonic–atonic seizures, a secondary endpoint of the study. Frequently reported adverse drug events included somnolence, fever, vomiting, and diarrhea. Sources: www.eisai.com; www.emea.europa.com; www. redorbit.com insufficient response to corticosteroids, immunoglobulins, or splenectomy. This drug should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk of bleeding. Eltrombopag should not be used in an attempt to normalize platelet counts. Drug Class: Eltrombopag is a nonpeptide thrombopoietin receptor agonist. Uniqueness of Drug: As an oral, once-daily agent, eltrombopag is designed to stimulate the proliferation and differentiation of megakaryocytes (bone marrow cells that give rise to blood platelets). Boxed Warning: Eltrombopag may cause hepatotoxicity. Serum levels of aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be measured before therapy begins, every two weeks during the dose-adjustment phase, and monthly after a stable dose is established. If bilirubin is elevated, fractionation is performed. Abnormal serum liver tests are evaluated with more testing within three to five days. If the abnormalities are confirmed, liver function tests are monitored weekly until the abnormalities resolve, stabilize, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase to more than three times the upper limit of normal (ULN) and if they are progressive, persist for four weeks or more, or are accompanied by increased direct bilirubin or by clinical symptoms of liver injury or evidence of hepatic decompensation. Warnings and Precautions: Increased levels of serum ALT, AST, and bilirubin have been observed. Liver chemistries must be measured before therapy begins and regularly during treatment. Caution is needed for patients with hepatic impairment. Eltrombopag may increase the risk of development of or progression of reticulin fiber deposition within bone marrow. Peripheral blood should be monitored for signs of marrow fibrosis. Discontinuation of therapy may result in worsened thrombocytopenia than was present before therapy. Complete blood counts (CBCs), including platelet counts, should be monitored for at least four weeks after discontinuation. Excessive doses of this agent may increase platelet counts to a level that produces thrombotic or thromboembolic complications. Eltrombopag may increase the risk of hematological malignancies, especially in patients with myelodysplastic syndrome. CBCs, platelet counts, and peripheral blood smears should be monitored weekly during the dose-adjustment phase and then monthly after a stable dose is established. Because of the risk for hepatotoxicity, eltrombopag is available only through a restricted distribution program called Promacta Cares. Prescribers, pharmacies, and patients, respectively, must be registered to be able to prescribe, dispense, and receive eltrombopag. Risk of hepatotoxicity. In controlled clinical studies, one patient experienced grade 4 elevations in serum liver test values during therapy, worsening of underlying cardiopulmonary disease, and death. No placebo patients experienced grade 4 liver test abnormalities. Overall, serum liver test abnormalities (predominantly grade 2 or less in severity) were reported in 10% of the eltrombopag patients and in 8% of the placebo groups. In the controlled studies, two treated patients (1%) and Eltrombopag (Promacta) Tablets Manufacturer: GlaxoSmithKline, Research Triangle Park, N.C. Indication: Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an 28 P&T® • January 2009 • Vol. 34 No. 1 http://www.eisai.com http://www.emea.europa.eu/ http://www.redorbit.com http://www.redorbit.com
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