Med Check

Aripiprazole gained FDA approval last month for“ maintaining efficacy” in patients with bipolar I disorder who have experienced a recent manic or mixed episode. The next-generation antipsychotic has already been approved for treatment of schizophrenia and acute mania. Clinical data demonstrated that the drug significantly delayed time to relapse. The approval was based on a double-blind, randomized, controlled trial in which 161 patients who had been stabilized on aripiprazole for at least six weeks were followed to monitor relapse to either mania or depression. Of those who experienced a relapse during follow-up, patients taking the drug relapsed significantly later than those taking placebo. In addition, fewer patients taking aripiprazole relapsed, compared with patients on placebo. Commonly observed adverse events in all aripiprazole clinical trials include akathisia, constipation, and accidental injury. Headache, agitation, anxiety, nervousness, insomnia, nausea, somnolence, light-headedness, and vomiting have also been observed.

Escitalopram has received a “nonapprovable” letter from the FDA for treatment of panic disorder. The March 1 letter was the second thumbs down the agency has given to the use of the highly selective SSRI for that indication. In August 2004 the agency issued its first nonapprovable letter, citing “issues related to methods and statistical analysis performed” for the two clinical trials Forest Labs had submitted. The company had filed a response to that initial determination, and the second nonapprovable letter reflects the agency's unfavorable review of the company's response. Forest said in a prepared statement that it “is currently reviewing the FDA's response to determine the appropriate action.” Escitalopram carries indications for major depression and generalized anxiety disorder.

Duloxetine will not be approved for the treatment of stress urinary incontinence (SUI) in the U.S. Eli Lilly and Co. and Boehringer Ingelheim jointly announced Lilly's withdrawal of its application for approval for the treatment of SUI. The serotonin-norepinephrine dual reuptake inhibitor was approved last year by the U.S. and the European Commission for the treatment of major depression and approved in the U.S. for the treatment of diabetic peripheral neuropathic pain.

A company statement noted the decision was based on discussions with the FDA in which the agency made it clear that it was “not prepared at this time to grant approval” for the SUI indication, based on the patient data submitted. However, it is not clear whether the agency's concerns related to efficacy or safety. Lilly and Boehringer noted they will explore all options and that clinical trials with SUI patients would continue. Duloxetine is marketed as Yentreve in 27 countries for the treatment of SUI.

Separately, the two companies announced that the Committee for Medicinal Products for Human Use of the European Medicines Agency had issued a positive opinion recommending the approval of duloxetine for the treatment of diabetic peripheral neuropathic pain. If the European Commission accepts the recommendation for approval, the drug would be approved for all three indications—depression, SUI and DPNP—in the 25 European Union countries.

GlaxoSmithKline's paroxetine–controlled release may be difficult to come by in the next few months. Unsatisfied with the company's efforts to alleviate long-standing manufacturing concerns involving the controlled-release SSRI, the FDA and the Department of Justice ordered U.S. marshals to seize thousands of bottles of the drug from three GSK facilities, two in Puerto Rico and one in Knoxville, Tenn. An FDA talk paper said the manufacturing problem allowed Paxil CR tablets to split apart, “and patients could receive a portion of the tablet that lacks any active ingredient, or alternatively that contains active ingredient that does not have the intended controlled-release effect.”

Methylphenidate may be linked to an increased risk of cytogenetic abnormalities in children at commonly used doses. In a small study of 12 children (average age 8.2 years) treated with therapeutic doses (20mg/day to 54mg/day) of methylphenidate, researchers examined three cytogenetic endpoints in peripheral blood lymphocytes, obtained before and three months after initiation of drug therapy. In all 12 children, treatment was associated with significantly increased frequencies of chromosome aberrations (three-fold increase), sister chromatid exchanges (4.3-fold increase), and micronuclei (2.4-fold increase).

Although no association between methylphenidate and increased cancer has been noted in the nearly 50 years the drug has been marketed, the study's authors said the findings “warrant further investigations... especially in view of the well-documented relationship between elevated frequencies of chromosome abnormalities and increased cancer risk.” They acknowledged, however, that one small study is not a reason to stop treatment in children who are otherwise responding well.

Cancer Lett 2005. The article can be accessed online ahead of print at<www.sciencedirect.com/science/journal/03043835> by clicking on “Articles in Press” and then entering the term“ methylphenidate” in the “Quick Search” box.

Ziprasidone is not associated with the adverse metabolic changes or weight gain observed in some patients taking olanzapine. A retrospective chart review of 191 patients showed no significant differences in QTc interval in patients taking either antipsychotic drug. Significant weight gain was observed in olanzapine-treated patients, while those taking ziprasidone experienced weight loss. Adverse changes were seen in total cholesterol, triglycerides, and hemoglobin (Hb)A1C in patients taking olanzapine compared with favorable changes in total cholesterol, low-density lipoprotein, high-density lipoprotein, and HbA1C in patients taking ziprasidone.

Int Clin Psychopharmacol 2005; 20:105-112

Risperidone can significantly and persistently improve symptoms of tardive dyskinesia (TD) associated with typical antipsychotics. A new study followed 40 patients with chronic schizophrenia and severe TD who were switched to risperidone therapy for 48 weeks. The average total Abnormal Involuntary Movement Scale (AIMS) score decreased from 15.7 at baseline to 10.6 at week 48 with an average dose of risperidone of 3.6 mg a day. Twenty-three patients (57.5 percent) were responders, with a greater than 50 percent reduction in their AIMS scores and an average AIMS score decrease of 8.0 points. Significant improvement in TD symptoms was seen as early as week eight and persisted through week 48.

Int Clin Psychopharmacol 2005; 20:79-85

Fluoxetine appears to have limited efficacy in treating dysthymia in elderly patients. A randomized, double-blind, placebo-controlled trial of 90 patients (aged 60 and older) revealed that scores on the Hamilton Depression Rating Scale (Ham-D) and the Cornell Dysthymia Rating Scale (CDRS) showed a treatment-by-time effect that favored fluoxetine over placebo. However, the percentage change in Ham-D scores was not significantly different between those on fluoxetine and those on placebo. Percentage changes in CDRS scores were significantly better in those on active drug compared with placebo; however, response rates were not significantly different (27.3 percent response for fluoxetine versus 19.6 percent for placebo).

Am J Geriatr Psychiatry 2005; 13:59-68

Shire Pharmaceuticals Group and New River Pharmaceuticals Inc. announced an agreement for the global commercialization of New River's NRP104, a novel compound developed for the treatment of ADHD. NRP104 is a prodrug of amphetamine—that is, it is an amphetamine conjugated to a specific amino acid. By conjugating the pair, NRP104 is intended to provide better overdose protection and reduced potential for addiction, compared with currently marketed stimulants. A preliminary review by the U.S. Drug Enforcement Administration last year indicated that.the agency did not consider NRP104 to be an amphetamine, and thus it is not subject to controlled-substance scheduling.