Med Check

The labeling information for Adderall (mixed salts of a single-entity amphetamine product, Shire) and methylphenidate hydrochloride (Methylin, Alliant Pharmaceuticals) chewable tablets and oral solution was revised in June. Notably, the “Precaution” section of the package inserts was revised to refer to the medication guide. Medication guides explaining the risks and benefits of the three drug products are designed for patients by the U.S. Food and Drug Administration (FDA).

The new package inserts and medication guides for these drugs can be accessed at<www.fda.gov/medwatch/safety/2007/jun07.htm>. 


The FDA rejected the New Drug Application (NDA) for the investigational schizophrenia drug bifeprunox, developed by Wyeth and its partner Solvay Pharmaceuticals. The drug was deemed not approvable at this time for the indications cited in their application to the FDA—the acute treatment of schizophrenia and the maintenance of stable adult patients with schizophrenia. According to a press release by Wyeth on August 10, the FDA concluded that the data on the drug's efficacy, compared with other similar drugs, were not sufficient for approval. The agency also requested further information on the metabolism of bifeprunox and adverseevent details related to a patient death during one of the clinical trials. Bifeprunox is a partial dopamine D₂ receptor agonist similar to aripiprazole. Wyeth said in a press release that the FDA's letter acknowledged bifeprunox's effectiveness in the long-term maintenance study and indicated the possibility for approving such a claim if a second maintenance study is conducted and yields positive results.


The European Medicines A gency (EMEA) recommended in a July 19 press release that a contraindication be added to rimonabant (marketed as Acomplia in Europe) for patients with ongoing major depression who are being treated with an antidepressant. Rimonabant has been approved in the European Union for the treatment of obesity since June 2006, but the NDA (under the proposed brand name of Zimulti) that Sanofi-Synthelabo had submitted to the FDA was rejected because of safety concerns regarding potential psychiatric adverse effects. The EMEA's Committee for Medicinal Products for Human Use (CHMP) evaluated the drug's safety data and concluded that the drug's benefits outweigh its risks except in patients with ongoing major depression or those being treated with antidepressants. The CHMP also recommended adding a warning that rimonabant should be discontinued if a patient develops depression and including additional warnings on the drug's psychiatric safety profile in the prescribing information.


The FDA approved armodafinil (Nuvigil) tablets (manufactured by Cephalon) in June for improving wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (as an adjunct to treatment of underlying obstruction), narcolepsy, and shift-work sleep disorder. Armodafinil is an isomer of modafinil (Provigil), also approved for these sleep disorders. Armodafinil has a longer half life than modafinil.


D-cycloserine, a broad-spectrum oral antibiotic originally developed to treat tuberculosis, may be effective as an adjunct to behavioral therapy in the treatment of obsessive-compulsive disorder (OCD), researchers at the University of Minnesota discovered. In a study published online in Biological Psychiatry on June 22, Matt Kushner, Ph.D., and colleagues compared D-cycloserine with placebo in patients with OCD. Ten 125 mg doses of D-cycloserine or placebo were given in a random, double-blind fashion to 15 and 17 patients, respectively; one dose was taken approximately two hours before each exposure/ritual prevention therapy session. Fourteen patients (93.3 percent) in the D-cycloserine group completed all 10 sessions, compared with 11 (64.7 percent) in the placebo group. During the first four therapy sessions, patients taking D-cycloserine reported a significantly greater decrease in obsession-related distress compared with the placebo group.

The D-cycloserine group reached the study endpoint (50 percent reduction in Subjective Units of Distress) two sessions earlier than the placebo group. However, after the entire 10 sessions, the patients remaining in the placebo group tended to catch up.

D-cycloserine is a glutamatergic partial N-methyl-D-aspartate agonist and is known to facilitate a process called “extinction learning,” in which it manipulates memory processes and causes the “extinction” of learning-related, externally cued fear in animals and humans. Researchers have speculated that the drug can enhance the extinction learning in psychotherapy and thus improve the effectiveness of the therapy.

The study was funded through grants from the Obsessive-Compulsive Foundation and the Minnesota Medical Foundation.

An abstract of “D-Cycloserine Augmented Exposure Therapy for Obsessive-Compulsive Disorder” can be accessed at<www.sciencedirect.com/science/journal/00063223> by clicking on “Next vol/iss.” 


Donepezil (Aricept) showed favorable efficacy compared with placebo in enhancing the cognition and global functioning of patients with severe Alzheimer's disease. A randomized, double-blind, placebo-controlled study was published in the July 31 Neurology; the study was sponsored by Ensai and Pfizer, which develop and market the drug worldwide.

Patients with severe Alzheimer's disease (defined as Mini-Mental State Examination [MMSE] score between 1 and 12 and Functional Assessment Stating score no less than 6) were given donepezil 10 mg (n=176) or placebo (n=167) once daily for 24 weeks. Compared with the placebo group, the donepezil group saw statistically significant improvement, defined as change from baseline (p=0.0001) in clinical endpoints measured by the Severe Impairment Battery, the Clinician's Interview-Based Impression of Change-Plus caregiver input, and MMSE scores. However, other indicators such as the Neuropsychiatric Inventory scores, activity of daily living, caregiver burden, and resource utilization measurements did not show significant difference between the two groups. The adverse events observed in the trial were consistent with those reported in patients with mild and moderate Alzheimer's disease, for whom donepezil is an FDA-approved treatment.