Med Check

Regulatory Briefs

• The Food and Drug Administration (FDA) has set up a consumer-education Web site about direct-to-consumer (DTC) prescription drug advertisements. Three types of DTC advertisements are described: product claims in which a drug, the condition it treats, and its benefits and risks are described; reminder ads in which only the drug name but no indication is given; and help-seeking ads in which a disease or condition is described but no specific drug is mentioned. The Web site encourages consumers to report inappropriate drug ads to the FDA's Division of Drug Marketing, Advertising, and Communications, the division responsible for regulating postmarketing promotions of prescription drugs.

The DTC Web site can be accessed at<www.fda.gov/cder/ethicad/index.htm>.

• The FDA issued two warning letters last month to the India-based generic drug manufacturer Ranbaxy Laboratories Ltd. and an import alert for its products from two plants in India. The agency was concerned about“ deviations from U.S. current Good Manufacturing Practice requirements” at facilities in Dewas and Paonta Sahib. The import alert means that these products can be blocked from importation into the United States. However, the Ranbaxy products named in the announcement have not been recalled, and the FDA advised consumers to continue taking their medications. Among the drugs affected by the alert are gabapentin and nafazedone hydrochloride. Ranbaxy Laboratories announced two days later that it retained Rudy Guiliani, the former New York City mayor, to advise it on legal issues in this matter.

The FDA announcement is posted at<www.fda.gov/bbs/topics/news/2008/new01886.html>, and the list of affected products is posted at<www.fda.gov/cder/drug/infopage/Ranbaxy/Ranbaxy_list.htm>.

• The FDA requested additional data to evaluate the new drug application for paliperidone palmitate intramuscular injection, according to an announcement in August by Johnson and Johnson Pharmaceutical Research and Development. The agency issued a “complete response letter” to the manufacturer. This letter is in the new format that replaces the approvable and not-approvable letters previously issued in response to new drug applications. The product is being developed as a once-monthly injectable formulation of the oral paliperidone tablets to treat schizophrenia. The company said the agency did not require additional studies, which suggests that the approval may come soon.

Research Briefs

• Researchers at 15 sites are recruiting patients for a clinical trial to test the effectiveness of a two-drug combination for major-depression. The Combining Medication to Enhance Outcome of Depression (CO-MED) trial has been designed to further the evidence for depression treatment on the basis of the Sequenced Treatment Alternatives to Relieve Depression (STAR^*D) study. This randomized, single-blind (patients), active-controlled trial will compare the effectiveness of a single drug with a two-drug combination in adults with major depression. All drugs tested in the trial are approved antidepressants. The primary outcome measured is remission rate after six months of treatment. The total number of patients planned for the study is 660.

The study is funded by the National Institute of Mental Health. The principal investigators are John Rush, M.D., a professor of clinical sciences and psychiatry, and Madhukar Trivedi, M.D., a professor of psychiatry, both at the University of Texas Southwestern Medical Center.

Detailed CO-MED study information can be accessed at<clinicaltrials.gov/ct2/show/NCT00590863>.

• Concerns about neuropsychiatric adverse effects of montelukast, a leukotriene receptor inhibitor to treat asthma and allergy, may be unfounded, a study sponsored by the American Lung Association (ALA) indicated.

The FDA issued an alert earlier this year to health care professionals and the public, noting that it suspects a link between the drug and psychiatric/behavioral symptoms such as depression, suicidal thoughts, and anxiousness based on postmarketing reports (Psychiatric News, May 16); Merck had added warnings about the symptoms to the drug's package insert. However, the ALA study, led by Janet Holbrook, Ph.D., M.P.H., found no evidence to support this adverse effect.

The authors reanalyzed pooled data on 1,352 patients, including children as young as age 6, who participated in three previous randomized, double-blind, placebo-controlled, clinical trials of montelukast. The emotional well-being of participants in these trials, measured by quality-of-life scales, showed no deterioration after taking montelukast in either adults over 24 weeks or children over 16 weeks, and no difference between the active-treatment and placebo groups. The authors acknowledged that these trials had not been designed to detect psychiatric disturbances, and this analysis did not entirely rule out possible rare psychiatric adverse effects of the drug. As of September 19, the study was scheduled for publication in the Journal of Allergy and Clinical Immunology.

• Children with autism who took risperidone at doses of up to 3.5 mg a day did not appear to have impairment in their cognitive performance, a randomized, double-blind study in the June Journal of Child and Adolescent Psychopharmacology showed.

Thirty-eight children aged 5 to 17 with autism and severe behavior disturbance (29 boys and nine girls) were randomly assigned to treatment with either risperidone 0.5 mg to 3.5 mg a day (n=20) or placebo (n=18) for eight weeks. Risperidone did not lead to significant decline in cognitive performance from baseline. Patients' performance on certain tests was better in the risperidone group than in the placebo group.

The study was led by Michael Aman, Ph.D., a professor of psychology and psychiatry at the Nisonger Center at Ohio State University and funded by grants from the National Institute of Mental Health.

An abstract of “Cognitive Effects of Risperidone in Children With Autism and Irritable Behavior” is posted at<www.liebertonline.com/doi/abs/10.1089/cap.2007.0133>.

Industry Briefs

• After a voluntary recall in June, Shire announced in late August that additional lots of methylphenidate transdermal system (marketed as Daytrana) have been recalled because of problems with the release liner, which could make it difficult for patients or parents to remove the liner before applying the patch on the skin. Indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD), the patches are manufactured by Noven Pharmaceuticals Inc. for Shire. Because the voluntary recalls were not related to safety issues, Shire advised patients to continue using the patches unless the release liners cannot be removed or the patches are damaged upon opening. The lot numbers of the recalled products are 2750211, 2764111, 2764211, and 2819811.

The recall announcements are posted at<www.daytrana.com/downloads/inthenews/VoluntaryRecall060908.pdf> and<www.daytrana.com/downloads/inthenews/VoluntaryRecall_0808.pdf>.

• Pfizer has announced that it will pay Medivation Inc. up to $725 million for the rights to develop and market the experimental drug dimebolin hydrochloride for Alzheimer's disease (AD). The drug is in phase 3 development for mild-to-moderate Alzheimer's disease and has shown promising results in clinical trials for Huntington's disease as well.

• Preliminary results from a phase 3 clinical trial indicated that a long-acting formulation of clonidine developed by Sciele Pharma Inc. and Addrenex Pharmaceuticals improved ADHD symptoms significantly more than placebo, according to an announcement by the two companies. The randomized, double-blind, placebo-controlled, eight-week study evaluated 228 ADHD patients aged 6 to 17.

• A Phase 2b trial of AZD3480 (also known as TC-1734), an experimental drug being developed by AstraZeneca and Targacept Inc. for treatment of AD, yielded inconclusive results, the companies announced in September. In the 12-week, randomized, placebo-controlled trial in patients with mild-to-moderate AD, neither AZD3480 nor the active comparator donepezil produced an improvement that was statistically significantly different from placebo in primary outcome of AD symptoms. The primary outcome was measured by the Alzheimer's Disease Assessment Scale-Cognition Scale (ADAS-Cog).

The molecule is also being investigated for treating cognitive dysfunction in schizophrenia and adult ADHD. AstraZeneca said it will announce the fate of the drug's clinical development in December.

•Duloxetine hydrochloride has been approved by the European drug regulatory agency for treatment of generalized anxiety disorder, Eli Lilly and Co. and Boehringer Ingelheim announced on August 22. The drug already carries this indication in the United States. ▪