Med Check

The safety sections in the labeling of risperidone (Risperdal), carbamazepine, and modafinil (Provigil) have been revised to include new data on adverse effects. The risperidone package insert now includes adverse reactions reported in clinical trials in children as well as adults. The Food and Drug Administration (FDA) recently expanded the drug's indications to include short-term treatment of schizophrenia and bipolar disorders in pediatric patients (Psychiatric News, September 21).

The changes to carbamazapine's package insert include the drug's cardiac adverse effects, possible adverse fetal effects, contraindication in patients with hepatic porphyria, and its interaction with nefazodone.

For modafinil, the modified package insert highlights warnings about serious rashes, including Stevens-Johnson syndrome in adults and children and hypersensitivity or anaphylaxis-like reactions. The FDA's concerns over serious rashes had previously prevented the approval of Cephalon's application for modafinil as a treatment for attention-deficit/hyperactivity disorder (Psychiatric News, April 21, 2006).

The changes to package inserts for these drugs can be accessed at<www.fda.gov/medwatch/safety/2007/aug07.htm>.

The FDA's Division of Drug Marketing, Advertising, and Communications issued a “Notice of Violation” letter in October to Eli Lilly regarding misleading promotional material in a pamphlet mailed to physicians for duloxetine hydrochloride (Cymbalta). The pamphlet promoted the drug's indication for treating neuropathic pain associated with diabetic peripheral neuropathy. The letter refers to the promotional information in the pamphlet as “false or misleading in that it overstates the efficacy of Cymbalta and omits some of the most serious and important risk information associated with its use.” The FDA also charged that the two other approved indications for duloxetine, the treatment of major depressive disorder and generalized anxiety disorder, were not mentioned in the promotional pamphlet.

The FDA requested that Lilly immediately stop using the material and any other promotional materials with similar content.

The FDA's warning letter is posted at<www.fda.gov/cder/warn/2007/Cymbalta_wl.pdf>.

Shire announced voluntary withdrawal of some methylphenidate transdermal system patches (Daytrana patches) from the market in September because of reported difficulty in removing the release liner. The packages withdrawn include those with an expiration date of March 31, 2009, and earlier and those with lot numbers 2563511, 2563611, and 2570411. In the announcement, Shire stated that the patches affected by the withdrawals can still be used unless the liner cannot be removed or the patches are damaged while being opened.

The press release about the patch withdrawal is posted at<www.shire.com/shire/NewsAndMedia/PressReleases/showShirePress.jsp?ref=821&tn=3&m1=8&m2=>.

A study in the September 27 New England Journal of Medicine adds to the mountain of evidence indicating that childhood vaccines do not cause autism. William Thompson, Ph.D., from the Centers for Disease Control and Prevention (CDC) and colleagues studied more than 1,000 children from ages 7 to 10 and found no association between their current neuropsychological performance and past exposure to mercury in thimerosal, a preservative used in vaccines and immune globulin products.

Each child was assessed on 42 neuropsychological outcomes. Their past mercury exposure, from the mothers' pregnancy through 7 months after birth, was calculated based on the vaccines and immune globulins the child had received in his or her medical and immunization records and through interviews with the mothers. Only a few statistically significant associations between neurological performance and the level of early mercury exposure were detected, which were “small and almost equally divided between positive and negative effects.” The authors concluded that there was no causal association between early exposure to mercury from thimerosal and neurological functioning in 7- to 10-year-olds.

“Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years” is posted at<http://content.nejm.org/cgi/content/full/357/13/1281>

A drug used to treat breast cancer, tamoxifen, was shown to have a rapid effect on symptoms of mania in a small pilot study conducted by Carlos Zarate, M.D., and other researchers at the National Institute of Mental Health. Sixteen adult patients were randomly assigned to receive either tamoxifen or placebo for three weeks in a 1:1 ratio. All patients had a current manic or mixed episode with or without psychotic features. The dose of tamoxifen tested ranged from 20 mg a day to 140 mg a day. At the end of three weeks, five of the eight patients taking tamoxifen achieved a 50 percent or greater response on Young Mania Rating Scale scores, while only 13 percent on placebo did. The superiority of tamoxifen treatment became significant at as early as day 5. The authors suggested that tamoxifen's rapid antimanic effect is due to the drug's blockade of protein kinase C (PKC), a family of enzymes important to the regulation of neurotransmission in the brain. The PKC signaling pathways have been implicated in the pathology of bipolar disorders and may be a promising target for a new class of drugs that can control bipolar symptoms faster than conventional treatments. The study was published online in the September Bipolar Disorders.

“Efficacy of a Protein Kinase C Inhibitor (Tamoxifen) in the Treatment of Acute Mania: A Pilot Study” is posted at<www.blackwell-synergy.com/doi/full/10.1111/j.1399-5618.2007.00530.x>.

British researchers found donepezil (Aricept) to be no more effective than placebo in reducing agitation in patients with Alzheimer's disease; the study was published in the October 4 New England Journal of Medicine. Patients with clinically significant agitation who had not responded to psychosocial treatment were randomly assigned to 10 mg a day donepezil treatment (128 patients) or placebo (131 patients). At the end of 12 weeks, patients' level of agitation symptoms, measured by change from baseline in the Cohen-Mansfield Agitation Inventory score, was not significantly different between the donepezil group and the placebo group. Patients, caregivers, clinicians, and outcome-assessing personnel were all blinded to treatment assignment during the study.

Donepezil, a cholinesterase inhibitor, carries a general indication approved by the FDA for the treatment of Alzheimer's disease.

This study was funded by the Medical Research Council at Neurogeneration Research Centre under the Institute of Psychiatry, King's College London, and the Alzheimer's Society, a U.K. organization.

An abstract of “Donepezil for the Treatment of Agitation in Alzheimer's Disease” is posted at<content.nejm.org/cgi/content/abstract/357/14/1382>.▪