Med Check

Duloxetine (Cymbalta) has been approved by the Food and Drug Administration (FDA) for maintenance treatment of major depressive disorder in adults, according to Eli Lilly and Company. The approval was based on a double-blind, placebo-controlled clinical trial, in which more than 500 patients with major depression were randomly assigned to either duloxetine or placebo for six months. The time to relapse of depression (defined as an increase from baseline of two or more points on the Clinical Global Impression Severity scale and meeting the diagnostic criteria for major depression at two consecutive visits) was significantly longer in the duloxetine group than the placebo group. Duloxetine inhibits the synaptic reuptake of serotonin as well as norepinephrine. It also carries the indications for acute treatment of major depressive disorder, management of diabetic peripheral neuropathic pain, and treatment of generalized anxiety disorder, all in adults.


The updated package insert containing the long-term depression study results is posted at<www.fda.gov/cder/foi/label/2007/021427s015s017lbl.pdf>. 


The once-daily formulation of quetiapine fumarate extended-release tablets (Seroquel XR) has been approved by the FDA for maintenance treatment of schizophrenia in adults. The approval was based on a randomized, placebo-controlled clinical trial of nearly 200 patients with schizophrenia, in which the drug was shown to be better than placebo in delaying first relapse and reducing the six-month relative risk of relapse.


The current package insert of quetiapine extended-release tablets is posted at<www.fda.gov/cder/foi/label/2007/022172lbl.pdf>. 


Gepirone extended-release tablets, a partial agonist of the serotonin 5HT_1A receptor intended for depression treatment, was given a “not approvable” letter from the FDA last November. The molecule is owned and developed by Fabre-Kramer Pharmaceuticals and GlaxoSmith Kline. A New Drug Application had been initially submitted to the agency in 2001 and was amended with additional clinical study data over the years.

The package insert and patient information for varenicline (Chantix), a smoking-cessation aid marketed by Pfizer, has been revised under the FDA's request to include possible psychiatric adverse effects. The labeling changes were prompted by reports of suicidal thoughts, aggressive and erratic behavior, and drowsiness that affected driving among patients who took the drug. FDA issued an early communication to health care professionals last November warning about these adverse effects, in which the agency stated that“ the role of Chantix in these [adverse effect reports] is not clear because smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and...the exacerbation of underlying psychiatric illness.” The new labeling information recommended that providers warn patients of these adverse effects, including “sleep and dreaming disturbance, depression, agitation, suicidal thoughts, and problems with driving or operating machinery.” The agency said it was still conducting ongoing review about the adverse-event reports.


The FDA early communication is posted at<www.fda.gov/cder/drug/early_comm/varenicline.htm>. 


An FDA advisory panel has recommended the expansion of the safety warnings in the package insert of modafinil (Provigil), Reuters reported last November. This recommendation followed an alert message distributed by the agency to health care professionals regarding the safety warnings that had been added to the package insert and patient guide for the drug. The revisions included warnings about serious rash due to Stevens-Johnson syndrome or hypersensitivity reactions, and psychiatric adverse effects such as anxiety, mania, hallucinations, and suicidal ideation. Rare cases of life-threatening severe rash have been reported in adults and children. The company's application for modafinil's use in treating attention-deficit/hyperactivity disorder in children was rejected by the FDA in 2006. The drug is not approved for pediatric use.

The FDA warning is posted at<www.fda.gov/medwatch/safety/2007/safety07.htm#Provigil>. 


An FDA Pediatric Advisory Committee has recommended that stronger warnings be added to the labeling information of two oral antiviral drugs for treatment of influenza to highlight possible neuropsychiatric adverse effects in young children. Oseltamivir (Tamiflu, made by Roche) and zanamivir (Relenza) have been linked to a small number of cases of hallucinations, delirium, and abnormal behaviors, including the deaths of several children in Japan after they took osteltamivir. The drugs are not directly implicated in these adverse phenomena, but experts believe the drugs' role cannot be ruled out, according to a Reuters report. A Japanese regulatory agency advised against prescribing oseltamivir to patients younger than 19 earlier this year. Oseltamivir is approved by the FDA for use in children as young as 1 year old, while zanamivir is approved for children 5 years old or older.

The weight-loss drug rimonabant carries a substantial risk of psychiatric adverse effects, especially depression and anxiety, according to a meta-analysis by a group of Danish researchers. Rimonabant is approved in Europe for treating obesity, but its application to the FDA was turned down earlier last year because of concerns about its association with increased psychiatric problems including suicidal thoughts. After pooling data from four randomized, placebo-controlled clinical trials, the researchers found that rimonabant caused significantly more adverse events than did placebo. Patients in the rimonabant groups were 2.5 more likely to discontinue the drug because of depression than those in the placebo groups, and 3.0 times more likely to discontinue because of anxiety. The study was published in the November 17, 2007, The Lancet. The accompanying editorial pointed out that the findings are particularly alarming for the use of rimonabant since the trials had screened and excluded those with significant psychiatric disorders, while obese patients in real-world settings are at high risk for depression.


An abstract of “Efficacy and Safety of Weight-Loss Drug Rimonabant: A Meta-analysis of Randomized Trials” is posted at<www.thelancet.com/journals/lancet/article/PIIS0140673607617218/abstract>. 


Naltrexone extended-release injection (Vivitrol), combined with counseling, appears to help patients with alcohol dependence stay abstinent longer than treatment with placebo and counseling, according to an article published in the October 2007, Journal of Clinical Psychopharmacology. Stephanie O'Malley, Ph.D., of Yale University and colleagues analyzed a subset of data from a previous phase 3 clinical trial. In the 82 participants who had been able to abstain from alcohol for at least four days before the study, naltrexone 380 mg, naltrexone 190 mg, or placebo was injected every four weeks. All participants received 12 sessions of low-intensity psychosocial therapy over 24 weeks.


The group that received naltrexone 380 mg (n=28) had a median time to first drink of 41 days. The time to first drink was 12 days in the placebo group (n=28). Patients in the naltrexone 380 mg group had a median of 0.2 heavy drinking days, statistically significantly lower than the placebo group which had a median of 2.9 heavy drinking days.


Naltrexone extended-release intramuscular injection was approved by the FDA for the treatment of alcohol dependence in 2006 and is given once monthly. The study was funded and conducted by the manufacturers Alkermes Inc. and Cephalon Inc.


An abstract of “Efficacy of Extended-Release Naltrexone in Alcohol-Dependent Patients Who Are Abstinent Before Treatment” can be accessed through<www.psychopharmacology.com/pt/re/jclnpsychopharm/home.htm> by clicking on “Archive,” then opening item 507. 


Barr Laboratories Inc. is legally challenging the patents for dexmethylphenidate hypdrochloride extended-release capsules (Focalin XR) so that it can market the generic version of the drug, according to a company announcement last November. Dexmethylphenidate is the d-isomer in methylphenidate. The drug is approved for treatment of attention-deficit/hyperactivity disorder in children at least 6 years old and marketed by Novartis. Barr filed an abbreviated new drug application with the FDA, which was accepted by the agency for review last October. Elan Pharmaceuticals, the company that owns the technology used in the extended-release oral formulation, filed a lawsuit last November to prevent the marketing of the generic drug. A generic version of rapid-release dexmethylphenidate was approved earlier this year.


Forest Laboratories has announced positive results from a phase 3 trial of escitalopram (Lexapro) in adolescents with major depression. In each of two randomly assigned groups, either escitalopram or placebo was given, in a double-blind manner, to 158 adolescents (12 to 17 years old) with major depression. After eight weeks, the escitalopram group had a statistically significant greater reduction in depression symptoms, as measured by the Children's Depression Rating Scale-Revised, than the placebo group. Forest's press release did not provide the percentages for response or remission in either group or the adverse events, but it acknowledged the company's intention to pursue FDA approval for the indication of depression treatment in adolescents. Currently fluoxetine is the only selective serotonin-reuptake inhibitor approved in the United States for treating depression in pediatric patients. ▪