Regulatory Briefs
• The Food and Drug Administration (FDA) on January 3 approved fluoxetine (Prozac, Eli Lilly and Co.) for the treatment of children and adolescents aged 7 to 17 for major depressive disorder and obsessive-compulsive disorder (OCD). This is the first approval of an SSRI for depression in the child and adolescent population. The approval was based on two placebo-controlled clinical trials in children and adolescents being treated for depression as outpatients. The OCD indication was also based on two clinical trials. The long-awaited approval legitimizes many years of use of fluoxetine in pediatric patients as the most common drug prescribed for depression in patients under 18 years of age.
Reported common side effects associated with use of fluoxetine in pediatric populations are similar to those reported in adults, including nausea, fatigue, nervousness, dizziness, and difficulty concentrating. Lilly agreed to an FDA request to conduct a Phase 4 postmarketing study to evaluate the long-term effects of the drug on growth after one trial noted a slight (about 1 cm and 1 kg) decrease in average height and weight of children treated with fluoxetine. An FDA Talk Paper on the topic is posted on the Web at www.fda.gov/bbs/topics/answers/2003/ans01187.html.
• The FDA also tentatively approved in mid-January generic forms for both nefazodone (Serzone, Bristol-Myers Squibb) and mirtazapine (Remeron, Organon.) Both generic approvals stem from patent challenges to the two brand names from generic manufacturers. Serzone is protected by two patents, the first expiring in September 2003 and the second expiring in October 2012. Remeron is protected by a single patent, a rare situation in an environment where most drug manufacturers gain multiple patents for each product in an attempt to maintain protection for longer periods. Remeron’s single patent expires in 2017. Courts would have to rule the existing patents invalid for final FDA approval to be granted. Neither company could be reached for comment on the patent challenges.
• In response to the filing of an abbreviated New Drug Application with the FDA, Shire Pharmaceuticals vowed to fight an attempt by the generic manufacturer to gain marketing approval for a generic form of Adderall XR (mixed amphetamine salts, extended release). In a press release dated January 9, Shire said that the extended-release formulation will remain under valid patent protection until at least mid-2005. If all the company’s multiple patents were to be upheld during patent-challenge litigation, the brand would be protected until 2018.
• GlaxoSmithKline has won a significant victory in its legal fight to preserve patent protection for Paxil. A U.S. District Court ruling upheld the validity of at least one of four contested patents for the SSRI, preserving patent protection until 2006. Court hearings on the patent expiring in 2006 were scheduled for mid-February. Apotex, a generic drug manufacturer, had sought the court’s relief in contesting the validity of the patents in 1998, only five years after the drug’s launch in the United States. Of the remaining three contested patents, the court decided in favor of Apotex on one patent, ruling that the patent was invalid. However, the court split on the remaining two patents, holding some claims within those patents valid while striking other specific claims.
Research Briefs
• Risperidone (Risperdal, Janssen) appears to be effective in treating global psychotic symptoms associated with posttraumatic stress disorder. In a five-week, prospective, randomized, double-blind, placebo-controlled trial, patients who received risperidone in addition to other common medications such as SSRIs showed a significantly greater reduction in psychotic symptoms as measured by Positive and Negative Syndrome Scale (PANSS) total scores. Ratings using the Clinician-Administered PTSD Scale (CAPS) also declined significantly; however, no statistically significant difference was seen between risperidone and placebo until the fifth week (end point) of the study. At week five, CAPS subscale scores for core re-experiencing symptoms were significantly more improved for patients taking risperidone than placebo.
(Int Clin Psychopharmacol2003; 18:1-8)
• Prazosin (Minipress, Pfizer), a centrally acting A1 adrenergic antagonist used as an antihypertensive, may be effective in reducing nightmares and other sleep disturbances associated with PTSD. In a brief report of data from a 20-week double-blind crossover study, researchers found that prazosin was superior to placebo in two outcome measures on the CAPS: subscores on the recurrent distressing dreams item and the difficulty falling/staying asleep item. In addition, the change in overall PTSD severity, as measured with the Clinical Global Impressions scale (CGI), was also statistically more improved with prazosin than placebo.
(Am J Psychiatry2003; 160: 371-373)
• Use of so-called “atypical neuroleptics”—more recently and perhaps more appropriately termed dopamine/serotonin modulators—has increased rapidly in the last several years, largely for symptoms other than psychosis. A new review reports on recent data on the use of the drugs to treat depression and mania, as well as other mood disorders. In addition, the review noted, “atypical antipsychotics are as effective as typical antipsychotics, but are safer and more efficacious than mood stabilizer monotherapy in the treatment of mania.”
(Curr Opin Psychiatry2003; 16:23-27)
• Divalproex (Depakote, Abbott), when combined with olanzapine (Zyprexa, Lilly) or risperidone, contributes to earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia, according to a new study. In a double-blind trial, 249 patients were randomly assigned to receive either olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Improvements were seen in all groups at all time points; however, combination therapy was significantly better as early as day 3 for PANSS total score, Brief Psychiatric Rating Scale (BPRS) total score, and their subscales.
(Neuropsychopharmacol2003; 28:182-192)
• The full report of the International Suicide Prevention Trial (InterSePT), which the FDA used to validate a new indication for clozapine (Clozaril, Novartis) (Psychiatric News, December 6, 2002) has been released. Olanzapine was compared with clozapine in 908 patients who had schizophrenia or schizoaffective disorder and were considered to be at high risk for suicide. Suicidal behaviors were found to be significantly less frequent in patients treated with clozapine compared with those treated with olanzapine.
(Arch Gen Psychiatry2003; 60:82-91)
• Paroxetine (Paxil, GlaxoSmithKline) and clomipramine (Anafranil, Mallinkrodt) appear to be equally beneficial in treating adolescents with severe major depression. A new study aimed to examine the “serotonin hypothesis”—the idea that SSRIs are more effective than tricyclics for adolescent depression because adolescent depression is largely modulated by serotonin and not norepinephrine. The randomized trial compared the two drugs in 121 patients, with 58 receiving clomipramine and 63 receiving paroxetine. Both agents had similar efficacy, measured on the Montgomery-Asberg Depression Rating Scale (MADRS) and CGI scales. Side effects were significantly more frequent with clomipramine than paroxetine.
(J Am Acad Adol Child Psychiatry2003; 42:22-29)
• A German study found that naltrexone (Revia, Barr Labs) combined with acamprosate—which the FDA deemed unapprovable last fall—provides the best outcome regarding delaying the time to first drink and time to relapse in patients with alcoholism. Subjects had significantly lower rates on both measures than did either medication alone, and all three therapies were significantly better than placebo. Comparing the two medications used as monotherapy, naltrexone showed a tendency toward better rates on both measures than did acamprosate.
(Arch Gen Psychiatry2003; 60:92-99)
Industry Briefs
• AstraZeneca announced January 2 that it had submitted a Supplemental New Drug Application to the FDA to market Seroquel (quetiapine) for the treatment of acute mania associated with bipolar disorder. Based on three clinical trials, the company is seeking approval to market the drug as both monotherapy and adjunctive therapy with a mood stabilizer.
• Bristol-Myers Squibb announced last month that it had reached agreements that would settle antitrust litigation concerning BuSpar (buspirone). The $535 million settlement will resolve claims that the company had taken allegedly illegal actions in an effort to protect patents and other intellectual property for the drug, which was developed by BMS. While the company did not admit wrongdoing, a press release said, “It would be prudent to enter into settlements to put the uncertainty and risk of this litigation behind the company.” ▪
