FDA Panel Agrees Fluoxetine Effective For PMDD.
SILVER SPRING, MD. -- Fluoxetine could become the first drug approved specifically for premenstrual dysphoric disorder, the severe form of premenstrual syndrome that is estimated to affect 3%-5% of regularly menstruating women.
The Food and Drug Administration's Psychopharmacologic Drugs Advisory Committee unanimously agreed that the data presented by Eli Lilly & Co., the drug's manufacturer, provided enough evidence to suggest that fluoxetine is safe and effective when used to treat women with premenstrual dysphoric disorder (PMDD).
Their votes on efficacy, however, were accompanied by several caveats, reflecting discomfort with the quality of some data.
Usually, a company designs and conducts studies for a new drug or indication in close consultation with the FDA. But in this case, the three studies of fluoxetine for PMDD were investigator-initiated and sponsored by Lilly. The company filed the application for the PMDD indication after the studies had been conducted.
The FDA usually follows the recommendations of its advisory panels, which are not binding.
If approved for this indication, Lilly hopes to market the selective serotonin reuptake inhibitor (SSRI) under a name other than Prozac because market research shows women with PMDD may attach a stigma to that name and be reluctant to take the drug.
Fluoxetine was the first SSRI approved for depression and has since been approved for obsessive-compulsive disorder, bulimia, and geriatric depression.
At the hearing, Lilly presented the results of three double-blind studies of women with PMDD; these compared the effects of 20 mg or 60 mg of fluoxetine daily vs. placebo. Study participants were treated for up to 6 months.
The largest study, conducted in Canada, enrolled about 300 women over the age of 18 with regular menstrual cycles who met the diagnostic criteria for PMDD; the majority were white and were in their mid-to late 30s.
Those treated with fluoxetine had significant reductions in all three symptom clusters that characterize PMDD, compared with placebo: mood symptoms (dysphoria, irritability, and tension); physical symptoms (bloating and breast tenderness); and social impairment. These improvements were seen in the first cycle and were maintained throughout the 6-month study, according to Dr. Rajinder Judge, director of Lilly Neurosciences, Indianapolis.
Responses to the larger fluoxetine dose were slightly higher than those obtained with the lower dose but not significantly so.
In an interview at the hearing, the study's lead author, Dr. Meir Steiner of McMaster University in Hamilton, Ont., estimated that fluoxetine works in about 60%-70% of women with PMDD.
The other two studies were smaller and less well designed than his. One also provided evidence that 20-mg and 60-mg doses of fluoxetine were significantly better than placebo; in the third study, 20 mg of fluoxetine was more effective in reducing PMDD symptoms than the antidepressant bupropion (Wellbutrin), which had an effect similar to placebo.
The side effects observed in the three trials were comparable with the known side-effect profile of the drug.
Because the lower dose was better tolerated than the 60-mg dose, the company is recommending a daily dose of 20 mg, although some patients may benefit from increasing the dose to 60 mg, Dr. Judge said.
Women on OCs were excluded from the studies, to avoid any possible effects OCs had on mood. But there is no clinical evidence, including extensive postmarketing surveillance, that concomitant use of OCs "augments or lessens the efficacy of fluoxetine," she added.
Since the onset of PMDD symptoms is cyclical and extremely predictable, an intermittent dosing schedule is being explored as an alternative treatment, which would reduce exposure to the drug. Anecdotal evidence suggests this may be effective, but the risks of treatment are uncertain at this point. Lilly is conducting two large multinational studies in which women start treatment on day 14 of their cycle until the onset of menses.
Robert M. Hamer, Ph.D., of the department of psychiatry at Robert Wood Johnson Medical School in Piscataway, N.J., emphasized that ob.gyns. and other primary care physicians, who will be the most likely to prescribe fluoxetine for PMDD, should be careful to distinguish PMDD from rapid cycling disorder, which can be exacerbated with fluoxerine treatment.
The pathophysiology of PMDD is not fully understood. The most plausible theory is based on the observation that cyclic changes in ovarian steroids "cause dramatic changes in the brain neurotransmitter system," including changes in serotonin, according to Jean Endicott, Ph.D., a well-known PMDD expert at Columbia University New York. She was at the hearing as a consultant to Lilly
There have been more than 30 published studies of fluoxetine and other serotinergic agents in women with PMDD or PMS, and the majority have found positive results with treatment, she said.
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|Publication:||OB GYN News|
|Date:||Dec 1, 1999|
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