Pharmacology Update
Fluoxetine Capsules (Sarafem—Eli Lilly)
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
Eli lilly has received fda approval to market fluoxetine for a new indication, premenstrual dysphoric disorder (PMDD). Fluoxetine, under the trade name Prozac, was the first selective serotonin reuptake inhibitor (SSRI) antidepressant approved in this country on December 29, 1987. But instead of adding the PMDD indication to fluoxetine as Prozac, Lilly has decided to market the drug for this indication under a new brand name, Sarafem, and with separate package labeling. Premenstrual dysphoric disorder is a severe form of premenstrual syndrome affecting 3-5% of women in their reproductive years. The predominant symptoms include anger/irritability, depressed mood, anxiety/tension, decreased energy and interest, and physical symptoms such as bloating and breast tenderness. These generally appear a week or two before and disappear within a few days after the onset of menses.1-3
Indications
Fluoxetine is indicated for the treatment of PMDD.
Dosage
The recommended dose of fluoxetine is 20 mg per day. Clinical trials have demonstrated efficacy for up to six months.1 Doses up to 60 mg per day have been studied but no significant clinical benefit has been shown for the 60-mg dose compared to the 20-mg dose. It may be taken without regard to meals.
Fluoxetine as Sarafem is available as 10-mg and 20-mg capsules.
Potential Advantages
Fluoxetine is the only drug approved for the treatment of premenstrual dysphoric syndrome.
Potential Disadvantages
Fluoxetine appears to be less effective in controlling physical symptoms of PMDD.2 The most commonly observed adverse events associated with the use of fluoxetine hydrochloride vs. placebo in combined U.S.-controlled clinical trials for depression, OCD, and bulimia were nausea (27% vs 11%), insomnia (24% vs 11%), anxiety (13% vs 9%), nervousness (14% vs 10%), and somnolence (13% vs 6%).3 In a small long-term study (n = 64; mean, 18.6 months), the most common side effect was sexual dysfunction, 17%.11 Fluoxetine may interact with certain drugs (e.g., carbamazepine, phenytoin, warfarin, alprazolam).3
Comments
Fluoxetine has been reported in a large study (n = 313) to be superior to placebo in reducing symptoms of tension, irritability, and dysphoria.4 Primary efficacy was assessed using visual-analogue scales for tension, irritability, and dysphoria. Improvement was defined as a percent change from baseline for these symptoms. These are 100-mm scales with 0 mm associated with "no symptoms" and 100 mm associated with extreme symptoms. The mean of each of these scales was calculated to obtain the total "psychological-system" score. Fluoxetine 20 mg (n = 96) resulted in a 43.9 ± 45.8 vs. 6.7 ± 54.0 for placebo (n = 95, P < 0.001). The effect of fluoxetine was generally moderate, as about one-third of the patients reported moderate improvement defined as a 50% improvement from baseline.4 Secondary end points, a 36-item scale completed by the patients and a 10-item scale completed by their therapists, also showed a statistical advantage for fluoxetine, 42.9 ± 44.6 vs. 9.5 ± 45.2 (P < 0.001). While only fluoxetine has received FDA approval, efficacy does not appear to be limited to fluoxetine. Other SSRIs (e.g., sertraline, paroxetine, citalopram) have been reported to be effective as well.6,12,13 Studies have generally used continuous therapy although limited data have suggested that intermittent luteal-phase therapy may be effective for selected patients.9,10,13
Clinical Implications
Many women experience psychological and physical symptoms associated with their menstrual cycle generally referred to as premenstrual syndrome. However, about 3-5% of women meet the criteria of PMDD. This disorder, previously named late luteal phase dysphoric disorder (LLPDD), has a significant effect on the daily lives of affected women including work performance and interpersonal relationships. PMDD is believed to be linked to serotonergic dysregulation and appears to have symptomatology similar to depression and anxiety states.7 Serotonergic antidepressants appear to be effective in the treatment of this disorder.5,8 Women reporting premenstrual symptoms should be evaluated for underlying psychiatric illness, and PMDD should be clearly associated with symptoms during the luteal phase. Women who are candidates for treatment may be willing to take fluoxetine marketed specifically for PMDD, rather than taking the same drug labeled as an antidepressant. Fluoxetine as Sarafem is priced the same as fluoxetine as Prozac.
References
1. Gehlert S, et al. J Womens Health 1999;8(1):75-85.
2. Stotland NL. In: Novak’s Gynecology. Baltimore, Md: Lippincott Williams & Wilkins; 1996.
3. Sarafem Product Information. Eli Lilly and Company. July 2000.
4. Steiner M, et al. N Engl J Med 1995;332:1529-1534.
5. Pearlstein TB, et al. J Clin Psychopharmacol 1997; 17(4):261-266.
6. Yonkers KA, et al. JAMA 1997;278(12):983-988.
7. Halbreich U, Tworek H. Int J Psychiatry Med 1993; 23(1):1-27.
8. Freeman EW, et al. Arch Gen Psychiatry 1999;56(10): 932-939.
9. Steiner M, et al. Psychopharmacol Bull 1997;33(4): 771-774.
10. Young SA, et al. J Clin Psychiatry 1998;59(2):76-80.
11. Pearlstein TB, Stone AB. J Clin Psychiatry 1994;55(8): 332-335.
12. Eriksson E, et al. Neuropsychopharmacology 1995; 12(2):167-176.
13. Wikander I, et al. J Clin Psychopharmacol 1998; 18(5):390-398.
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