Pharmacology Update
Once-a-Week Fluoxetine, Prozac Weekly’
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
With the pending patent expiration of fluoxetine (Prozac), Eli Lilly is introducing another version of their blockbuster selective serotonin reuptake inhibitor (SSRI). Following the introduction of fluoxetine as Sarafem for premenstrual dysphoric disorder, Lilly has received FDA approval to market a once-weekly formulation of the drug for the treatment of depression. This takes advantage of the long elimination half-lives of the fluoxetine and its active metabolite, norfluoxetine, along with formulation of the drug in enteric-coated pellets. The product is marketed as Prozac Weekly.
Indications
Fluoxetine is indicated for maintaining an antidepressant response after initial acute treatment with fluoxetine 20 mg.1,2
Dosage
Fluoxetine 90 mg is dosed once-weekly. Weekly dosing should be initiated 7 days after the last daily dose of fluoxetine 20 mg. Fluoxetine Weekly is available as a 90-mg capsule.
Potential Advantages
Once-weekly dosing may improve compliance and may also enhance psychological well being.1 Findings from a study by Lilly suggest that compliance with once-weekly dosing was higher compared to daily dosing, 85.9% vs. 79.4%.3
Potential Disadvantages
It is not clear if once-weekly administered fluoxetine provides the same degree of protection from relapse as once-daily fluoxetine.2 Average trough plasma concentrations were 76% lower for fluoxetine and 47% lower for the active metabolite, norfluoxetine.2 A weekly dosing regimen is an uncommon regimen, and some patients may have difficulty remembering their doses.
The effect of variation in GI transit time (eg, diarrhea) on the pharmacokinetics of fluoxetine-weekly is not known. Fluoxetine-weekly has not been studied for other conditions such as obsessive compulsive disorders, bulimia nervosa, or premenstrual dysphoric disorder.
Comments
The long elimination half-lives of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (about 9 days) are conducive to less frequent dosing. The efficacy of a weekly regimen is supported primarily by a multicenter, placebo-controlled, double-blind, randomized study.1
Patients with DSM-IV criteria for nonpsychotic major depression and who had a modified 17-item Hamilton Rating Scale for Depression (HAM-D-17) of 18 or greater and a Clinical Global Impression-Severity of Illness scale (CGI-S) score of 4 or greater were treated with fluoxetine 20 mg for 13 weeks. A total of 501 responders (HAM-D-17 of 9 or less and CGI-S of 2 or less) were then randomized to fluoxetine 90 mg weekly, fluoxetine 20 mg, or placebo for 25 weeks. The primary end points were the percent of patients that relapsed and time to relapse. Relapse was defined as meeting criteria for major depression and an increase in CGI-S score of 2 or more relative to the rating before randomization. The percentages of relapse were 26% for fluoxetine 20 mg, 37% for fluoxetine-weekly, and 50% for placebo. While there was no statistical difference between fluoxetine regimens, daily dosing was numerically higher.
The times to relapse were 105 days, 109 days, and 86 days for fluoxetine 90 mg, 20 mg, and placebo, respectively. Nervousness and impaired concentration or thought process were the most frequent side effects for the 90-mg dose compared to the 20-mg dose, 13.7% vs. 6.3% and 8.9% vs. 1.6%, respectively. However, these side effects were similar to the frequencies seen with placebo. Prozac Weekly is priced about 5% less than Prozac daily.
Clinical Implications
Fluoxetine 90 mg weekly may be considered for maintenance therapy for patients who have responded to daily administered fluoxetine. The effectiveness may be less than that of a daily regimen in preventing relapse. If a satisfactory response is not achieved, returning to a daily regimen should be considered.
References
1. Schmidt ME, et al. J Clin Psychiatry. 2000;61(11):
851-857.
2. Prozac Product Information. Eli Lilly & Company. February 2001.
3. Claxton A, et al. J Clin Psychiatry. 2000;61(12): 928-932.
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