Fluoxetine

Fluoxetine
Prozac®, Prozac® Weekly™, Sarafem®

Classification:
Psychotropic Agents

• Antidepressants
  
  • Selective serotonin reuptake inhibitors (SSRIs)

Description: Fluoxetine is an antidepressant agent belonging to the selective serotonin reuptake inhibitors (SSRIs); this was the first SSRI approved in the US and exhibits the longest half-life of all the SSRIs. The SSRIs are structurally distinct from the other classes of antidepressants (e.g., monoamine oxidase inhibitors and tricyclics). Fluoxetine was originally FDA-approved in December 1987 for the treatment of depression and in February 1994 for obsessive-compulsive disorder (OCD) in adults. In 1994, Eli Lilly & Co. withdrew a NDA for a higher-dosage form of fluoxetine (e.g., Lovan) for the treatment of obesity. In November 1996, the FDA granted approval for the treatment of bulimia nervosa in adults, the first drug to be approved for this condition. Fluoxetine was specifically approved for use in geriatric depression in October 1999. Fluoxetine was FDA-approved for premenstrual dysphoric disorder (PMDD) in July 2000 and is marketed under the name Sarafem®; intermittent luteal-phase dosing of Sarafem® was approved in June 2002. In February 2001, the FDA approved Prozac® Weekly™ for the maintenance treatment of depression. Other uses of fluoxetine have included the treatment of panic disorder (FDA-approved in July 2002) and post-traumatic stress. On January 3, 2003 the FDA approved fluoxetine for pediatric use in depression and OCD; fluoxetine is the only SSRI approved for the treatment of depression in children.

On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006. The dextro-isomer (R-fluoxetine) is no longer under investigation since the clinical data have revealed a possibility for QT interval prolongation.

Mechanism of Action: The precise action of SSRIs is not fully understood, but it is believed that the most important effect is the enhancement of the actions of serotonin due to highly specific serotonin reuptake blockade at the neuronal membrane. Fluoxetine also weakly inhibits the dopamine transporter. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do the tricyclic antidepressant drugs due to dramatically decreased binding to receptors of histamine, acetylcholine, and norepinephrine. Monoamine oxidase is not inhibited by any of the SSRIs. Anticholinergic activity is virtually absent. Fluoxetine is metabolized to norfluoxetine which is also active.

Pharmacokinetics: Fluoxetine is administered orally and is well absorbed from the GI tract. The presence of food can delay the rate of absorption, but not the extent. There may be some first-pass metabolism. Peak plasma concentrations from regular capsules and tablets occur in 6-8 hours. Steady-state plasma concentrations of fluoxetine and its principal active metabolite norfluoxetine are achieved in 2-4 weeks. Both fluoxetine and the active metabolite, norfluoxetine, exist as enantiomers. In-vitro, each enantiomer, except R-norfluoxetine appears to have equivalent potency in the inhibition of serotonin reuptake. However, these four compounds differ in kinetics and no relationship between serum concentrations and clinical effect has been defined. Fluoxetine is highly protein-bound (94.5%) to predominantly alpha1-acid glycoprotein. The drug is well distributed, and it readily crosses the blood-brain barrier and presumably the placenta. Fluoxetine is distributed into breast milk.

Fluoxetine is demethylated in the liver to several metabolites. The only known active metabolite is norfluoxetine, which appears to be as effective as its parent in the blockade of serotonin reuptake. Fluoxetine has the slowest elimination of the SSRIs. The elimination half-life of after chronic fluoxetine administration is 4-6 days and that of norfluoxetine is 16 days. There is considerable individual variation, which may be associated with variance in the rates of N-demethylation and hydroxylation. About 60% of an oral dose is excreted in urine within 35 days, and about 12% of the dose is excreted in the feces within 28 days.