Fluoxetene (anti-depressant)
Pharmacology.
Fluoxetine is a bicyclic antidepressant that is a selective and potent inhibitor of presynaptic reuptake of serotonin (an SSRI). It does not affect re-uptake of norepinephrine or dopamine and has a relative lack of affinity for muscarinic, histamine,
1- and
2-adrenergic, and serotonin receptors.
Administration and Adult Dosage.
PO for depression or OCD 20 mg/day initially, administered in the morning. Increase dosage no more frequently than q 3-5 weeks. Divide higher dosages, with the last dose given in early afternoon. Although the maximum labeled dosage is 80 mg/day, 20 mg is equal in efficacy for major depression to higher dosages with the benefit of fewer adverse effects.
For depression maintenance, Prozac Weekly 90 mg once/week can be started one week after the last 20 mg/day dose.
PO for bulimia 60 mg/day in the morning.
PO for premenstrual dysphoric disorder 20 mg/day; higher dosages appear to have no increased efficacy. Administration for the 14 days before menses can be as effective as continuous use.
Special Populations.
Pediatric Dosage. (<18 yr) safety and efficacy not established.
Geriatric Dosage. Reduce initial dosage and rate of dosage increase in the elderly. Single-dose studies suggest no difference in maintenance dosage in the elderly, but data from multiple-dose studies are needed.
Other Conditions. Reduce initial dosage and rate of dosage increase in patients with hepatic impairment. Dosage adjustment in renal impairment is unnecessary.
Dosage Forms.
Cap 10, 20, 40 mg; SR cap 90 mg (Prozac Weekly); Soln 4mg/mL; Tab 10 mg.
Patient Instructions.
This drug requires at least 2 weeks for a noticeable response in mood and up to 4 weeks for full therapeutic benefit. Take fluoxetine in the morning or early afternoon. Inform your physician of any other medications you are taking.
Pharmacokinetics.
Onset and Duration. Onset is delayed 2-4 weeks, which is similar to other antidepressants.
Fate. Oral bioavailability is 95% with all dosage forms. It is 94% bound to plasma proteins, with a Vd of 35 ± 21 L/kg; Cl is 0.58 ± 0.41 L/hr/kg, decreasing with repeated administration. The primary active metabolite is norfluoxetine; the metabolic rate is possibly under polygenic control.
t¹⁄₂.
(Fluoxetine) 1-3 days after a single oral dose, increasing with multiple doses to 4-5 days; (norfluoxetine) 7-15 days. Half-lives do not appear to be altered in the elderly or in patients with renal impairment. Patients with alcohol-induced cirrhosis have fluoxetine half-life increased by 100% and norfluoxetine half-life increased by 60% compared with controls.
Adverse Reactions.
Nausea, anxiety, insomnia, nervousness, diarrhea, anorexia, dry mouth, headache, and tremor occur with a frequency greater than 10%. Delayed ejaculation and anorgasmia occurs with fluoxetine and all SSRIs in at least 30-55% of patients. Unlike TCAs, which typically cause weight gain, fluoxetine dosages over 40 mg/day cause a weight loss of 1-2 kg within the first 6 weeks of treatment.Fluoxetine rarely causes sedation except at dosages over 40 mg/day and has no adverse cardiovascular or anticholinergic effects. Initial case reports of patients developing new and intense suicidal preoccupation, agitation, and impulsiveness after several weeks of fluoxetine therapy have been adequately evaluated and found not to be directly related to the drug.
Contraindications.
Pregnancy.
Concurrent use of an MAOI; 5 weeks must elapse between discontinuation of fluoxetine and starting an MAOI.
Precautions.
Use cautiously in the elderly and in patients with hepatic impairment.
Use fluoxetine with caution in depressed patients with psychomotor agitation and anxiety or with anorexia and weight loss.
Drug Interactions.
Fluoxetine is a potent inhibitor of CYP2D6, causing decreased metabolism and increased serum levels and adverse effects of many drugs, including most other antidepressants, antipsychotics, -blockers, and type Ic antiarrhythmics. Fluoxetine’s effect on other P450 isoenzymes has not been well defined.
Parameters to Monitor.
Monitor liver function tests periodically during longterm therapy.
Notes.
Fluoxetine is a useful alternative to TCAs because of its greater safety in overdose and relative lack of anticholinergic and cardiovascular effects. For severely depressed elderly patients, fluoxetine is less effective than nortriptyline.
Fluoxetine and other SSRIs have demonstrated efficacy for OCD and panic disorder.
