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Pharmacology: The antidepressant, antiobsessional and antibulimic actions of fluoxetine are presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. At clinically relevant dose, fluoxetine blocks the uptake of serotonin into human platelets. Antagonism of muscarinic, histaminergic and alpha-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects classical tricyclic antidepressant drugs. In vitro receptor binding studies have demonstrated that fluoxetine binds to these and other membrane receptors (opiate, serotonergic (5-HT1, 5-HT2), adrenergic (1, 2, B) and dopaminergic) much less potently than do the tricyclic drugs.
Pharmacokinetics: Fluoxetine is well absorbed after oral administration. In man, following a single 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/ml are observed after 6 to 8 hours. Capsule and oral solution dosage forms of fluoxetine are bioequivalent. Foods does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food.
Fluoxetine is extensively metabolized in the liver to norfluoxetine and other unidentified metabolites. The pharmacological activity of norfluoxetine, which is formed by desmethyl metabolite is similar to that of the parent drug. Norfluoxetine contributes to the long duration of action of fluoxetine. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
A two-way, single-dose, randomized, crossover bioavailability study using 18 normal male volunteers was conducted to evaluate the relative bioavailability of APO-FLUOXETINE 20 mg and Prozac 20 mg capsules (manufactured by Eli Lilly Inc.). The mean pharmacokinetics parameters obtained are listed as follows: (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageClinical Issues Related To Metabolism/Elimination: The complexity of fluoxetine's metabolism has several consequences which may potentially affect its clinical use.
Accumulation And Slow Elimination: The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) results in significant accumulation during chronic use. After 30 days of dosing at 20 mg/day, mean plasma concentrations of fluoxetine 79.1 + 33.4 ng/mL and norfluoxetine 129 + 42.0 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single dose studies, presumably because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days.
Steady state plasma levels were attained after 4 to 8 weeks on continuous drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day over periods as long as 3 years exhibited, on average, plasma concentrations similar to those seen among patients treated for 4 to 5 weeks.
Similarly because of the long half-lives of fluoxetine and norfluoxetine, it may take up to 1 to 2 months for the active drug substances to disappear from the body, this is of potential consequences in the withdrawal of fluoxetine (see Warnings).
Age: The disposition of single doses of fluoxetine in healthy elderly subjects (greater than 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases.
The effects of age upon the metabolism of fluoxetine have been investigated in a subset of 260 elderly, but otherwise healthy, depressed patients (mean age: 67.4 years, range 60 to 85 years) who received 20 mg fluoxetine for 6 weeks. The mean plasma concentrations were found to be 89.5 + 53.6 ng/mL for fluoxetine and 119 + 51.3 ng/mL for norfluoxetine.
Protein Binding: Approximately 94% of fluoxetine is protein bound. The interaction between fluoxetine and other highly protein bound drugs has not been fully evaluated, but may be important (see Warnings).
Liver Diseases: As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. In patients with cirrhosis, the elimination half-life of fluoxetine was prolonged with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver disease, norfluoxetine elimination half-life was also delayed, with a mean duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution (see Warnings and Dosage & Administration).
Renal Disease: In single dose studies, the pharmacokinetics of fluoxetine and norfluoxetine were similar among subjects with all levels of impaired renal function including anephric patients on chronic hemodialysis. However, with chronic administration, additional accumulation of fluoxetine or its metabolites [possibly including some not frequent dose is advised (see Warnings)].
The efficacy of fluoxetine was established in 6- and 5-week placebo-controlled trials in depressed outpatients (≥18 years of age), who met the DSM-III criteria for major depressive disorder.
Two-6-weeks placebo-controlled clinical trials in depressed elderly patients, who met the DSM-III-R criteria for major depressive disorder (mean age 67.4 years, range 60 to 85 years) have shown fluoxetine, 20 mg/day, to be effective.
