Fluoxetine (fluoxetine HCl)

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Last reviewed · Source: First Databank (FDB) drug data

Overview

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant.

Like other selective serotonin-reuptake inhibitors (SSRIs), fluoxetine inhibits the uptake of serotonin in the CNS. In vitro, fluoxetine also antagonizes muscarinic, histaminergic, and alpha-1 adrenergic receptors in the brain less potently than tricyclic antidepressants (TCAs).

The conventional and delayed-release capsules, tablets, and solution of fluoxetine hydrochloride reportedly are bioequivalent. However, onset of absorption of once weekly fluoxetine hydrochloride delayed-release capsules is delayed 1-2 hours relative to the onset of absorption when the medication is administered as a conventional preparation. Food appears to delay absorption, but does not affect bioavailability of fluoxetine.

Peak plasma fluoxetine concentrations usually occur within 6-8 hours after oral administration of conventional preparations. Peak plasma concentrations achieved following weekly administration of fluoxetine 90-mg delayed-release capsules are in the range of the average concentrations achieved following daily administration of 20-mg conventional preparations; however, average trough concentrations are reported to be lower following weekly administration of the delayed-release preparation. Peak-to-trough fluctuations in plasma concentrations of fluoxetine and norfluoxetine (the principal metabolite) reportedly are greater following weekly administration of the delayed-release capsules (164% and 43%, respectively) compared with daily administration of conventional preparations (24% and 17%, respectively).

The relatively slow elimination of fluoxetine and its active metabolite, norfluoxetine, leads to clinically important accumulation in chronic use and delayed attainment of steady state, even when a fixed dose is used. In healthy adults receiving fluoxetine 40 mg daily for 30 days, plasma concentrations of 91-302 ng/mL and 72-258 ng/mL of fluoxetine and norfluoxetine, respectively, were attained. These plasma concentrations of fluoxetine were higher than those predicted by single-dose studies because fluoxetine's metabolism is not proportional to dose.

In addition, prolonged administration of the medication and/or patient's disease states did not appear to affect steady-state concentrations. Average steady-state fluoxetine and norfluoxetine concentrations, however, were affected by patient age. In pediatric patients with major depressive disorder or obsessive-compulsive disorder (OCD) who received fluoxetine 20 mg daily for up to 62 days, average steady-state concentrations of fluoxetine and norfluoxetine in children 6-12 years of age were 2- and 1.5-fold higher, respectively, than in adolescents 13-17 years of age who received the same fluoxetine regimen.

These results are consistent with those observed in another study in 94 pediatric patients 8-17 years of age diagnosed with major depressive disorder, and can be almost entirely explained by differences in children's weight. Higher average steady-state fluoxetine and norfluoxetine concentrations were also observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing.

Following daily oral administration of the medication, steady-state plasma fluoxetine and norfluoxetine concentrations generally are achieved within about 3-4 weeks.

The manufacturer states average steady-state plasma fluoxetine concentrations are approximately 50% lower with weekly administration of the 90-mg delayed-release capsules compared with daily administration of a 20-mg conventional preparation. In patients being switched from daily therapy with fluoxetine 20-mg conventional preparations to weekly therapy with fluoxetine 90-mg delayed-release capsules, peak plasma fluoxetine concentrations reportedly were 1.7 times higher with the weekly regimen than with the established daily regimen when there was no transition period (i.e., therapy with delayed-release fluoxetine was initiated the day after the last daily dose of fluoxetine 20 mg). When weekly therapy was initiated one week after the last daily dose of fluoxetine 20 mg, peak plasma fluoxetine concentrations for the 2 regimens were similar.

Fluoxetine is approximately 94.5% bound to plasma proteins, including albumin and alpha1-acid glycoprotein (alpha1-AGP). Fluoxetine is distributed into human milk. Fluoxetine and norfluoxetine, the principal metabolite, are eliminated slowly.

Following oral administration of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 1-3 days after acute administration and 4-6 days after chronic administration, and that of norfluoxetine averages about 4-16 days after acute and chronic administration. The long elimination half-life of fluoxetine and norfluoxetine cause the drug to persist in the body for weeks following medication discontinuation. Fluoxetine appears to be metabolized extensively in the liver to norfluoxetine and several other metabolites.

The potency and selectivity of norfluoxetine's serotonin-reuptake inhibiting activity appear to be similar to those of the parent drug. Single-dose studies suggest pharmacokinetics of fluoxetine in healthy geriatric individuals do not differ substantially from those in younger adults. However, because the medication has a relatively long half-life and nonlinear disposition following multiple-dose administration, single-dose studies are not sufficient to exclude the possibility of altered pharmacokinetics in geriatric individuals, particularly those with systemic disease and/or in those receiving multiple medications concomitantly.

The elimination half-lives of fluoxetine and norfluoxetine may be prolonged in patients with hepatic impairment.

USES: This long-acting form of fluoxetine is used to treat depression in people who have been successfully treated with the form of fluoxetine that is taken daily. Fluoxetine belongs to a class of drugs known as selective serotonin reuptake inhibitors (SSRIs). It works by helping to restore the balance of a certain natural substance (serotonin) in the brain.

Generic name: fluoxetine HCl
Pronunciation: (flew-OX-eh-teen)

Reference product & biosimilars

No reference, biosimilar or interchangeable associated with this drug.

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Indications

The following indications are listed for Fluoxetine:

  • Major Depressive Disorder

Also known as: Major Unipolar Illness, Unipolar Mood Disorder.

Dosing

Dosage of fluoxetine hydrochloride is expressed in terms of fluoxetine.

Consider prolonged elimination half-life of fluoxetine and norfluoxetine (active metabolite) when titrating dosage or discontinuing therapy. Several weeks will be required before the full effect of such alterations is realized.

Drug interactions

Fluoxetine is extensively metabolized; it is known to inhibit cytochrome P-450 (CYP) 2D6 and to a lesser extent CYP3A4.

Contraindications

*Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase inhibitor (MAOI). MAOIs are contraindicated within 5 weeks after fluoxetine discontinuation.

*Concurrent pimozide therapy.

*Concurrent thioridazine therapy. Thioridazine is contraindicated within 5 weeks after fluoxetine discontinuation.

*Known hypersensitivity to fluoxetine.

Adverse reactions

The most common adverse effects reported in at least 5% of patients in clinical studies receiving fluoxetine for major depressive disorder, OCD, bulimia nervosa, or panic disorder include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn.

Precautions

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ICD codes

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Formulary status

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Last reviewed · Source: First Databank (FDB) drug data