indication

Labeled indication include: major depressive disorder (MDD), moderate to severe bulimia nervosa, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), panic disorder with or without agoraphobia, and combination treatment with olanzapine for treatment-resistant or bipolar I depression. Unlabeled indications include: selective mutism, mild dementia-associated agitation in nonpsychotic patients, post-traumatic stress disorder (PTSD), social anxiety disorder, chronic neuropathic pain, fibromyalgia, and Raynaud's phenomenon.

pharmacology

Fluoxetine, an antidepressant agent belonging to the selective serotonin reuptake inhibitors (SSRIs), is used to treat depression, bulimia nervosa, premenstrual dysphoric disorder, panic disorder and post-traumatic stress. According to the amines hypothesis, a functional decrease in the activity of amines, such as serotonin and norepinephrine, would result in depression; a functional increase of the activity of these amines would result in mood elevation. Fluoxetine's effects are thought to be associated with the inhibition of 5HT receptor, which leads to an increase of serotonin level.

mechanism of action

Metabolized to norfluoxetine, fluoxetine is a selective serotonin-reuptake inhibitor (SSRI), it blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.

toxicity

Symptoms of overdose include agitation, restlessness, hypomania, and other signs of CNS excitation. LD₅₀=284mg/kg (orally in mice). The most frequent side effects include: nervous system effects such as anxiety, nervousness, insomnia, drowsiness, fatigue or asthenia, tremor, and dizziness or lightheadedness; GI effects such as anorexia, nausea, and diarrhea; vasodilation; dry mouth; abnormal vision; decreased libido; abnormal ejaculation; rash; and sweating. Withdrawal symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory changes and hyperactivity.

biotransformation

Limited data from animal studies suggest that fluoxetine may undergo first-pass metabolism may occur via the liver and/or lungs. Fluoxetine appears to be extensively metabolized, likely in the liver, to norfluoxetine and other metabolites. Norfluoxetine, the principal active metabolite, is formed via N-demethylation of fluoxetine. Norfluoxetine appears to be comparable pharmacologic potency as fluoxetine. Fluoxetine and norfluoxetine both undergo phase II glucuronidation reactions in the liver. It is also thought that fluoxetine and norfluoxetine undergo O-dealkylation to form p-trifluoromethylphenol, which is then subsequently metabolized to hippuric acid.

absorption

Well absorbed from the GI tract following oral administration. Oral bioavailability is estimated to be at least 60-80%. Peak plasma concentrations occur within 4-8 hours following oral administration of conventional dosage preparations.

half life

1-3 days

route of elimination

The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

drug interactions

Acenocoumarol: The SSRI, fluoxetine, increases the effect of anticoagulant, acenocoumarol.

Almotriptan: Increased risk of CNS adverse effects

Amitriptyline: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amitriptyline if fluoxetine is initiated, discontinued or dose changed.

Amoxapine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amoxapine if fluoxetine is initiated, discontinued or dose changed.

Amphetamine: Risk of serotoninergic syndrome

Anisindione: The SSRI, fluoxetine, increases the effect of anticoagulant, anisindione.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Benzphetamine: Amphetamines may enhance the adverse/toxic effect of Serotonin Modulators. The risk of serotonin syndrome may be increased. Monitor patients closely for signs and symptoms of serotonin syndrome (e.g., agitation, tremor, tachycardia, etc.) when using amphetamines and serotonin modulators in combination.

Carbamazepine: Carbamazepine may decrease the serum concentration of fluoxetine by increasing its metabolism. Fluoxetine may increase the serum concentration of carbamazepine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or doses are changed.

Carvedilol: The SSRI, fluoxetine, may increase the bradycardic effect of the beta-blocker, carvedilol.

Cilostazol: Fluoxetine, a moderate CYP2C19 inhibitor, may decrease the metabolism of cilostazol. Monitor for changes in the therapeutic and adverse effects of cilostazol if fluoxetine is initiated, discontinued or dose changed.

Clarithromycin: Possible serotoninergic syndrome with this combination

Clomipramine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of clomipramine if fluoxetine is initiated, discontinued or dose changed.

Clozapine: The antidepressant increases the effect of clozapine

Cyclosporine: The antidepressant increases the effect and toxicity of cyclosporine

Cyproheptadine: Possible antagonism of action

Desipramine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of desipramine if fluoxetine is initiated, discontinued or dose changed.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dexfenfluramine: Risk of serotoninergic syndrome

Dextroamphetamine: Risk of serotoninergic syndrome

Dextromethorphan: Combination associated with possible serotoninergic syndrome

Dicumarol: The SSRI, fluoxetine, increases the effect of anticoagulant, dicumarol.

Diethylpropion: Risk of serotoninergic syndrome

Dihydroergotamine: Possible ergotism and severe ischemia with this combination

Doxepin: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, doxepin, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of doxepin if fluoxetine is initiated, discontinued or dose changed.

Eletriptan: Increased risk of CNS adverse effects

Ergotamine: Possible ergotism and severe ischemia with this combination

Erythromycin: Possible serotoninergic syndrome with this combination

Ethotoin: Fluoxetine increases the effect of phenytoin

Fenfluramine: Risk of serotoninergic syndrome

Fosphenytoin: Fluoxetine increases the effect of phenytoin

Frovatriptan: Increased risk of CNS adverse effects

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Imipramine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of imipramine if fluoxetine is initiated, discontinued or dose changed.

Isocarboxazid: Possible severe adverse reaction with this combination

Josamycin: Possible serotoninergic syndrome with this combination

Ketoprofen: Concomitant therapy may result in additive antiplatelet effects and increase the risk of bleeding. Monitor for increased risk of bleeding during concomitant therapy.

Linezolid: Linezolide, a MAO inhibitor, may increase the serotonergic effect of fluoxetine, a SSRI. Increased for of serotonin syndrome. Concomitant therapy should be avoided.

Lithium: The SSRI, fluoxetine, increases serum levels of lithium.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mazindol: Risk of serotoninergic syndrome

Mephenytoin: Fluoxetine increases the effect of phenytoin

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Methamphetamine: Risk of serotoninergic syndrome

Metoprolol: The SSRI, fluoxetine, may increase the bradycardic effect of the beta-blocker, metoprolol.

Moclobemide: Risk of serotoninergic syndrome

Naratriptan: Increased risk of CNS adverse effects

Nortriptyline: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of nortriptyline if fluoxetine is initiated, discontinued or dose changed.

Oxycodone: Increased risk of serotonin syndrome

Phendimetrazine: Risk of serotoninergic syndrome

Phenelzine: Possible severe adverse reaction with this combination

Phentermine: Risk of serotoninergic syndrome

Phenylpropanolamine: Risk of serotoninergic syndrome

Phenytoin: Fluoxetine increases the effect of phenytoin

Propafenone: Additive QTc-prolongation may occur increasing the risk of serious life-threatening arrhythmias. Fluoxetine may also increase the serum concentration of propafenone. Use caution during concomitant therapy and monitor for QTc-prolongation.

Propranolol: The SSRI, fluoxetine, may increase the bradycardic effect of the beta-blocker, propranolol.

Protriptyline: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, protriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of protriptyline if fluoxetine is initiated, discontinued or dose changed.

Rasagiline: Possible severe adverse reaction with this combination

Risperidone: The SSRI, fluoxetine, increases the effect and toxicity of risperidone.

Ritonavir: Increased risk of serotonin syndrome

Rizatriptan: Increased risk of CNS adverse effects

Selegiline: Possible severe adverse reaction with this combination

Sibutramine: Risk of serotoninergic syndrome

St. John's Wort: St. John's Wort increases the effect and toxicity of the SSRI, fluoxetine.

Sumatriptan: Increased risk of CNS adverse effects

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by Fluoxetine, a CYP1A2 inhibitors. Monitor the efficacy and toxicity of Tacrine if Fluoxetine is initiated, discontinued or if the dose is changed.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Tamoxifen: Fluoxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Tamsulosin: Fluoxetine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Fluoxetine is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Fluoxetine. Consider alternate therapy or monitor for therapeutic/adverse effects of Fluoxetine if Terbinafine is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tiaprofenic acid: Additive antiplatelet effects increase the risk of bleeding. Consider alternate therapy or monitor for increased bleeding.

Tipranavir: Tipranavir increases the concentration of Fluoxetine. The Fluoxetine dose may require an adjustment.

Tizanidine: Fluoxetine may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Fluoxetine. Consider alternate therapy or monitor for changes in Fluoxetine therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Tolmetin: Increased antiplatelet effects may enhance the risk of bleeding. Alternate therapy may be considered or monitor for inreased bleeding during concomitant therapy.

Tolterodine: Fluoxetine may decrease the metabolism and clearance of Tolterodine. Monitor for adverse/toxic effects of Tolterodine.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: The use of two serotonin modulators, such as fluoxetine and tramadol, may increase the risk of serotonin syndrome. Fluoxetine may decrease the effect of tramadol by decreasing active metabolite production.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Fluoxetine. Monitor for increased bleeding during concomitant thearpy.

Trimipramine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, trimipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used cautiously.

Triprolidine: The CNS depressants, Triprolidine and Fluoxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Troleandomycin: Possible serotoninergic syndrome with this combination

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Warfarin: The SSRI, fluoxetine, increases the effect of anticoagulant, warfarin.

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and fluoxetine, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). Fluoxetine, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if fluoxetine is initiated, discontinued or dose changed.