indication

Labeled indications include: major depressive disorder (MDD), panic disorder with or without agoraphobia, obsessive-compulsive disorder (OCD), social anxiety disorder (social phobia), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD). Unlabeled indications include: eating disorders, impulse control disorders, vasomotor symptoms of menopause, obsessive-compulsive disorder (OCD) in children, and mild dementia-associated agitation in nonpsychotic individuals.

pharmacology

Paroxetine, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type, has no active metabolites and has the highest specificity for serotonin receptors of all the SSRIs. It is used to treat depression resistant to other antidepressants, depression complicated by anxiety, panic disorder, social and general anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder, premature ejaculation, and hot flashes of menopause in women with breast cancer.

mechanism of action

Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine likely inhibits the reuptake of serotonin at the neuronal membrane, enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter, therefore it prolongs its activity at synaptic receptor sites and potentiates 5-HT in the CNS; paroxetine is more potent than both sertraline and fluoxetine in its ability to inhibit 5-HT reuptake. Compared to the tricyclic antidepressants, SSRIs have dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors.

toxicity

LD₅₀=500mg/kg (orally in mice). Symptoms of overdose include: coma, dizziness, drowsiness, facial flushing, nausea, sweating, tremor, vomiting. Side effects include: nervous system effects such as asthenia, somnolence, dizziness, insomnia, tremor, and nervousness; GI effects such as nausea, decreased appetite, constipation, diarrhea, and dry mouth; impotence, ejaculatory dysfunction (principally ejaculatory delay), and other male genital disorders; female genital disorders (principally anorgasmia or difficulty reaching climax/orgasm); and sweating. Discontinuation syndrome may occur with abrupt withdrawal. Symptoms of discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory changes, and hyperactivity.

biotransformation

Paroxetine is extensively metabolized, likely in the liver. The main metabolites are polar and conjugated products of oxidation and methylation, which are readily eliminated by the body. The predominant metabolites are glucuronic acid and sulfate conjugates. Paroxetine metabolites do not possess significant pharmacologic activity (less than 2% that of parent compound). Paroxetine is metabolized by cytochrome P450 (CYP) 2D6. Enzyme saturation appears to account for the nonlinear pharmacokinetics observed with increasing dose and duration of therapy.

absorption

Paroxetine hydrochloride is slowly, but completely absorbed following oral administration. The oral bioavailability appears to be low due to extensive first-pass metabolism. Paroxetine hydrochloride oral tablets and suspension are reportedly bioequivalent. Paroxetine mesylate is completely following oral administration. Absorption of either salt form is not substantially affected by food.

half life

21-24 hours

route of elimination

Paroxetine is extensively metabolized and the metabolites are primarily excreted in the urine and to some extent in the feces.

drug interactions

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

Almotriptan: Increased risk of CNS adverse effects

Amphetamine: Risk of serotoninergic syndrome

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

Atomoxetine: The CYP2D6 inhibitor, paroxetine, may 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.

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

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, paroxetine, increases the effect of anticoagulant, dicumarol.

Diethylpropion: Risk of serotoninergic syndrome

Eletriptan: Increased risk of CNS adverse effects

Fenfluramine: Risk of serotoninergic syndrome

Frovatriptan: Increased risk of CNS adverse effects

Galantamine: Paroxetine increases the effect and toxicity of galantamine

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

Isocarboxazid: Possible severe adverse reaction 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: Combination associated with possible serotoninergic syndrome

Mazindol: Risk of serotoninergic syndrome

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Methamphetamine: Risk of serotoninergic syndrome

Metoprolol: The SSRI increases the effect of the beta-blocker

Moclobemide: Possible severe adverse reaction with this combination

Naratriptan: Increased risk of CNS adverse effects

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

Pimozide: Increased risk of cardiotoxicity and arrhythmias.

Propafenone: Paroxetine may increase the effect and toxicity of propafenone.

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

Rasagiline: Possible severe adverse reaction with this combination

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

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, paroxetine.

Sumatriptan: Increased risk of CNS adverse effects

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

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

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

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

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

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

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

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

Tramadol: Tramadol may increase the risk of serotonin syndrome and seizures. Paroxetine 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, Paroxetine. Monitor for increased bleeding during concomitant thearpy.

Trimipramine: The SSRI, Paroxetine, may decrease the metabolism and clearance of Trimipramine. Increased risk of serotonin syndrome. Monitor for changes in Trimipramine efficacy and toxicity if Paroxetine is initiated, discontinued or dose changed.

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

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

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

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

Zuclopenthixol: Paroxetine, 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 paroxetine is initiated, discontinued or dose changed.