Antidepressants
- Selective serotonin reuptake inhibitors (SSRIs)
Description: Paroxetine is an oral antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type. Paroxetine has no active metabolites and has the highest specificity for serotonin receptors of all the SSRIs. It is efficacious in treating adults with depression resistant to other antidepressants, depression complicated by anxiety, and for all the major anxiety syndromes. Off-label uses in adults include the treatment of premature ejaculation, and hot flashes in menopausal women with breast cancer. It is unclear whether paroxetine is effective for diabetic neuropathy; further study is needed. Paroxetine is not currently approved for use in pediatric patients < 18 years of age. The FDA has issued a statement that paroxetine should not be used in children or adolescents with major depressive disorder. On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. According to the FDA, there are 3 well-controlled trials that have shown paroxetine is no more effective than placebo for treatment of depression in pediatric patients; additionally package labeling for paroxetine states that efficacy in pediatric depression has not been demonstrated. British regulators have banned the use of many SSRIs in pediatric patients due to the apparent risk of suicide. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006. Paroxetine (Paxil®) was originally approved by the FDA in December 1992 for the treatment of major depression in adults. In 1996, paroxetine was subsequently approved for obsessive-compulsive disorder (OCD) and panic disorder in adults. FDA-approval for the treatment of social anxiety disorder in adults was awarded in May 1999. Paroxetine (Paxil®) was additionally FDA-approved for generalized anxiety disorder (GAD) in adults in April 2001; and for the treatment of adults with post-traumatic stress disorder (PTSD) in December 2001. An extended-release tablet (Paxil® CR™) was initially FDA-approved for the treatment of depression in adults in February 1999; followed by an indication for panic disorder in February 2002, continuous (approved September 2003) and intermittent (approved February 2004) treatment of premenstrual dysphoric disorder (PMDD), and social anxiety disorder (SAD) in adults in October 2003. A generic version of paroxetine hydrochloride was FDA-approved in August 2003 and is commercially available as of September 2003. A new salt form of paroxetine, paroxetine mesylate (Pexeva™; Synthon Pharmaceuticals), was FDA-approved in July 2003 for the treatment of depression, OCD and/or panic disorder. Pexeva™ is commercially available as of March 2004, and is bioequivalent to Paxil®.
Mechanism of Action: Paroxetine potentiates serotonin (5-HT) in the CNS. Paroxetine does not affect norepinephrine as do many tricyclic antidepressants. The precise action of SSRIs is not fully understood, but it is believed that paroxetine and related agents inhibit reuptake of serotonin at the neuronal membrane. According to rat brain in vitro studies, paroxetine is several fold more potent than sertraline and significantly more potent than fluoxetine in ability to inhibit 5-HT reuptake. SSRIs have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs due to dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors. Monoamine oxidase is not inhibited by any of the SSRIs. Anticholinergic activity is virtually absent.
Pharmacokinetics: Paroxetine formulations are administered orally and are completely absorbed. Paxil® CR™ controlled-release tablets are enteric coated to delay the start of drug release until the tablets have left the stomach; they are also designed via the Geomatrix™ polymeric matrix to allow for a 4 - 5 hour dissolution rate, with a Tmax occurring roughly 6 - 10 hours after dosing. The bioavailability of paroxetine, regardless of dosage form, is not affected by food. There appears to be individual patient variation in response, but steady-state concentrations are achieved in about 10 - 14 days with either the immediate-release or controlled-release formulations. The onset of action, however, may require 1 - 4 weeks of therapy. The drug is widely distributed, including into the CNS. Only 1% of paroxetine remains in the plasma, and it is 93 - 95% bound to plasma protein; however, the drug does not displace other highly protein-bound drugs.
Based on pharmacokinetic studies, the steady state paroxetine exposure based on AUC is several fold higher than with a single dose. The excess accumulation is a consequence of a saturable metabolic pathway. Paroxetine is extensively metabolized via oxidation, methylation and conjugation to several metabolites, none of which shows any appreciable pharmacological activity. Conjugates with glucuronic acid and sulfate predominate. Metabolism is partly achieved by cytochrome P-450 isoenzymes, predominantly CYP2D6. Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by alternative CYP450 isozymes like CYP3A4, which, unlike CYP2D6, do not show evidence of saturation. Excretion is mainly renal (about 62%), mostly as metabolites and about 2% as unchanged drug. Roughly 36% is excreted in the feces, mainly via the bile as metabolites. The mean elimination half-life of the immediate-release paroxetine is approximately 21 hours while the elimination half-life for the controlled-release product is 15 - 20 hours.
- Special populations: The elderly and patients with severe renal or hepatic impairment are predisposed to increased plasma concentrations of paroxetine, and thus these populations require lower initial dosing. Patients with mild to moderate renal impairment (CrCl 30 - 60 ml/min) may exhibit a two-fold increase in AUC and peak serum concentrations of paroxetine compared to normal subjects. Patients with severe renal dysfunction (CrCl < 30 ml/min) may exhibit a four-fold increase in mean plasma concentrations of paroxetine compared to normal subjects, and the elimination half-life may be prolonged to 55 hours. Cirrhosis results in increased plasma concentrations and a prolonged elimination half-life of roughly 30 hours.
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