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Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (β1, β2, α), dopaminergic, serotonergic (5HT1, 5HT2), or histaminergic receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine receptor was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.
Clinical Trials: Depression: The efficacy of paroxetine as a treatment for depression has been established in six placebo controlled clinical trials of 6 weeks in duration performed in patients with depression (ages 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating depression according to the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI) - severity of illness.
Obsessive-Compulsive Disorder: Three double-blind, placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in obsessive-compulsive disorder: two flexible dose studies (20-60 mg/day) and one fixed dose study (20, 40 & 60 mg/day). Results for the fixed dose study and one of the flexible dose studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at endpoint according to a Clinical Global Impression of Improvement was 15% (13/88) in the placebo group, 20% (17/85) in the 20 mg/day group, 36% (30/83) in the 40 mg/day group, and 37% (31/83) in the 60 mg/day group. In the two flexible dose studies, placebo response rates according to this criterion were 28% (28/99) and 25% (19/75), while paroxetine response rates were 45% (89/198) and 35% (28/79), respectively.
Panic Disorder: One fixed dose and three flexible dose placebo-controlled clinical trials of 10 to 12 weeks in duration have been performed to investigate the efficacy of paroxetine in panic disorder. The fixed dose study and two of the three flexible dose studies were supportive of differences from placebo in favour of paroxetine for measures of panic attack frequency. At endpoint, in the fixed dose study, the proportion of patients who were free of panic attacks was 44% (29/66) for the placebo group, 56% (33/59) for the 10 mg/day paroxetine group, 57% (35/61) for the 20 mg/day paroxetine group, and 76% (47/62) for the 40 mg/day paroxetine group.
Social Phobia (Social Anxiety Disorder): One fixed dose and two flexible dose placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in social phobia (social anxiety disorder). These studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Liebowitz Social Anxiety Scale and the percentage of therapeutic responders according to the Clinical Global Impression of Improvement. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at week 12 of treatment according to the Clinical Global Impression of Improvement was 28.3% (26/92) in the placebo group, 44.9% (40/89) in the 20 mg/day group, 46.6% (41/88) in the 40 mg/day group, and 42.9% (39/91) in the 60 mg/day group. In the two flexible dose (20-50 mg/day) studies, placebo response rates according to this criterion were 23.9% (22/92) and 32.4% (47/145), while paroxetine response rates were 54.9% (50/91) and 65.7% (90/137), respectively.
Generalized Anxiety Disorder: The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) (DSM IV) was demonstrated in two 8-week, multicentre, placebo-controlled studies. One trial was a flexible dose (20-50 mg/day) study while the other was a multiple fixed dose (20 or 40 mg/day) study. In both studies paroxetine demonstrated statistically significant superiority over placebo on the primary outcome measure - the Hamilton Rating Scale for Anxiety (HAM-A) total score, and on a number of secondary outcomes including the HAM-A anxiety and tension items, the Clinical Global Impression (CGI) responder criterion and the Sheehan Disability Scale (SDS). An additional 8-week flexible dose study did not demonstrate a significant difference between paroxetine (20-50 mg/day), and placebo on the primary outcome measure. However, paroxetine (20-50 mg/day) was more effective than placebo on many secondary study outcomes.
Post-traumatic Stress Disorder: The efficacy of paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12 week, multicenter placebo controlled studies (Study 1 and Study 2) in adult patients who met the DSM-IV criteria for PTSD. Study outcome was assessed by (i) the Clinician Administered PTSD Scale Part (CAPS-2) score and (ii) the Clinical Global Impression Global Improvement Item (CGI-I). The CAPS-2 is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of: re-experiencing/intrusion, avoidance/numbing and hyper arousal. The two primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved).
Study 1 was a 12 week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Paroxetine 20 mg and 40 mg were demonstrated to be significantly superior to placebo for the CAPS-2 total score, and on proportion of responders on the CGI-I.
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 mg to 50 mg daily) to placebo. Paroxetine was demonstrated to be significantly superior to placebo for the CAPS-2 total scorer, and on proportion of responders on the CGI-I. The majority (66-68%) of patients in these trials were women. Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years or older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.
Pharmacokinetics: Human Pharmacokinetics: Paroxetine is well absorbed after oral administration. In healthy volunteers, the absorption of a single 30 mg oral dose of paroxetine was not appreciably affected by the presence or absence of food. Owing to the extensive distribution of paroxetine into the tissues, less than 1% of the total drug in the body is believed to reside in the systemic circulation.
Paroxetine is subject to a biphasic process of metabolic elimination which involves presystemic (first-pass) and systemic pathways. First-pass metabolism is extensive, but may be partially saturable, accounting for the increased bioavailability observed with multiple dosing. The metabolism of paroxetine is accomplished in part by cytochrome P450(IID6). Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). The majority of the dose appears to be oxidized to a catechol intermediate which is converted to highly polar glucuronide and sulphate metabolites through methylation and conjugation reactions. The glucuronide and sulphate conjugates of paroxetine are about >10,000 and 3,000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes. Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in the faeces. Less than 2% of the dose is recovered in the form of the parent compound.
A wide range of interindividual variation is observed for the pharmacokinetic parameters.
Following the single or multiple dose administration of paroxetine at doses of 20 to 50 mg, the mean elimination half-life value for healthy subjects appears to be about 24 hours, although a range of 3 to 65 hours has been reported. Both the rate of absorption and the terminal elimination half-life appear to be independent of dose. Steady-state plasma concentrations of paroxetine are generally achieved in 7 to 14 days. No correlation has been established between paroxetine plasma concentrations and therapeutic efficacy or the incidence of adverse reactions.
No clear dose relationship has been demonstrated for the antidepressant effects of paroxetine at doses above 20 mg/day. The results of fixed-dose studies comparing paroxetine and placebo in the treatment of depression, panic disorder, generalized anxiety disorder and posttraumatic stress disorder revealed a dose dependency for some adverse events.
In healthy young volunteers receiving a 20 mg daily dose of paroxetine for 15 days, the mean maximal plasma concentration was 41 ng/mL at steady state (see Table 1). Peak plasma levels generally occurred within 3 to 7 hours.
In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half life were observed relative to younger adult controls (Table 1). Elderly patients should, therefore, be initiated and maintained at the lowest daily dosage of paroxetine which is associated with clinical efficacy.
The results from a multiple dose pharmacokinetic study in subjects with severe hepatic dysfunction suggest that the clearance of paroxetine is markedly reduced in this patient group (see Table 1). As the elimination of paroxetine is dependent upon extensive hepatic metabolism, its use in patients with hepatic impairment should be undertaken with caution (see DOSAGE & ADMINISTRATION).
In a single dose pharmacokinetic study in patients with mild to severe renal impairment, plasma levels of paroxetine tended to increase with deteriorating renal function (see Table 2).
As multiple-dose pharmacokinetic studies have not been performed in patients with renal disease, paroxetine should be used with caution in such patients.
At therapeutic concentrations, the plasma protein binding of paroxetine is approximately 95%. After the administration of a single 50 mg oral dose to lactating women, the concentrations of paroxetine detected in breast milk were similar to those in plasma. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageAbbreviations: Cmax = maximum plasma concentration; Tmax = time to reach Cmax.
AUCss = area under the plasma concentration time curve between dosing intervals (i.e. 24 hrs) at steady state.
AUC∞ = area under the plasma concentration time curve at infinity.
t½ = terminal elimination half-life; ss = steady state.
