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Pharmacology: Pharmacodynamics: Seroxat: Mechanism of Action: Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and effectiveness in the treatment of OCD, Social Anxiety disorder/Social Phobia, General Anxiety Disorder, Post-Traumatic Stress Disorder and Panic Disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones. Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants.
Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties.
In accordance with this selective action, in vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for alpha1, alpha2 and beta-adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties.
Pharmacodynamic Effects: Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol.
As with other selective 5-HT uptake inhibitors, paroxetine causes symptoms of excessive 5-HT receptor stimulation when administered to animals previously given monoamine oxidase (MAO) inhibitors or tryptophan.
Behavioural and EEG studies indicate that paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature.
Animal studies indicate that paroxetine is well tolerated by the cardiovascular system. Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects.
Studies indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.
In the treatment of depressive disorders, paroxetine exhibits comparable efficacy to standard antidepressants.
There is also some evidence that paroxetine may be of therapeutic value in patients who have failed to respond to standard therapy.
Morning dosing with paroxetine does not have any detrimental effect on either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy.
Adult suicidality analysis: A paroxetine-specific analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (aged 18-24 years) treated with paroxetine compared with placebo (2.19% vs 0.92%). In the older age groups, no such increase was observed. In adults with major depressive disorder (all ages), there was an increase in the frequency of suicidal behaviour in patients treated with paroxetine compared with placebo (0.32% vs 0.05%); all of the events were suicide attempts. However, the majority of these attempts for paroxetine (8 of 11) were in younger adults (see Precautions).
Dose response: In the fixed dose studies there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, there are some clinical data suggesting that up-titrating the dose might be beneficial for some patients.
Long-term efficacy: The long-term efficacy of paroxetine in depression has been demonstrated in a 52-week maintenance study with relapse prevention design: 12% of patients receiving paroxetine (20-40 mg daily) relapsed, versus 28% of patients on placebo.
The long-term efficacy of paroxetine in treating obsessive compulsive disorder has been examined in three 24-week maintenance studies with relapse prevention design. One of the three studies achieved a significant difference in the proportion of relapsers between paroxetine (38%) compared to placebo (59%).
The long-term efficacy of paroxetine in treating panic disorder has been demonstrated in a 24-week maintenance study with relapse prevention design: 5% of patients receiving paroxetine (10-40 mg daily) relapsed, versus 30% of patients on placebo. This was supported by a 36-week maintenance study.The long-term efficacy of paroxetine in treating social anxiety disorder and generalised anxiety disorder and Post-Traumatic Stress Disorder has not been sufficiently demonstrated.
Adverse Events from Paediatric Clinical Trials: In short-term (up to 10-12 weeks) clinical trials in children and adolescents, the following adverse events were observed in paroxetine-treated patients at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Increased hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age. Additional events that were more often seen in the paroxetine compared to placebo group were: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations).
In studies that used a tapering regimen, symptoms reported during the taper phase or upon discontinuation of paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain (see Precautions).
In five-parallel group studies with a duration of eight weeks up to eight months of treatment, bleeding related adverse events, predominantly of the skin and mucous membranes, were observed in paroxetine-treated patients at a frequency of 1.74% compared to 0.74% observed in placebo-treated patients.
Seroxat CR: Mechanism of Action: Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) reuptake. This activity of the drug on brain neurons is thought to be responsible for its antidepressant and anxiolytic action in the treatment of depression, panic disorder and social anxiety disorder.
Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), 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 SEROXAT CR controlled-release tablets as a treatment for depression has been established in two 12-week, flexible dose, placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study included patients in the age range 18-65 years, and a second study included elderly patients, ranging in age from 60-88. In both studies, SEROXAT CR was shown to be significantly more effective than placebo in treating depression as measured by the following: Hamilton Depression Rating Scale Total Score (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness score.
A study of outpatients with recurrent major depressive disorder who had responded to immediate-release paroxetine tablets (HDRS total score < 8) during an initial 8-week open-treatment phase and were then randomized to continuation on immediate-release paroxetine tablets or placebo for 1 year demonstrated that a significantly lower proportion of patients treated with paroxetine (15%) compared to placebo (39%) met criteria for partial relapse1. Criteria for full relapse2 were met by a significantly lower percentage of paroxetine treated patients (12%) compared to placebo treated patients (28%). Effectiveness was similar for male and female patients.
1. Partial relapse was characterized by requirement for additional antidepressant medication and fulfillment of DSM IIIR criteria for major depressive episode.
2. Full relapse was characterized by requirement for additional antidepressant treatment, fulfillment of DSM IIIR criteria for major depressive episode, deterioration in depressive symptoms for at least 1 week, increase in CGI-Severity of Illness score by ≥ 2 points and CGI-Severity of Illness score of ≥ 4 (least moderately ill).
Panic Disorder: The effectiveness of SEROXAT CR in the treatment of panic disorder was evaluated in three 10-week, multicentre, flexible dose studies (Studies 1, 2, and 3) comparing paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their outcomes on three variables: (1) the proportions of patients free of full panic attacks at endpoint; (2) change from baseline to endpoint in the median number of full panic attacks; and (3) change from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1 and 2, SEROXAT CR was consistently superior to placebo on two of these three variables. Study 3 failed to consistently demonstrate a significant difference between SEROXAT CR and placebo on any of these variables.
For all three studies, the mean SEROXAT CR dose for completers at endpoint was approximately 50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.
Social Anxiety Disorder: The effectiveness of SEROXAT CR in the treatment of social anxiety disorder was demonstrated in a 12-week, multicentre, double-blind, flexible dose, placebo-controlled study of adult outpatients with a primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of SEROXAT CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1) change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the proportion of responders who scored 1 or 2 (very much improved or much improved) on the Clinical Global Impression (CGI) Global Improvement score.
SEROXAT CR demonstrated statistically significant superiority over placebo on both the LSAS total score and the CGI Improvement responder criterion. For patients who completed the trial, 64% of patients treated with SEROXAT CR compared to 34.7% of patients treated with placebo were CGI Improvement responders.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of gender. Subgroup analyses of studies utilizing the immediate release formulation of paroxetine generally did not indicate differences in treatment outcomes as a function of age, race or gender.
Premenstrual Dysphoric Disorder (PMDD): The effectiveness of SEROXAT CR for the treatment for Premenstrual Dysphoric Disorder (PMDD) has been assessed in 4 placebo-controlled trials. Patients in these trials met DSM-IV criteria for PMDD. In 3 studies, patients (n=1030) were treated with SEROXAT CR 12.5 or 25 mg/day or placebo continuously throughout the menstrual cycle for a period of 3 months. In the fourth study, patients (n=366) were treated for the 2 weeks prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with SEROXAT CR 12.5 or 25 mg/day or placebo for a period of 3 months. The Visual Analogue Scale (VAS)-Mood score which consists of the mean VAS scores for the 4 core PMDD symptoms, irritability, tension, depressed mood and affective lability, was the primary efficacy measure. SEROXAT CR 25 mg/day as continuous dosing and as luteal phase dosing were significantly more effective than placebo as measured by change from baseline luteal phase VAS-Mood score in all 4 studies. SEROXAT CR 12.5 mg/day was significantly more effective than placebo as measured by change from baseline luteal phase VAS-Mood score in 2 of the 3 continuous studies and in the one luteal phase study.
There is insufficient information to determine the effect of race or age on outcome in these studies.
Patients on systemic hormonal contraceptives were excluded from these trials. Therefore, the efficacy of SEROXAT CR in combination with systemic (including oral) hormonal contraceptives for the treatment of PMDD is unknown.
Pharmacokinetics: Seroxat: Absorption: Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. Partial saturation of the first-pass effect and reduced plasma clearance occur as the body burden increases with higher single doses or on multiple dosing. This results in disproportionate increases in plasma concentrations of paroxetine and hence pharmacokinetic parameters are not constant, resulting in non-linear kinetics. However, the non-linearity is generally small and is confined to those subjects who achieve low plasma levels at low doses.
Steady state systemic levels are attained by 7 to 14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy.
Distribution: Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate that only 1% of the paroxetine in the body resides in the plasma.
Approximately 95% of the paroxetine present is protein bound at therapeutic concentrations.
No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).
Biotransformation: The principal metabolites of paroxetine are polar and conjugated products of oxidation and methylation which are readily cleared. In view of their relative lack of pharmacological activity, it is most unlikely that they contribute to paroxetine's therapeutic effects.
Metabolism does not compromise paroxetine's selective action on neuronal 5-HT uptake.
Elimination: Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.
Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine.
The elimination half-life is variable but is generally about one day.
Special Patient Populations: Older people and Renal/Hepatic Impairment: Increased plasma concentrations of paroxetine occur in elderly subjects and in those subjects with severe renal impairment or in those with hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.
Seroxat CR: SEROXAT CR tablets contain a degradable polymeric matrix designed to control the dissolution rate of paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until SEROXAT CR tablets have left the stomach.
Absorption: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male and female subjects (n=23) received single oral doses of SEROXAT CR at four dosage strengths (12.5 mg, 25 mg, 37.5 mg and 50 mg), paroxetine Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate-release formulations). Mean Cmax and AUC0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL, and 121, 261, 338, and 540 ng/hr/mL, respectively. Tmax was observed typically between 6 and 10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release formulations. The mean elimination half-life of paroxetine was 15 to 20 hours throughout this range of single SEROXAT CR doses. The bioavailability of 25 mg SEROXAT CR is not affected by food.
During repeated administration of SEROXAT CR (25 mg once daily), steady state was reached within two weeks (i.e., comparable to immediate-release formulations). In a repeat-dose study in which normal male and female subjects (n=23) received SEROXAT CR (25 mg daily), mean steady state Cmax, Cmin and AUC0-24 values were 30 ng/mL, 20 ng/mL and 550 ng.hr./mL, respectively.
Based on studies using immediate-release formulations, steady-state drug exposure based on AUC0-24 was several-fold greater than would have been predicted from single-dose data. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of the immediate-release formulation of 20 to 40 mg daily for the elderly and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.
In healthy young volunteers receiving a 20 mg daily dose of immediate-release 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.
Distribution: Approximately 95% of the paroxetine present is protein bound at therapeutic concentrations.
Metabolism: 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 Interactions). 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.
Excretion: Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in faeces. Less than 2% of the dose is recovered in the form of the parent compound.
Special Patient Populations: Geriatrics: 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 (see Dosage & Administration).
Hepatic Insufficiency: The results from a multiple dose pharmacokinetic study with immediate-release paroxetine, 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).
Renal Insufficiency: 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 (see Dosage & Administration). (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageToxicology: Seroxat: Preclinical safety data: Toxicology studies have been conducted in rhesus monkeys and albino rats; in both, the metabolic pathway is similar to that described for humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies of up to one-year duration at doses that were six times higher than the recommended range of clinical doses.
Carcinogenesis: In two-year studies conducted in mice and rats, paroxetine had no tumorigenic effect.
Genotoxicity: Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Reproduction toxicity studies in rats have shown that paroxetine affects male and female fertility by reducing fertility index and pregnancy rate. In rats, increased pup mortality and delayed ossification were observed. The latter effects were likely related to maternal toxicity and are not considered a direct effect on the foetus/neonate.
Seroxat CR: General toxicity studies have been conducted in rhesus monkeys and rats, in both of which the metabolic pathway for paroxetine is the same as in man.
Acute Toxicity: In relation to the clinical dose, the acute LD50 of paroxetine is very high in both mice and rats (approximately 350 mg/kg).
Long-Term Toxicity: The no-toxic effect levels in the rhesus monkeys and rats were 4-10 times and 6-15 times the recommended range of clinical doses respectively. At higher doses (40 mg/kg for 3 months and 25 mg/kg for 12 months), lipidosis was observed in several tissues of rats (lungs, mesenteric lymph nodes, epididymides, retinal tissues - the latter by electron microscopy only). As paroxetine is a lipophilic amine with both hydrophobic and hydrophilic moieties, it may accumulate in lysosomes leading to an impairment of lipid catabolism and, hence, the accumulation of lipids within the lysosomes. It should be noted that the slight degree of lipidosis seen in the rat was restricted to doses and plasma levels much higher than those observed in man. In a clinical study investigating lamellated inclusion bodies in peripheral white blood cells during long-term therapy, no difference between placebo and paroxetine could be detected.
Carcinogenicity: No carcinogenic potential was detected in rat (dose levels of 1, 5 and 20 mg/kg/day) and mouse (dose levels of 1, 5 and 25 mg/kg/day) life-span studies. A non dose-related increase in malignant liver cell tumours occurred in male mice at 1 and 5 mg/kg/day which was statistically significant at 5 mg/kg/day. There was no increase at 25 mg/kg/day or in female mice and the incidence was within the historical control range.
Reproduction and Impairment of Fertility Studies: 5-Hydroxytryptamine and compounds modulating this amine are known to affect reproductive function in animals and at high dose levels cause marked overt toxicity. Paroxetine at 15 and 50 mg/kg (hydrochloride salt) has been shown to impair reproductive function in rats.
Teratology Studies: In male rats, chronic administration of a 50 mg/kg dose has been associated with granulomatous reactions in the epididymides accompanied by atrophy and degeneration of the seminiferous tubules. There were no biologically significant effects on fertility of female rats but corpora lutea count was slightly reduced and preimplantation loss slightly increased at 50 mg/kg in association with marked maternal toxicity.
Reproduction studies were performed in rats and rabbits at doses up to 42 and 5 times the maximum recommended daily human dose (60 mg) on a mg/kg basis. These are 8.3 (rat) and 1.7 (rabbit) times the maximum recommended human dose on a mg/m2 basis. These studies have revealed no evidence of teratogenic effects or of selective toxicity to the embryo.
Immunotoxicity Studies: Specific studies have demonstrated that paroxetine is unlikely to possess the potential for immunotoxicity.
Serum samples were obtained from depressed patients who had received 30 mg of paroxetine daily for between six and twelve months, from groups of rats on a repeat dose toxicity study in which daily doses of 1, 5 and 25 mg/kg of paroxetine were administered for 52 weeks, from guinea pigs epicutaneously exposed (topically under an occlusive patch) to paroxetine and from New Zealand White (NZW) rabbits parenterally (i.m. and s.c.) injected with paroxetine in Freund's adjuvant. In addition as a positive control, sera were obtained from NZW rabbits which had been immunized by i.m. and s.c. injections of Freund's adjuvant emulsions containing paroxetine chemically conjugated to bovine gamma globulin (BGG).
Serum antibody levels were assessed by enzyme- or radio-immunoassays (ELISA or RIA). No anti-paroxetine antibody activity was detected in serum samples from patients, from rats in the toxicity study, from guinea pigs epicutaneously exposed to paroxetine, or from rabbits parenterally injected with paroxetine. Serum anti-paroxetine antibody was detected in rabbits immunized with Freund's adjuvant emulsions containing paroxetine coupled with BGG, verifying that the RIA system employed was capable of detecting antibodies directed against paroxetine.
Paroxetine also did not induce contact sensitivity reactions in guinea pigs following epicutaneous exposure.
