Seroxat/Seroxat CR

Paroxetine hydrochloride hemihydrate.

Excipients/Inactive Ingredients: Seroxat: Dibasic calcium phosphate dihydrate, Type A sodium starch glycolate, Magnesium stearate, Opradry White YS-1R-7003.
Seroxat CR: Lactose monohydrate, Hypromellose, Povidone, Silicon dioxide, Magnesium Stearate, Glyceryl behenate, Methacrylic acid copolymer dispersion, Talc, Triethyl citrate.
12.5 mg tab: Yellow ferric oxide; Opadry Yellow, YS-1-2007.
25 mg tab: Red ferric oxide; Opadry Pink, Y-1-1262.

Pharmacotherapeutic group: Antidepressants-selective serotonin reuptake inhibitors. ATC code: N06A B05.
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 C_max and AUC_0-inf increased disproportionately with dose (as seen also with immediate-release formulations). Mean C_max and AUC_0-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. T_max 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 C_max, C_min and AUC_0-24 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 AUC_0-24 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 C_min 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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Toxicology: 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.

Seroxat: Treatment of Major Depressive Episode.
Treatment of Obsessive Compulsive Disorder (OCD).
Treatment of Panic Disorder with or without agoraphobia.
Treatment of Social Anxiety Disorder/Social Phobia.
Treatment of Generalised Anxiety Disorder.
Treatment of Post-traumatic Stress Disorder.
Seroxat CR: Adults: Depression: SEROXAT CR is indicated for symptomatic relief of Major Depressive Disorder.
SEROXAT CR has not been systematically evaluated beyond 12 weeks in controlled clinical trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a response in depression for at least 6 months has been demonstrated in a placebocontrolled trial (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). The physician who elects to use SEROXAT CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Panic Disorder: SEROXAT CR is indicated for the symptomatic treatment of panic disorder, with or without agoraphobia.
Panic disorder (DSM-IV) is characterised by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Social Phobia (Social Anxiety Disorder): SEROXAT CR is indicated for the symptomatic relief of generalized social phobia (social anxiety disorder), a disorder characterized by marked and persistent fear, anxious anticipation, or avoidance of multiple social situations (e.g. interacting with strangers, attending social gatherings, dealing with authority figures) and/or performance situations (e.g. eating, writing, working while being observed, or public speaking). A diagnosis of social phobia/social anxiety disorder should not be made unless the fear, anxious anticipation, or avoidance of social and/or performance situations interferes significantly with the person's normal routine, occupational functioning, social life, or causes marked distress.
Premenstrual Dysphoric Disorder: SEROXAT CR is indicated for the symptomatic treatment of premenstrual dysphoric disorder (PMDD). The efficacy of SEROXAT CR in the treatment of PMDD has been established in 3 placebo-controlled trials (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
The essential features of PMDD, according to DSM-IV, include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly, in most menstrual cycles, during the luteal phase and remit within a few days following the onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. Typically, the symptoms are comparable in severity (but not duration) to those of a major depressive episode. The presence of the cyclical pattern of symptoms must be confirmed by at least two consecutive months of prospective daily symptom ratings. It is estimated that at least 75% of women report minor or isolated premenstrual changes; however, only 3 to 5% of women experience symptoms that may meet the criteria for PMDD. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
Long-Term Use of SEROXAT CR: The effectiveness of SEROXAT CR in long-term use (i.e. more than 12 weeks for depression, panic disorder and social phobia and more than 3 menstrual cycles for premenstrual dysmorphic disorder), has not yet been established in controlled trials for depression, panic disorder, social phobia or premenstrual dysmorphic disorder. Therefore, the physician who elects to use SEROXAT CR for extended periods in these indications should periodically re-evaluate the long-term usefulness of the drug for the individual patient. (see Dosage & Administration).
Geriatrics (> 65 years of age): Evidence from clinical studies indicates that there are differences in the pharmacokinetic profile of paroxetine in the geriatric population relative to younger adults, which may be associated with differences in safety or effectiveness. A brief discussion can be found in the appropriate sections (see Precautions, Pharmacology under Actions and Dosage & Administration).
Pediatrics (<18 years of age): SEROXAT CR is not indicated for use in patients below the age of 18 years (see Precautions).

Seroxat: Major Depressive Episode: The recommended dose is 20 mg daily. In general, improvement in patients starts after one week but may only become evident from the second week of therapy.
As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within three to four weeks of initiation of therapy and thereafter as judged clinically appropriate. In some patients, with insufficient response to 20 mg, the dose may be increased gradually up to a maximum of 50 mg a day in 10 mg steps according to the patient's response.
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
Obsessive Compulsive Disorder: The recommended dose is 40 mg daily. Patients should start on 20 mg/day and the dose may be increased gradually in 10 mg increments to the recommended dose. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 60 mg/day.
Patients with OCD should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer (see Pharmacology: Pharmacodynamics under Actions).
Panic Disorder: The recommended dose is 40 mg daily. Patients should be started on 10 mg/day and the dose gradually increased in 10 mg steps according to the patient's response up to the recommended dose. A low initial starting dose is therefore recommended to minimize the potential worsening of panic symptomatology, which is generally recognised to occur early in the treatment of this disorder. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 60 mg/day.
Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer (see Pharmacology: Pharmacodynamics under Actions).
Social Anxiety Disorder/Social Phobia: The recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see Pharmacology: Pharmacodynamics under Actions).
Generalised Anxiety Disorder: The recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see Pharmacology: Pharmacodynamics under Actions).
Post-traumatic Stress Disorder: The recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see Pharmacology: Pharmacodynamics under Actions).
General Information: Withdrawal symptoms seen on discontinuation of SEROXAT Tablets: Abrupt discontinuation should generally be avoided (see Precautions and Adverse Reactions). The taper phase regimen used in clinical trials involved decreasing the daily dose by 10 mg at weekly intervals. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Special patient populations: Older people: Increased plasma concentrations of paroxetine occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects. Dosing should commence at the adult starting dose. Increasing the dose might be useful in some patients, but the maximum dose should not exceed 40 mg daily.
Children and adolescents (7-17 years): Paroxetine should not be used for the treatment of children and adolescents as controlled clinical trials have found paroxetine to be associated with increased risk for suicidal behaviour and hostility. In addition, in these trials efficacy has not been adequately demonstrated (see Precautions and Adverse Reactions).
Children aged below 7 years: The use of paroxetine has not been studied in children less than 7 years. Paroxetine should not be used, as long as safety and efficacy in this age group have not been established.
Renal/hepatic impairment: Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance <30 ml/min) or in those with hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range.
Method of administration: It is recommended that paroxetine is administered once daily in the morning with food.
The tablet should be swallowed rather than chewed.
Seroxat CR: General: SEROXAT CR is not indicated for use in children under 18 years of age (see Precautions).
SEROXAT CR should be administered as a single daily dose, usually in the morning, with or without food. Patients should be cautioned that SEROXAT CR tablet should not be chewed or crushed, and should be swallowed whole.
Discontinuation of Treatment with SEROXAT CR: Symptoms associated with the discontinuation of immediate-release paroxetine and SEROXAT CR have been reported in clinical trials and post marketing. Patients should be monitored for these and other symptoms when discontinuing treatment, regardless of the indication for which SEROXAT CR is being prescribed (see Precautions and Adverse Reactions).
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Adverse Reactions).
Adults: Depression: Usual Initial Dosage: The recommended initial dose is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials demonstrating the effectiveness of SEROXAT CR in the treatment of depression. As with all drugs effective in the treatment of depression, the full effect may be delayed. Some patients not responding to a 25-mg dose may benefit from dose increases, in 12.5-mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with SEROXAT CR should remain on it for the symptoms of panic and depression. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has shown that efficacy is maintained for at least 6 months with doses that averaged about 30 mg, which corresponds to a 37.5-mg dose of SEROXAT CR, based on relative bioavailability considerations.
Panic Disorder: Usual Initial Dosage: Patients should be started on 12.5 mg/day. Dose changes should occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of SEROXAT CR. The maximum dosage should not exceed 75 mg/day.
Maintenance Therapy: Panic disorder is a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Social Phobia (Social Anxiety Disorder): Usual Initial Dosage: The recommended initial dose is 12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial demonstrating the effectiveness of SEROXAT CR in the treatment of social anxiety disorder. Some patients not responding to a 12.5 mg dose may benefit from dose increases, , in increments of 12.5 mg/day, up to a maximum of 37.5 mg/day. Dose changes should occur at intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with SEROXAT CR should remain on it. Although the efficacy of SEROXAT CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognised as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Premenstrual Dysphoric Disorder: Usual Initial Dosage: In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective with continuous dosing, or intermittent luteal phase dosing.
The recommended dose is 12.5 mg/day limited to the luteal phase of the menstrual cycle, starting 14 days prior to the expected onset of menses, and terminating on the first day of menses. Some patients not responding to a 12.5 mg dose may benefit from a dose increase to 25 mg/day. Dose changes should occur at intervals of at least 1 week.
Continuous dosing of SEROXAT CR, administered daily throughout the menstrual cycle may be considered if efficacy with luteal phase dosing is sub-optimal. Dose changes should occur at intervals of at least 1 week.
Maintenance/Continuation Therapy: The effectiveness of SEROXAT CR in long-term use, that is, for more than 3 menstrual cycles has not been evaluated in controlled trials. Therefore, the physician who elects to use SEROXAT CR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Special Populations: Treatment of Pregnant Women: Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking SEROXAT CR, she should be informed of the current estimate of risk to the fetus (see Precautions) and consideration should be given to switching to other treatment options. Treatment with SEROXAT CR should only be continued for an individual patient, if the potential benefits outweigh the potential risks. For women who intend to become pregnant, or are in their first trimester of pregnancy, initiation of paroxetine should be considered only after other treatment options have been evaluated (see Precautions).
Post-marketing reports indicate that some neonates exposed to SEROXAT CR, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. (see Precautions) When treating pregnant women with SEROXAT CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering SEROXAT CR in the third trimester.
Dosage for Elderly (> 65 years) or Debilitated: Administration of SEROXAT CR to the elderly is associated with increased plasma levels and prolongation of the elimination half life relative to younger adults (see Pharmacology under Actions). The recommended initial dose of SEROXAT CR is 12.5 mg/day for elderly patients and debilitated patients. Increases may be made if indicated. Dosage should not exceed 50 mg/day.
Pediatrics: SEROXAT CR is not indicated for use in children under 18 years of age (see Indications and Precautions).
Renal/Hepatic Impairment: SEROXAT CR should be used with caution in patients with renal or hepatic impairment. The recommended initial dose is 12.5 mg/day in patients with clinically significant renal or hepatic impairment. A maximum dose of 50 mg/day should not be exceeded (see Precautions and Pharmacology under Actions).

Symptoms and Signs: Seroxat: A wide margin of safety is evident from available overdose information on paroxetine.
Experience of paroxetine overdose has indicated that, in addition to those symptoms mentioned under Adverse Reactions, fever and involuntary muscle contractions have been reported. Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol.
Seroxat CR: The most commonly reported adverse events subsequent to paroxetine-only overdose include: somnolence, nausea, tremor, dizziness, vomiting, diarrhea, agitation, aggression, anxiety, confused state, headache, fatigue, insomnia, tachycardia, hyperhydrosis, mydriasis, convulsion, paraesthesia, serotonin syndrome, fever, blood pressure changes, involuntary muscle contraction and loss of consciousness. It should be noted that in some cases, patients may have consumed alcohol in addition to taking an overdose of paroxetine. Some of these symptoms may also be seen with clinical use.
Events such as coma or ECG changes have occasionally been reported.
Treatment: No specific antidote is known.
The treatment should consist of those general measures employed in the management of overdose with any antidepressant.
Seroxat: Administration of 20-30 g activated charcoal may be considered if possible within a few hours after overdose intake to decrease absorption of paroxetine. Supportive care with frequent monitoring of vital signs and careful observation is indicated. Patient management should be as clinically indicated.
Seroxat CR: Establish and maintain an airway; ensure adequate oxygenation and ventilation.
Induction of emesis is not recommended. Due to the large volume of distribution of SEROXAT CR, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
Supportive care with frequent monitoring of vital signs and careful observation is indicated. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality. Patient management should be as clinically indicated.
In managing overdosage, consider the possibility of multiple drug involvement.
A specific caution involves patients taking or recently having taken SEROXAT CR who might ingest, by accident or intent, excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.

Known hypersensitivity to active substance (s) or to any of the excipients listed in Descriptions.
Seroxat: SEROXAT is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). In exceptional circumstances, linezolid (an antibiotic which is a reversible non-selective MAOI) can be given in combination with paroxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure (see Interactions).
Treatment with paroxetine can be initiated: Two weeks after discontinuation of an irreversible MAOI or; At least 24 hours after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (methylene blue); a preoperative visualising agent which is a reversible non-selective MAOI).
At least two weeks should elapse between discontinuation of paroxetine and initiation of therapy with any MAOI.
SEROXAT should not be used in combination with thioridazine, because, as with other drugs which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma levels of thioridazine (see Interactions). Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes, and sudden death.
SEROXAT should not be used in combination with pimozide (see Interactions).
Seroxat CR: Monoamine Oxidase Inhibitors: In patients receiving serotonin reuptake inhibitors (SSRIs) in combination with a MAO inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have begun treatment on a MAO inhibitor. Some cases presented with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Precautions). Therefore, SEROXAT CR should not be used in combination with MAO inhibitors [including methylthioninium chloride (methylene blue)] or within a minimum of 2 weeks of terminating treatment with MAO inhibitors. Treatment with SEROXAT CR should then be initiated cautiously and dosage increased gradually until optimal response is reached. MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with SEROXAT CR.
SEROXAT CR should not be started in a patient receiving linezolid. Wait until 24 hours after the last dose of linezolid before starting SEROXAT CR.
Thioridazine: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.
An in vivo study suggests that drugs which inhibit P450 2D6, including certain SSRI's such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, SEROXAT CR should not be used in combination with thioridazine or within a minimum of 2 weeks of terminating treatment with thioridazine. At least 2 weeks should be allowed after discontinuing SEROXAT CR therapy before initiating treatment with thioridazine.
Pimozide: The concomitant use of SEROXAT CR and pimozide is contraindicated as paroxetine has been shown to increase plasma pimozide levels. Elevation of pimozide blood concentration may result in QT interval prolongation and severe arrhythmias including torsade de pointes (see Interactions).

Seroxat: Treatment with paroxetine should be initiated cautiously two weeks after terminating treatment with an irreversible MAOI or 24 hours after terminating treatment with a reversible MAO inhibitor. Dosage of paroxetine should be increased gradually until an optimal response is reached (see Contraindications and Interactions).
Suicide/suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which paroxetine is prescribed can be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with Major Depressive Disorder (MDD). The same precautions observed when treating patients with MDD should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old (see Pharmacology: Pharmacodynamics under Actions).
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients, (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Akathisia/psychomotor restlessness: The use of paroxetine has been associated with the development of akathisia, which is characterised by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with paroxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Paroxetine should not be used in combination with serotonin-precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome (see Contraindications and Interactions).
Mania: As with all antidepressants, paroxetine should be used with caution in patients with a history of mania. Paroxetine should be discontinued in any patient entering a manic phase.
Renal/hepatic impairment: Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see Dosage & Administration).
Diabetes: In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted. Additionally, there have been studies suggesting an increase in blood glucose levels may occur when paroxetine and pravastatin are co-administered (see Interactions).
Epilepsy: As with other antidepressants, paroxetine should be used with caution in patients with epilepsy.
Seizures: Overall the incidence of seizures is <0.1% in patients treated with paroxetine. The drug should be discontinued in any patient who develops seizures.
Electroconvulsive therapy (ECT): There is little clinical experience of the concurrent administration of paroxetine with ECT.
Glaucoma: As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.
Cardiac Conditions: The usual precautions should be observed in patients with cardiac conditions.
Hyponatraemia: Hyponatraemia has been reported rarely, predominantly in the elderly. Caution should also be exercised in those patients at risk of hyponatraemia e.g. from concomitant medications and cirrhosis. The hyponatraemia generally reverses on discontinuation of paroxetine.
Haemorrhage: There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Other haemorrhagic manifestations e.g. gastrointestinal and gynaecological haemorrhage have been reported. Elderly patients may be at an increased risk for non-menses related events of bleeding.
Caution is advised in patients taking SSRIs concomitantly with oral anticoagulants, drugs known to affect platelet function or other drugs that may increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding (see Adverse Reactions).
Interaction with tamoxifen: Paroxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, paroxetine should whenever possible be avoided during tamoxifen treatment (see Interactions).
Drugs affecting gastric pH: In patients receiving oral suspension, the paroxetine plasma concentration may be influenced by gastric pH. In vitro data have shown that an acidic environment is required for release of the active drug from the suspension, hence absorption may be reduced in patients with a high gastric pH or achlorhydria, such as after the use of certain drugs (antacid drugs, histamine H2-receptor antagonists, proton pump inhibitors), in certain disease states (e.g. atrophic gastritis, pernicious anemia, chronic Helicobacter pylori infection), and after surgery (vagotomy, gastrectomy). The pH dependency should be taken into account when changing paroxetine formulation (e.g. the plasma paroxetine concentration may decrease after changing from tablet to oral suspension in patients with a high gastric pH). Caution is therefore recommended in patients when initiating or ending treatment with drugs increasing gastric pH. Dose adjustments may be necessary in such situations.
Withdrawal symptoms seen on discontinuation of SEROXAT treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see Adverse Reactions). In clinical trials adverse events seen on treatment discontinuation occurred in 30% of patients treated with paroxetine compared to 20% of patients treated with placebo. The occurrence of withdrawal symptoms is not the same as the drug being addictive or dependence producing.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.
Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported. Generally these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that paroxetine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see Dosage & Administration).
Effects on ability to drive and use machines: Clinical experience has shown that therapy with paroxetine is not associated with impairment of cognitive or psychomotor function. However, as with all psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery.
Although paroxetine does not increase the mental and motor skill impairments caused by alcohol, the concomitant use of paroxetine and alcohol is not advised.
Use in children: Paroxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Seroxat CR: General: Potential Association with Behavioural and Emotional Changes, including Self-Harm.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressant compared to placebo.
Discontinuation Symptoms: Patients currently taking SEROXAT CR should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.
Discontinuation of Treatment with SEROXAT CR: When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, sleep disturbances including abnormal dreams, sensory disturbances (including paresthesias, electric shock sensations and tinnitus), agitation, anxiety, headache, tremor, confusion, diarrhea, nausea, vomiting and sweating) or other symptoms which may be of clinical significance [see Adverse Reactions]. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See Adverse Reactions and Dosage & Administration).
SEROXAT CR Treatment During Pregnancy Effects on Newborns: Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking SEROXAT CR, consideration should be given to switching to other treatment options. Treatment with SEROXAT CR should only be continued for an individual pregnant patient, if the potential benefits outweigh the potential risks. Initiation of paroxetine, for women who intend to become pregnant, or are in their first trimester of pregnancy, should be considered only after other treatment options have been evaluated (see Precautions).
Post-marketing reports indicate that some neonates exposed to SEROXAT CR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with SEROXAT CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Precautions and Dosage & Administration).
Potential for reduced efficacy of Tamoxifen with concomitant SSRI use, including SEROXAT CR: The antitumor agent tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 can lead to reduced plasma concentrations of a primary active metabolite (endoxifen). Chronic use of CYP2D6 inhibitors, including certain SSRIs, together with tamoxifen can lead to persistent reduction in levels of endoxifen (see Interactions). Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when coprescribed with SEROXAT CR as a result of paroxetine's irreversible inhibition of CYP2D6. This risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
Psychomotor Impairment: Although paroxetine did not cause sedation or interfere with psychomotor performance in placebo-controlled studies in normal subjects, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that SEROXAT CR does not affect them adversely.
Bone fracture risk: Epidemiological studies show an increased risk of bone fracture following exposure to some antidepressants, including SSRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with SEROXAT CR. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal.
Preliminary data from observational studies show association of SSRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long-term treatment with SSRIs, including SEROXAT CR, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.
The following additional precautions are listed alphabetically.
Carcinogenesis and Mutagenesis: See Pharmacology: Toxicology: Preclinical safety data under Actions.
Cardiovascular: SEROXAT CR or immediate-release paroxetine have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. The usual precautions should be observed in patients with cardiac conditions.
Concomitant Illnesses: Clinical experience with SEROXAT CR or immediate-release paroxetine in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using SEROXAT CR in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Dependence Liability: SEROXAT CR or immediate-release paroxetine have not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of SEROXAT CR.
Endocrine and Metabolism: Serum Cholesterol Elevation: Several public domain studies have shown increased LDL-cholesterol levels of ~10% in volunteers and patients taking paroxetine for 8 to 12 weeks, which generally normalized after paroxetine discontinuation. In addition, of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, total serum levels of cholesterol showed a mean increase of ~ 1.5 mg/dL in paroxetine-treated patients (n = 653), compared to a mean decrease of ~ 5.0 mg/dL in placebo-treated patients (n = 379). Increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients (see Monitoring and Laboratory Tests, Serum Cholesterol Elevation). These data should be taken into consideration when treating patients with underlying cardiac risk factors.
Hematologic: Abnormal Bleeding: SSRIs including SEROXAT CR may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening haemorrhages. Gastrointestinal and gynaecological bleeding have also been reported following treatment with SEROXAT CR.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of SEROXAT CR and NSAIDs, ASA, or other drugs that affect coagulation (see Interactions). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia). (See Adverse Reactions.)
Hepatic/Biliary/Pancreatic: Hepatic Impairment: Pharmacokinetic studies of immediate-release paroxetine in subjects with clinically significant hepatic impairment suggest that prolongation of the elimination half-life and increased plasma levels can be expected in this patient group. SEROXAT CR should be used with caution and dosages restricted to the lower end of the range in patients with clinically significant hepatic impairment (see Dosage & Administration and Pharmacology under Actions).
Neurologic: Epilepsy: As with other antidepressants, SEROXAT CR should be used with caution in patients with epilepsy.
Seizures: During clinical trials, the overall incidence of seizures was 0.15% in patients treated with immediate-release paroxetine. However, patients with a history of convulsive disorders were excluded from these studies. Caution is recommended when the drug is administered to patients with a history of seizures. The drug should be discontinued in any patient who develops seizures.
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occured in association with treatment of SEROXAT CR, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with SEROXAT CR should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma, and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome SEROXAT CR should not be used in combination with MAO inhibitors [including methylthioninium chloride (methylene blue)] or serotonin precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (e.g., triptans, lithium, tramadol, St. John's Wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see Contraindications and Interactions).
Ophthalmologic: Angle-Closure Glaucoma: As with other antidepressants, SEROXAT CR can cause mydriasis which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Caution should be used when paroxetine is prescribed for patients with untreated narrow angles. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients should be informed to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.
Psychiatric: Suicide: The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. Notwithstanding, high risk patients should be closely supervised throughout therapy with appropriate consideration to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for SEROXAT CR should be written for the smallest quantity of drug consistent with good patient management.
Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Precautions).
Activation of Mania/Hypomania: During clinical testing in a patient population comprised primarily of unipolar depressed patients, approximately 1% of patients treated with immediate-release paroxetine experienced manic reactions. When bipolar patients were considered as a sub-group the incidence of mania was 2%. As with all drugs effective in the treatment of depression, SEROXAT CR should be used with caution in patients with a history of mania. A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.
Electroconvulsive Therapy (ECT): The efficacy and safety of the concurrent use of SEROXAT CR and ECT have not been studied.
Renal: Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when immediate-release paroxetine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Renal Impairment: Since SEROXAT CR is extensively metabolized by the liver; excretion of unchanged drug in urine is a minor route of elimination. However, single dose pharmacokinetic studies in subjects with clinically significant renal impairment suggest that plasma levels of paroxetine are elevated in such subjects. Paroxetine should therefore be used with caution and the dosage restricted to the lower end of the range in patients with clinically significant renal impairment (see Dosage & Administration and Pharmacology under Actions).
Sexual Function/Reproduction: Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality. This effect appears to be reversible following discontinuation of treatment. Changes in sperm quality may affect fertility in some men (see also Pharmacology: Toxicology: Preclinical safety data under Actions).
Monitoring and Laboratory Tests Serum Cholesterol Elevation: Of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients (see Adverse Reactions and Precautions). These data should be taken into consideration when treating patients with underlying cardiac risk factors.
Special Populations: Pregnant Women and Newborns: Risk of Cardiovascular Malformations following first trimester exposure to SSRIs: Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50 (2%), compared with an expected rate for such defects of approximately 1/100 (1%) infants in the general population. In general, septal defects range from those that are symptomatic and may require surgery, to those that are asymptomatic and may resolve spontaneously. Information about the severity of the septal defects reported in the studies is not available.
While on SEROXAT CR: Pregnancy, or intent to become pregnant: If a patient becomes pregnant while taking SEROXAT CR, or intends to become pregnant, she should be informed of the current estimate of increased risk to the fetus with SEROXAT CR over other antidepressants. Examinations of additional databases, as well as updated analyses, may result in changes to the current risk estimates. Consideration should be given to switching to other treatment options, including another antidepressant or non-pharmaceutical treatment such as cognitive behavioural therapy. Treatment with SEROXAT CR should only be continued for an individual patient, if the potential benefits outweigh the potential risks. Due to the potential for discontinuation symptoms, if a decision is taken to discontinue SEROXAT CR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Precautions, Adverse Reactions and Dosage & Administration).
Complications following late third trimester exposure to SSRIs: Post-marketing reports indicate that some neonates exposed to SEROXAT CR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Precautions). When treating a pregnant woman with SEROXAT CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage & Administration).
There have been post-marketing reports of premature birth in pregnant women exposed to paroxetine or other SSRIs. The causal relationship between SEROXAT CR and the emergence of these events has not been established.
Risk of PPHN and exposure to SSRIs (including paroxetine): Epidemiological studies on persistent pulmonary hypertension of the newborn (PPHN) have shown that the use of SSRIs (including SEROXAT CR) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy (Odds Ratio 6.1, 95% CI 2.2-16.8). A study using data from the Swedish Medical Birth Register for 831,324 infants born in 1997-2005 found an increased risk of PPHN of approximately 2-fold associated with patient-reported maternal use of SSRIs in the first trimester of pregnancy (Risk Ratio 2.4, 95% CI 1.2-4.3), and an increased risk of PPHN of approximately 4-fold associated with a combination of patient-reported maternal use of SSRIs in the first trimester and an antenatal SSRI prescription in later pregnancy (Risk Ratio 3.6, 95% CI 1.2-8.3).
Nursing Women: The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in the mother's plasma. Lactating women should not nurse their infants while receiving paroxetine unless in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.
Pediatrics (< 18 years of age): SEROXAT CR is not indicated for use in patients below the age of 18 years (see Precautions, Indications and Dosage & Administration).
Controlled clinical studies in depression failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children under the age of 18 years with depression. Moreover, a higher incidence of adverse events related to behavioural and emotional changes, including self harm, was reported with paroxetine treatment compared to placebo during controlled clinical trials in depression, OCD and social anxiety disorder (see Adverse Reactions).
Geriatrics (≥ 65 years of age): Administration of SEROXAT CR to the elderly is associated with increased plasma levels and prolongation of the elimination half life relative to younger adults (see Pharmacology under Actions). Elderly patients should be initiated and maintained at the lowest daily dose of paroxetine which is associated with clinical efficacy (see Dosage & Administration).
Evaluation of approximately 800 elderly patients (≥ 65 years) treated with immediate-release paroxetine (10-40 mg daily) in worldwide premarketing clinical trials revealed no unusual pattern of adverse events relative to the clinical experience in younger patients.
In a controlled study focusing specifically on elderly patients with depression, SEROXAT CR (12.5-50 mg daily) was demonstrated to be safe and effective in the treatment of elderly patients (> 60 years of age) with depression (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions and Adverse Reactions). However, it is not possible to rule out potential age-related differences in safety and effectiveness during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs.
Use in Children: Placebo-Controlled Clinical Trial Data: Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.
Adult and Pediatrics: Additional data: There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, and depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Seroxat: Pregnancy: Some epidemiological studies suggest an increased risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septum defects), associated with the use of paroxetine during the first trimester. The mechanism is unknown. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is less than 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population. Paroxetine should only be used during pregnancy when strictly indicated. The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant. Abrupt discontinuation should be avoided during pregnancy (see Dosage & Administration).
Neonates should be observed if maternal use of paroxetine continues into the later stages of pregnancy, particularly the third trimester.
The following symptoms may occur in the neonate after maternal paroxetine use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty in sleeping. These symptoms could be due to either serotonergic effects or withdrawal symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The observed risk was approximately five cases per 1000 pregnancies. In the general population one to two cases of PPHN per 1000 pregnancies occur.
Animal studies showed reproductive toxicity, but did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
When treating a pregnant woman with SEROXAT during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment.
Lactation: Small amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 ng/ml) or very low (<4 ng/ml) and no signs of drug effects were observed in these infants. Since no effects are anticipated, lactation can be considered.
Fertility: Animal data have shown that paroxetine may affect sperm quality (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). In vitro data with human material may suggest some effect on sperm quality, however, human case reports with some SSRIs (including paroxetine) have shown that an effect on sperm quality appears to be reversible.
Impact on human fertility has not been observed so far.
Seroxat CR: Pregnant Women and Newborns: Risk of Cardiovascular Malformations following first trimester exposure to SSRIs: Epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50 (2%), compared with an expected rate for such defects of approximately 1/100 (1%) infants in the general population. In general, septal defects range from those that are symptomatic and may require surgery, to those that are asymptomatic and may resolve spontaneously. Information about the severity of the septal defects reported in the studies is not available.
While on SEROXAT CR: Pregnancy, or intent to become pregnant: If a patient becomes pregnant while taking SEROXAT CR, or intends to become pregnant, she should be informed of the current estimate of increased risk to the fetus with SEROXAT CR over other antidepressants. Examinations of additional databases, as well as updated analyses, may result in changes to the current risk estimates. Consideration should be given to switching to other treatment options, including another antidepressant or non-pharmaceutical treatment such as cognitive behavioural therapy. Treatment with SEROXAT CR should only be continued for an individual patient, if the potential benefits outweigh the potential risks. Due to the potential for discontinuation symptoms, if a decision is taken to discontinue SEROXAT CR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Precautions; Adverse Reactions and Dosage & Administration).
Complications following late third trimester exposure to SSRIs: Post-marketing reports indicate that some neonates exposed to SEROXAT CR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Precautions). When treating a pregnant woman with SEROXAT CR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage & Administration).
There have been post-marketing reports of premature birth in pregnant women exposed to paroxetine or other SSRIs. The causal relationship between SEROXAT CR and the emergence of these events has not been established.
Risk of PPHN and exposure to SSRIs (including paroxetine): Epidemiological studies on persistent pulmonary hypertension of the newborn (PPHN) have shown that the use of SSRIs (including SEROXAT CR) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy (Odds Ratio 6.1, 95% CI 2.2-16.8). A study using data from the Swedish Medical Birth Register for 831,324 infants born in 1997-2005 found an increased risk of PPHN of approximately 2-fold associated with patient-reported maternal use of SSRIs in the first trimester of pregnancy (Risk Ratio 2.4, 95% CI 1.2-4.3), and an increased risk of PPHN of approximately 4-fold associated with a combination of patient-reported maternal use of SSRIs in the first trimester and an antenatal SSRI prescription in later pregnancy (Risk Ratio 3.6, 95% CI 1.2-8.3).
Nursing Women: The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in the mother's plasma. Lactating women should not nurse their infants while receiving paroxetine unless in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.

Seroxat: Some of the adverse drug reactions listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.
Blood & lymphatic system disorders: Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (including ecchymosis and gynaecological bleeding).
Very rare: thrombocytopenia.
Immune system disorders: Very rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema).
Endocrine disorders: Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Metabolism & nutrition disorders: Common: increases in cholesterol levels, decreased appetite.
Uncommon: altered glycaemic control has been reported in diabetic patients (see Precautions).
Rare: hyponatraemia.
Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Psychiatric disorders: Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).
Uncommon: confusion, hallucinations.
Rare: manic reactions, anxiety, depersonalisation, panic attacks, akathisia (see Precautions).
Frequency not known: suicidal ideation, suicidal behaviour, aggression.
Cases of suicidal ideation and suicidal behaviour have been reported during paroxetine therapy or early after treatment discontinuation (see Precautions).
Cases of aggression were observed in post marketing experience.
These symptoms may also be due to the underlying disease.
Nervous system disorders: Common: dizziness, tremor, headache, concentration impaired.
Uncommon: extrapyramidal disorders.
Rare: convulsions, restless legs syndrome (RLS).
Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor).
Reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.
Eye disorders: Common: blurred vision.
Uncommon: mydriasis (see Precautions).
Very rare: acute glaucoma.
Ear and labyrinth disorders: Frequency not known: tinnitus.
Cardiac disorders: Uncommon: sinus tachycardia.
Rare: bradycardia.
Vascular disorders: Uncommon: transient increases or decreases in blood pressure, postural hypotension.
Transient increases or decreases of blood pressure have been reported following treatment with paroxetine, usually in patients with pre-existing hypertension or anxiety.
Respiratory, thoracic and mediastinal disorders: Common: yawning.
Gastrointestinal disorders: Very common: nausea.
Common: constipation, diarrhoea, vomiting, dry mouth.
Very rare: gastrointestinal bleeding.
Hepato-biliary disorders: Rare: elevation of hepatic enzymes.
Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure).
Elevation of hepatic enzymes has been reported. Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure) have also been received very rarely. Discontinuation of paroxetine should be considered if there is prolonged elevation of liver function test results.
Skin & subcutaneous tissue disorders: Common: sweating.
Uncommon: skin rashes, pruritus.
Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, photosensitivity reactions.
Renal & urinary disorders: Uncommon: urinary retention, urinary incontinence.
Reproductive system & breast disorders: Very common: sexual dysfunction.
Rare: hyperprolactinaemia/galactorrhoea, menstrual disorders (including merorrhagia, metrorrhagia, amenorrhoea, menstruation delayed and menstruation irregular).
Very rare: priapism.
Musculoskeletal & connective tissue disorders: Rare: arthralgia, myalgia.
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
General disorders & administration site conditions: Common: asthenia, body weight gain.
Very rare: peripheral oedema.
Withdrawal symptoms seen on discontinuation of paroxetine treatment: Common: Dizziness, sensory disturbances, sleep disturbances, anxiety, headache.
Uncommon: Agitation, nausea, tremor, confusion, sweating, emotional instability, visual disturbances, palpitations, diarrhoea, irritability.
Discontinuation of paroxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances have been reported.
Generally these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when paroxetine treatment is no longer required, gradual discontinuation by dose tapering be carried out (see Dosage & Administration and Precautions).
Adverse Events from Paediatric Clinical Trials: The following adverse events were observed: 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 MDD. 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 seen are: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations), bleeding related adverse events, predominantly of the skin and mucous membranes.
Events seen after discontinuation/tapering of paroxetine are: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain (see Precaution).
See Pharmacology under Actions for more information on paediatric clinical trials.
Seroxat CR: Adverse Drug Reaction Overview: Commonly Observed Adverse Events: Depression: The most commonly observed adverse events associated with the use of SEROXAT CR in a pool of two trials (incidence of 5.0% or greater and incidence for SEROXAT CR at least twice that for placebo, derived from Table 8 below) were: abnormal ejaculation, abnormal vision, constipation, decreased libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma, tremor, and yawning.
Using the same criteria, the adverse events associated with the use of SEROXAT CR in a study of elderly patients with depression were: abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.
Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these criteria were: abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating, and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
Social Anxiety Disorder: The most commonly observed adverse events associated with the use of SEROXAT CR (incidence of 5.0% or greater and incidence for SEROXAT CR at least twice that for placebo, derived from Table 11 as follows) in the social phobia (social anxiety disorder) study were nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence, insomnia, and libido decreased.
Premenstrual Dysphoric Disorder: The most commonly observed adverse events associated with the use of SEROXAT CR, either during continuous dosing or luteal phase dosing (incidence of 5.0% or greater and incidence for SEROXAT CR at least twice that for placebo, derived from Table 12 as follows) were: nausea, asthenia, libido decreased, somnolence, insomnia, female genital disorders, sweating, dizziness, diarrhea and constipation.
In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day of SEROXAT CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the 3 off-drug phases were combined, the following adverse events were reported at an incidence of 2% or greater for SEROXAT CR and were at least twice the rate of that reported for placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).
Adverse Events Leading to Discontinuation of Treatment: The information included under the "Adverse Events Leading to Discontinuation of Treatment" subsection of Adverse Reactions is based on data from seven short-term placebo-controlled clinical trials. Three of these studies were conducted in patients with depression, three studies were done in patients with panic disorder, and one study was conducted in patients with social anxiety disorder. Two of the studies in depression, which enrolled patients in the age range 18 to 65 years, are pooled. Information from a third study of depression, which focused on elderly patients (ages 60 to 88), is presented separately as is the information from the panic disorder studies and the information from the social anxiety disorder study. Information on additional adverse events associated with SEROXAT CR and the immediate-release formulation of paroxetine hydrochloride is included in a separate subsection.
Depression: Ten percent (21/212) of SEROXAT CR patients discontinued treatment due to an adverse event in a pool of two studies of patients with depression. The most common events (≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for SEROXAT CR compared to placebo) included the following: (See Table 3.)

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In a placebo-controlled study of elderly patients with depression, 13% (13/104) of SEROXAT CR patients discontinued due to an adverse event. Events meeting the above criteria included the following: (See Table 4.)

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Panic Disorder: Eleven percent (50/444) of SEROXAT CR patients in panic disorder studies discontinued treatment due to an adverse event. Events meeting the above criteria included the following: (See Table 5.)

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Social Anxiety Disorder: Three percent (5/186) of patients treated with SEROXAT CR in the social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the above criteria included the following: (See Table 6.)

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Premenstrual Dysphoric Disorder: Thirteen percent (88/681) of patients treated with SEROXAT CR in PMDD studies of continuous dosing discontinued treatment due to an adverse event. Nine percent (34/366) of patients treated with SEROXAT CR in PMDD studies of luteal phase dosing discontinued treatment due to an adverse event.
The most common events (> 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for SEROXAT CR compared to placebo) included the following: (See Table 7.)

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Adverse Events following Discontinuation of Treatment (or Dose Reduction): Clinical Trials: Adverse events while discontinuing therapy with SEROXAT CR were not systematically evaluated in most clinical trials; however, in one placebo-controlled clinical trial in social anxiety disorder involving 370 patients (186 on SEROXAT CR and 184 on placebo), utilizing daily doses of SEROXAT CR up to 37.5 mg/day, spontaneously reported adverse events while discontinuing therapy with SEROXAT CR were evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in dose. With this regimen, the following adverse events were reported at an incidence of 2% or greater for SEROXAT CR and were at least twice that reported for placebo: dizziness (13.9 versus 2.2%), insomnia (4.4 versus 2.2%), paresthesia (4.4 versus 0%) vertigo (3.3 versus 0%), and additional symptoms described by the investigator as associated with tapering or discontinuing SEROXAT CR including electric shock sensations (5.6 versus 0.6%). These events were reported as serious in 1.7% (3/180) of patients who discontinued therapy with SEROXAT CR. The following adverse events have been reported at an incidence of 2% or greater for immediate-release paroxetine and were at least twice that reported for placebo: abnormal dreams (2.3 vs 0.5%), paresthesias (2.0 vs 0.4%), and dizziness (7.1 vs 1.5%). The majority of these events were mild to moderate, self-limiting and did not require medical intervention. These adverse events were noted in GAD and PTSD clinical trials employing a taper phase regimen for discontinuation of treatment. This regimen involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
Post-Marketing: There have been spontaneous reports of adverse events upon the discontinuation of paroxetine and SEROXAT CR (particularly when abrupt), including but not limited to the following: dizziness, sensory disturbances (including paresthesias, electric shock sensations and tinnitus), agitation/restlessness, anxiety, nausea, tremor, confusion, diarrhea, vomiting, sweating, headache, and sleep disturbances (abnormal dreams). Generally these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors.
Patients should be monitored for these or any other symptoms when discontinuing treatment. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Precautions and Dosage & Administration).
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Incidence in Controlled Clinical Trials: Adults: Table 8 enumerates adverse events that occurred at an incidence of 1% or more among SEROXAT CR-treated patients, aged 18 to 65, who participated in two short-term (12-week) placebo-controlled trials in depression in which patients were dosed in a range of 25 to 62.5 mg/day. Table 9 enumerates adverse events reported at an incidence of 5% or greater among elderly SEROXAT CR-treated patients (ages 60-88) who participated in a short-term (12-week) placebo-controlled trial in depression in which patients were dosed in a range of 12.5 to 50 mg/day. Table 10 enumerates adverse events reported at an incidence of 1% or greater among SEROXAT CR treated patients (ages 19-72) who participated in short-term (10-week) placebo-controlled trials in panic disorder in which patients were dosed in a range of 12.5 to 75 mg/day. Table 11 enumerates adverse events reported at an incidence of 1% or greater among adult patients treated with SEROXAT CR who participated in a short-term (12-week) double-blind, placebo-controlled trial in Table 12 social anxiety disorder in which patients were dosed at a range of 12.5 to 37.5 mg/day enumerates adverse events that occurred at an incidence of 1% or more among SEROXAT CR treated patients who participated in three 12-week placebo-controlled trials in PMDD in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses (luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified using a standard COSTART-based dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. (See Tables 8, 9, 10, 11, and 12.)

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Dose Dependency of Adverse Events: The following table shows results in PMDD trials of common adverse events, defined as events with an incidence of 1% with 25 mg of SEROXAT CR that was at least twice that with 12.5 mg of SEROXAT CR and with placebo. (See Table 13.)

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A comparison of adverse event rates in a fixed-dose study comparing immediate-release paroxetine with placebo in the treatment of depression revealed a clear dose dependency for some of the more common adverse events associated with the use of immediate-release paroxetine.
Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence.
The percentage of patients reporting symptoms of sexual dysfunction in the pool of two placebo-controlled trials in non-elderly patients with depression, in the pool of three placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients with social anxiety disorder, and in the luteal phase dosing and in the pool of 3 placebo-controlled trials in female patients with PMDD are as follows: See Table 14.

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There are no adequate, controlled studies examining sexual dysfunction with paroxetine treatment.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Laboratory Changes - Cholesterol: Clinically and statistically relevant increases in cholesterol levels have been noted in studies using paroxetine (see Precautions).
Of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, total serum levels of cholesterol showed a mean increase of ~ 1.5 mg/dL in paroxetine-treated patients (n = 653), compared to a mean decrease of ~ 5.0 mg/dL in placebo-treated patients (n = 379). Increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients.
Pediatrics: In placebo-controlled clinical trials conducted with pediatric patients aged 7 to 18 years with depression, OCD and Social Anxiety Disorder (involving 633 patients treated with paroxetine and 542 patients treated with placebo), the following adverse events were reported in at least 2% of pediatric patients treated with immediate-release paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, (predominantly aggression, oppositional behaviour and anger) decreased appetite, tremor, sweating, hyperkinesia, and agitation.
In the pediatric clinical trials in depression, OCD and Social Anxiety: Disorder that included a taper phase regimen (307 patients aged 7 to 18 years treated with paroxetine and 291 patients treated with placebo), events reported upon discontinuation of treatment, which occurred in at least 2% of patients who received immediate-release paroxetine and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Precautions).
Other Events Observed During the Clinical Development of Paroxetine: The following adverse events were reported during the clinical development of SEROXAT CR tablets and/or the clinical development of the immediate-release formulation of paroxetine. Adverse events for which frequencies are provided below occurred in clinical trials with the controlled release formulation of paroxetine. During its premarketing assessment in depression, panic disorder, social anxiety disorder, and PMDD, multiple doses of SEROXAT CR were administered to 1627 patients in phase 3 double-blind, controlled, outpatient studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of the 1627 patients exposed to SEROXAT CR controlled release who experienced an event of the type cited on at least one occasion while receiving SEROXAT CR. All reported events are included except those already listed in Tables 8, 9, 10, 11 or 12 and those events where a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was deleted or, when possible, replaced with a more informative term. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Adverse events for which frequencies are not provided occurred during the premarketing assessment of immediate-release paroxetine in phase 2 and 3 studies of depression, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to immediate-release paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. Only those events not previously listed for controlled release paroxetine are included. The extent to which these events may be associated with SEROXAT CR is unknown.
Events are listed alphabetically within the respective body system. Events of major clinical importance are also described in the Precautions section.
Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare were abscess, anticholinergic syndrome, hypothermia; also observed were adrenergic syndrome, neck rigidity, sepsis.
Immune System Disorders: Very rare were severe allergic reactions (including anaphylactoid reactions and angioedema).
Cardiovascular System: Infrequent were angina pectoris, bradycardia, bundle branch block, hematoma, hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia, syncope; rare was bundle branch block; also observed were arrhythmia nodal, atrial fibrillation, cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.
Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function tests abnormal, melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis, glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction, peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue edema.
Endocrine System: Infrequent were, ovarian cyst, testes pain; rare were diabetes mellitus, hyperthyroidism; also observed were, goiter, hypothyroidism, thyroiditis.
Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare was thrombocytopenia; also observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis, lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.
Metabolic and Nutritional Disorders: Frequent were increases in cholesterol levels. Infrequent were generalized edema, hyperglycemia, hyperkalemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare were billirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased, gout, hypercalcemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.
Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis, tenosynovitis, tetany.
Nervous System: Frequent was depression; infrequent were amnesia, convulsion, depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis, vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis, withdrawal syndrome; also observed were abnormal gait, akathisis, akinesia, aphasia, choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction, manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, reflexes decreased, reflexes increased, stupor, trismus.
Respiratory System: Frequent was pharyngitis; infrequent were asthma, dyspnea, epistaxis, laryngitis, pneumonia; rare was stridor; also observed were dysphonia, emphysema, hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum increased.
Skin and Appendages: Frequent was rash; infrequent were acne, alopecia, dry skin, eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash, seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash; very rare were severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).
Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis, photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.
Urogenital System: Frequent was dysmennorhea*; infrequent were albuminuria, amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia, nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria, urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.
*Based on the number of men and women as appropriate.
Post-Marketing Adverse Drug Reactions: Adverse events not listed above which have been reported since market introduction in patients taking immediate-release paroxetine hydrochloride include acute pancreatitis, hepatic events such as elevation of hepatic enzymes, and hepatitis, sometimes associated with jaundice, and/or liver failure (in very rare circumstances, with fatal outcomes), Guillain-Barre syndrome, priapism, thrombocytopenia, aggravated hypertension, syndrome of inappropriate ADH secretion, symptoms suggestive of hyperprolactinemia and galactorrhea, menstrual disorders (including menorrhagia, metrorrhagia and amenorrhea), blurred vision, extrapyramidal symptoms which have included akathisia, (characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress), bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and trismus, abnormal dreams (including nightmares), restless legs syndrome (RLS), vomiting, neuroleptic malignant syndrome-like events; serotonin syndrome (see Precautions), persistent pulmonary hypertension (PPHN; see also Precautions). There has been a case report of an elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin co-administration. There has been a case report of severe hypotension when immediate-release paroxetine was added to chronic metoprolol treatment. The causal relationship between immediate-release paroxetine and the emergence of these events has not been established.
There have been spontaneous reports of adverse events upon the discontinuation of SEROXAT CR and other selective serotonin reuptake inhibitors (particularly when abrupt) (see Precautions and Adverse Reactions).

Seroxat: Serotonergic drugs: As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5-HT associated effects (see Serotonin Syndrome under Precautions). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue)), SSRIs, lithium, pethidine and St. John's Wort - Hypericum perforatum - preparations) are combined with paroxetine. Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin syndrome (see Contraindications).
Pimozide: Increased pimozide levels of an average 2.5 times have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with 60 mg paroxetine. This may be explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see Contraindications).
Drug metabolising enzymes: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolising enzymes.
When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor, consideration should be given to using paroxetine doses at the lower end of the range.
No initial dosage adjustment is considered necessary when the drug is to be co-administered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage adjustment (either after initiation or following discontinuation of an enzyme inducer) should be guided by clinical effect (tolerability and efficacy).
Neuromuscular blockers: SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.
Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20 mg daily in healthy volunteers for 10 days significantly decreased plasma levels of paroxetine by approximately 55%. The plasma levels of fosamprenavir/ritonavir during co-administration of paroxetine were similar to reference values of other studies, indicating that paroxetine had no significant effect on metabolism of fosamprenavir/ritonavir. There are no data available about the effects of long-term co-administration of paroxetine and fosamprenavir/ritonavir exceeding 10 days.
Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.
Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients.
CYP2D6 inhibitory potency of paroxetine: As with other antidepressants, including other SSRIs, paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolised by this enzyme. These include certain tricyclic antidepressants (e.g. chlomipramine, nortriptyline and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see Contraindications), risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol. It is not recommended to use paroxetine in combination with metoprolol when given in cardiac insufficiency, because of the narrow therapeutic index of metoprolol in this indication.
Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRIs antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including paroxetine) should whenever possible be avoided (see Precautions).
Alcohol: As with other psychotropic drugs patients should be advised to avoid alcohol use while taking paroxetine.
Oral anticoagulants: A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants can lead to an increased anticoagulant activity and haemorrhagic risk. Therefore, paroxetine should be used with caution in patients who are treated with oral anticoagulants (see Precautions).
NSAIDs and acetylsalicylic acid, and other antiplatelet agents: A pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid can lead to an increased haemorrhagic risk (see Precautions).
Caution is advised in patients taking SSRIs, concomitantly with oral anticoagulants, drugs known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions that may predispose to bleeding.
Pravastatin: An interaction between paroxetine and pravastatin has been observed in studies suggesting that co-administration of paroxetine and pravastatin may lead to an increase in blood glucose levels. Patients with diabetes mellitus receiving both paroxetine and pravastatin may require dosage adjustment of oral hypoglycaemic agents and/or insulin (see Precautions).
Drugs affecting gastric pH: In vitro data have shown that dissociation of paroxetine from the oral suspension is pH-dependant. Therefore, drugs that alter gastric pH (such as antacid drugs, proton pump inhibitors or histamine H2-receptor antagonists) may affect plasma paroxetine concentrations in patients taking the oral suspension (see Precautions).
Seroxat CR: Serious Drug Interactions (see Contraindications): Monoamine Oxidase Inhibitors; Thioridazine; Pimozide.
Overview: Like some other selective serotonin re-uptake inhibitors, paroxetine inhibits the specific hepatic cytochrome P450 isozyme CYP2D6 which is responsible for the metabolism of debrisoquine and sparteine. Poor metabolizers of debrisoquine/sparteine represent approximately 5-10% of Caucasians. The median C_min (ss) for paroxetine (20 mg daily) at steady state in poor metabolizers (n=8) was almost triple that reported for extensive metabolizers (n=9). Although the full clinical significance of this effect has not been established, inhibition of CYP2D6 can lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme. Consideration should be given to decreasing the dose of the CYP2D6 metabolized drug or paroxetine and/or monitoring of drug plasma levels, especially when paroxetine is co-administered with drugs with a narrow therapeutic index. SEROXAT CR co-administration has been associated with elevated levels of the anti-cholinergic procyclidine, certain neuroleptics/antipsychotics (e.g. perphenazine, risperidone), tricyclic antidepressants (e.g. desipramine), atomoxetine, type 1C antiarrhythmics (e.g. propafenone), and theophylline.
Co-administration of phenobarbitol or phenytoin with SEROXAT CR has been associated with decreased levels of SEROXAT CR or immediate-release paroxetine. When co-administered with cimetidine, SEROXAT CR levels were elevated.
The concomitant use of SEROXAT CR and alcohol has not been studied.
Drug-Drug Interactions: Monoamine Oxidase Inhibitors: Combined use of SEROXAT CR and monoamine oxidase inhibitors [including methylthioninium chloride (methylene blue)] is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Precautions).
Thioridazine: Combined use of SEROXAT CR and thioridazine is contraindicated due to a potential for elevated thioridazine plasma levels. Thioridazine treatment alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death (see Contraindications).
Pimozide: In an open label study of healthy volunteers, co-administration of a single dose of 2 mg pimozide, under steady state conditions of immediate-release paroxetine (titrated to 60 mg daily) was associated with mean increases in pimozide AUC of 151% and C_max of 62%, compared to pimozide administered alone. This is likely explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, and produce severe cardiac arrhythmias including torsade de pointes, concomitant use of pimozide and SEROXAT CR is contraindicated (see Contraindications).
Drugs Metabolized by Cytochrome P450 (CYP2D6): In two studies, daily dosing of immediate-release paroxetine (20 mg qd) under steady state conditions increased the following mean pharmacokinetic parameters for a single (100 mg) dose of desipramine in extensive metabolizers: C_max (2 fold), AUC (6 fold), and T_½ (3-5 fold). Concomitant steady-state immediate-release paroxetine treatment did not result in any further impairment of desipramine elimination in poor metabolizers. Insufficient information is available to provide recommendations on the necessary dosage adjustments for tricyclic antidepressants or SEROXAT CR, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances.
Concomitant use of SEROXAT CR with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either SEROXAT CR or the other drug. Drugs metabolized by CYP2D6 include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), risperidone, atomoxetine, Type IC antiarrhythmics (e.g. propafenone and flecainide), and metoprolol. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, SEROXAT CR and thioridazine should not be co-administered (see Contraindications).
Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~ 60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Tamoxifen: Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see Precautions).
Neuromuscular Blockers: In vitro studies, as well as a small number of clinical reports suggest that some antidepressants including paroxetine may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of succinylcholine.
Drugs metabolized by Cytochrome P450 (CYP3A4): An in vivo interaction study involving the co-administration under steady state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam and cyclosporin. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity would not be expected to be of clinical significance.
Microsomal Enzyme Inhibition/Induction: The metabolism and pharmacokinetics of SEROXAT CR may be affected by the induction or inhibition of drug metabolizing enzymes.
Drugs Highly Bound to Plasma Protein: Paroxetine is highly bound to plasma protein, therefore administration of SEROXAT CR to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.
Alcohol: The concomitant use of SEROXAT CR or immediate-release paroxetine and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking SEROXAT CR.
Anti-cholinergic Drugs: Immediate-release paroxetine has been reported to increase significantly the systemic bioavailability of procyclidine. Steady state plasma levels of procyclidine (5 mg daily) were elevated by about 40% when 30 mg paroxetine was co-administered to steady-state. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.
Antiretroviral: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~ 60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Phenobarbital: Chronic daily dosing with phenobarbital (100 mg qid for 14 days) decreased the systemic availability of a single 30 mg dose of paroxetine in some subjects. The AUC and t_1/2 of immediate-release paroxetine were reduced by an average of 25 and 38% respectively compared to immediate-release paroxetine administered alone. The effect of SEROXAT CR or immediate-release paroxetine on phenobarbital pharmacokinetics was not studied. No initial SEROXAT CR or immediate-release paroxetine dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
Anticonvulsants: In a limited number of patients with epilepsy on long-term treatment with anticonvulsants (carbamazepine 600-900 mg/day, n=6; phenytoin 250-400 mg/day, n=6; sodium valproate 300-2500 mg/day, n=8) the co-administration of immediate-release paroxetine (30 mg/day for 10 days) had no significant effect on the plasma concentrations of these anticonvulsants. In healthy volunteers, co-administration of paroxetine with phenytoin has been associated with decreased plasma levels of paroxetine and an increased incidence of adverse experiences. However, no initial dosage adjustment of SEROXAT CR is considered necessary when the drug is to be co-administered with known drug metabolizing enzyme inducers (e.g. carbamazepine, phenytoin, sodium valproate) and any subsequent dosage adjustment should be guided by clinical effect. Co-administration of SEROXAT CR with anticonvulsants may be associated with an increased incidence of adverse experiences.
Antipsychotic Drugs/Neuroleptic Malignant Syndrome: As with other SSRIs, SEROXAT CR should be used with caution in patients already receiving antipsychotics/ neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination (see Precautions).
Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when SEROXAT CR is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, fentanyl and its anologues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine or St. John's Wort. (See Precautions). Concomitant use of SEROXAT CR and MAO inhibitors is contraindicated (see Contraindications).
Drugs Affecting Platelet Function (e.g. NSAIDs, ASA and other anticoagulants): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when SEROXAT CR is initiated or discontinued (see Precautions).
Lithium: In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, due to the potential for serotonin syndrome, caution is advised when SEROXAT CR is coadministered with lithium.
Triptans: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and the 5HT₁ agonist, sumatriptan. If concomitant treatment with triptan and an SSRI (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. The possibility of such interactions should also be considered if other 5HT₁ agonists are to be used in combination with SSRIs (see Precautions).
Tryptophan: Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of SEROXAT CR together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome. Consequently, concomitant use of SEROXAT CR with tryptophan is not recommended (see Precautions).
CNS Drugs: Experience in a limited number of healthy subjects has shown that immediate-release paroxetine does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when given in combination. Since the effects of concomitant administration of SEROXAT CR or immediate-release paroxetine with neuroleptics have not been studied, the use of SEROXAT CR with these drugs should be approached with caution.
Diazepam: A multiple dose study of the interaction between immediate-release paroxetine and diazepam showed no alteration in the pharmacokinetics of immediate-release paroxetine that would warrant changes in the dose of SEROXAT CR for patients receiving both drugs. The effects of immediate-release paroxetine or SEROXAT CR on the pharmacokinetics of diazepam were not evaluated.
Cardiovascular Drugs: Multiple dose treatment with immediate-release paroxetine 30 mg/day has little or no effect on the steady-state pharmacokinetics of digoxin (0.25 mg qd) or propanolol (80 mg bid).
Theophylline: Reports of elevated theophylline levels associated with paroxetine treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.
Cimetidine: Steady state levels of paroxetine (30 mg daily) were elevated by about 50% when cimetidine (300 mg tid), a known drug metabolizing enzyme inhibitor, was co-administered to steady-state. Consideration should be given to using doses of SEROXAT CR towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.
Drug-Food Interactions: At steady state, the bioavailability of 25 mg SEROXAT CR is not affected by food.
Drug-Herb Interactions: St. John's Wort: In common with other SSRI's, pharmacodynamic interactions between paroxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.

Antidepressants

N06AB05 - paroxetine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

P₁S₁S₃