Paxil

Combined use of PAXIL 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).

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 T½ of PAXIL were reduced by an average of 25% and 38% respectively compared to PAXIL administered alone. The effect of PAXIL on phenobarbital pharmacokinetics was not studied. No initial PAXIL dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

The concomitant use of PAXIL and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking PAXIL.

The metabolism and pharmacokinetics of PAXIL may be affected by the induction or inhibition of drug metabolizing enzymes.

Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when PAXIL is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, or St. John's wort (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Concomitant use of PAXIL and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated (see Contraindications).

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 PAXIL is coadministered with lithium.

As with other SSRIs, PAXIL 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 Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine and other antidepressants can lead to reduced plasma concentrations of an active metabolite and hence potential for reduced efficacy of tamoxifen (see Warnings and Precautions, Potential for Reduced Efficacy of Tamoxifen with Concomitant SSRI use, Including PAXIL).

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 PAXIL (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 PAXIL 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 PAXIL with anticonvulsants may be associated with an increased incidence of adverse experiences.

PAXIL 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 anticholinergic effects are seen, the dose of procyclidine should be reduced.

A multiple dose study of the interaction between PAXIL and diazepam showed no alteration in the pharmacokinetics of PAXIL that would warrant changes in the dose of PAXIL for patients receiving both drugs. The effects of PAXIL on the pharmacokinetics of diazepam were not evaluated.

Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of PAXIL 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 PAXIL with tryptophan is not recommended (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Combined use of PAXIL and monoamine oxidase inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

An in vivo interaction study involving the co-administration under steady state conditions of PAXIL and terfenadine, a substrate for CYP3A4, revealed no effect of PAXIL 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.

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 PAXIL (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 PAXIL is co-administered with drugs with a narrow therapeutic index.

PAXIL coadministration has been associated with elevated levels of the anticholinergic 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 PAXIL has been associated with decreased levels of PAXIL. When co-administered with cimetidine, PAXIL levels were elevated.

The concomitant use of PAXIL and alcohol has not been studied.

In an open label study of healthy volunteers, co-administration of a single dose of 2 mg pimozide, under steady state conditions of PAXIL (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 the QT interval, and produce severe cardiac arrhythmias including Torsade de Pointes, concomitant use of pimozide and PAXIL is contraindicated (see Contraindications).

Multiple dose treatment with PAXIL 30 mg/day has little or no effect on the steady-state pharmacokinetics of digoxin (0.25 mg qd) or propanolol (80 mg bid).

Paroxetine is highly bound to plasma protein, therefore administration of PAXIL 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.

The absorption and pharmacokinetics of PAXIL are not affected by food or antacids.

In two studies, daily dosing of PAXIL (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 T½ (3-5 fold). Concomitant steady-state PAXIL 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 PAXIL, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances.

Concomitant use of PAXIL with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either PAXIL 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, PAXIL and thioridazine should not be co-administered (see Contraindications).

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).

Interactions with laboratory tests have not been established.

Reports of elevated theophylline levels associated with PAXIL 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.

Experience in a limited number of healthy subjects has shown that PAXIL does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when given in combination. Since the effects of concomitant administration of PAXIL with neuroleptics have not been studied, the use of PAXIL with these drugs should be approached with caution.

In common with other SSRI's, pharmakodynamic interactions between paroxetine and the herbal remedy St. John's wort may occur and may result in an increase in undesirable effects.

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).

Steady state levels of PAXIL (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 PAXIL towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.

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 Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Symptoms associated with the discontinuation of PAXIL 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 PAXIL is being prescribed (see Warnings and Precautions, Discontinuation of Treatment with PAXIL and Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction)).

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).

The recommended starting dosage is 20 mg/day.

During long term therapy for any indication, the dosage should be maintained at the lowest effective level.

There is no body of evidence available to answer the question of how long a patient should continue to be treated with PAXIL. 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 paroxetine hydrochloride has shown that efficacy is maintained for at least 6 months with doses that averaged about 30 mg.

PAXIL is not indicated for use in children under 18 years of age (see Indications and Clinical Use and Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Based on pharmacokinetic parameters, steady-state paroxetine plasma levels are achieved over a 7-14 day interval. Hence, dosage adjustments in 10 mg increments should be made at 1-2 week intervals or according to clinician judgment.

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 PAXIL, she should be informed of the current estimate of risk to the fetus (see Warnings and Precautions, Special Populations) and consideration should be given to switching to other treatment options. Treatment with PAXIL 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 Warnings and Precautions, Special Populations for more details).

Post-marketing reports indicate that some neonates exposed to PAXIL, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Warnings and Precautions, Special Populations). When treating pregnant women with PAXIL during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering PAXIL in the third trimester.

PAXIL is not indicated for use in children under 18 years of age (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Lower initial doses of PAXIL are recommended for elderly and debilitated patients, and patients with renal or hepatic impairment (see Dosage and Administration, Special Patient Populations).

PAXIL should be administered once daily in the morning and may be taken with or without food. The tablet should be swallowed rather than chewed.

PAXIL should be used with caution in patients with renal or hepatic impairment. The recommended initial dose is 10 mg/day in patients with clinically significant renal or hepatic impairment. A maximum dose of 40 mg should not be exceeded (see Warnings and Precautions and Action and Clinical Pharmacology).

Some patients not responding adequately to a 20 mg/day dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Administration of PAXIL to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults (see Action and Clinical Pharmacology). The recommended initial dose is 10 mg/day for elderly and/or debilitated patients. The dose may be increased if indicated up to a maximum of 40 mg daily.

The most commonly observed adverse experiences associated with the use of PAXIL in clinical trials and not seen at an equivalent incidence among placebo-treated patients were: nausea, somnolence, sweating, tremor, asthenia, dizziness, dry mouth, insomnia, constipation, diarrhea, decreased appetite and male sexual dysfunction (see Table 1 and Table 2).

Frequent: nausea and vomiting. Infrequent: bruxism, buccal cavity disorders, dysphagia, eructation, gastroenteritis, gastrointestinal flu, glossitis, increased salivation, liver function tests abnormal, mouth ulceration, vomiting and diarrhea, rectal hemorrhage. Rare: aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, colitis, duodenitis, esophagitis, fecal impaction, fecal incontinence, gastritis, gingivitis, hematemesis, hepatitis, ileitis, ileus, jaundice, melena, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue edema, tooth caries.

Adverse events not listed above which have been reported since market introduction in patients taking PAXIL 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-Barré syndrome, toxic epidermal necrolysis, priapism, thrombocytopenia, aggravated hypertension, syndrome of inappropriate ADH secretion, symptoms suggestive of hyperprolactinemia and galactorrhea, 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, neuroleptic malignant syndrome-like events and serotonin syndrome (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome), persistent pulmonary hypertension (PPHN; see also Warnings and Precautions, Pregnant Women and Newborns, Risk of PPHN and Exposure to SSRIs (including paroxetine)). There has been a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin co-administration. There has been a case report of severe hypotension when PAXIL was added to chronic metoprolol treatment. The causal relationship between PAXIL and the emergence of these events has not been established.

There have been spontaneous reports of adverse events upon the discontinuation of PAXIL and other selective serotonin reuptake inhibitors (particularly when abrupt) (see Warnings and Precautions, General, Discontinuation of Treatment with PAXIL and Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction)).

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.

Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive-Compulsive Disorder, Panic Disorder, Social Phobia (Social Anxiety Disorder), Generalized Anxiety Disorder and Post-Traumatic Stress Disorder^a

Clinically and statistically relevant increases in cholesterol levels have been noted in studies using paroxetine (see Warnings and Precautions, Endocrine and Metabolism).

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 n=653 paroxetine-treated patients, 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.

There are no adequate and well-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.

Twenty-one percent of over 4000 patients who received PAXIL in worldwide clinical trials in depression discontinued treatment due to an adverse experience. In obsessive-compulsive disorder, panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder and post-traumatic stress disorder studies, 11.8% (64/542), 9.4 % (44/469), 16.1% (84/522) 10.7% (79/735) and 11.7% (79/676), respectively, of patients treated with PAXIL discontinued treatment because of adverse events. The most common events leading to discontinuation (reported by 1% or more of subjects) included: asthenia, headache, nausea, somnolence, insomnia, agitation, tremor, dizziness, constipation, impotence, abnormal ejaculation, sweating and diarrhea.

Infrequent: abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis media, tinnitus. Rare: amblyopia, cataract specified, conjunctival edema, corneal lesion, corneal ulcer, exophthalmos, eye hemorrhage, acute glaucoma, hyperacusis, otitis externa, photophobia, retinal hemorrhage, taste loss, anisocoria, deafness, keratoconjunctivitis.

Rare: diabetes mellitus, fertility decreased female, goiter, hyperthyroidism, hypothyroidism, thyroiditis.

Frequent: malaise, pain. Infrequent: allergic reaction, chills, face edema, infection, moniliasis, neck pain, overdose. Rare: abnormal laboratory value, abscess, adrenergic syndrome, cellulitis, chills and fever, cyst, hernia, intentional overdose, neck rigidity, pelvic pain, peritonitis, substernal chest pain, sepsis, ulcer.

There have been spontaneous reports of adverse events upon the discontinuation of PAXIL (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, regardless of the indication for which PAXIL is being prescribed. 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 Warnings and Precautions and Dosage and Administration).

The following adverse events have been reported at an incidence of 2% or greater for PAXIL 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 requiremedical 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.

Frequent: pruritus. Infrequent: acne, alopecia, dry skin, ecchymosis, eczema, furunculosis, herpes simplex, urticaria. Rare: angioedema, contact dermatitis, erythema nodosum, exfoliative dermatitis, herpes zoster, maculopapular rash, photosensitivity, skin discolouration, skin ulcer, skin hypertrophy, sweating decreased.

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 PAXIL 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 PAXIL 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 Warnings and Precautions, Discontinuation of Treatment with PAXIL).

Infrequent: anemia, leukopenia, lymphadenopathy, purpura, WBC abnormality. Rare: abnormal bleeding, predominately of the skin and mucous membranes (mostly ecchymosis), bleeding time increased, eosinophilia, iron deficiency anemia, leukocytosis, lymphedema, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocytopenia.

Frequent: hypertension, syncope, tachycardia. Infrequent: bradycardia, conduction abnormalities, electrocardiogram abnormal, hypotension, migraine, ventricular extrasystoles. Rare: angina pectoris, arrhythmia, atrial arrhythmia, atrial fibrillation, bundle branch block, cardiac disorder, cerebral ischemia, cerebrovascular accident, cerebrovascular disorder, congestive heart failure, extrasystoles, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombosis, varicose vein, vascular disorder, vascular headache.

In the tabulations which follow, a COSTART or modified COSTART-based Dictionary terminology has been used to classify reported adverse experiences. The frequencies presented therefore represent the portion of the 4126, 542, 469, 522, 735 and 676 PAXIL-exposed individuals in depression, OCD, panic, social phobia (social anxiety disorder), generalized anxiety disorder and post-traumatic stress disorder trials, respectively, who experienced an event of the type cited on at least one occasion while receiving PAXIL. Experiences are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent experiences are defined as those occurring on one or more occasion in at least 1/100 patients; infrequent adverse experiences are those occurring in less than 1/100 but at least 1/1000 patients; rare experiences are those occurring in less than 1/1000 patients.

All adverse experiences are included except those already listed in Table 1 and Table 2, those reported in terms so general as to be uninformative and those experiences for which the drug cause was remote. It is important to emphasize that although the experiences reported did occur during treatment with PAXIL, they were not necessarily caused by it.

Frequent: CNS stimulation, concentration impaired, depression, emotional lability, vertigo. Infrequent: akinesia, alcohol abuse, amnesia, ataxia, convulsion, depersonalization, hallucinations, hyperkinesia, hypertonia, incoordination, lack of emotion, manic reaction, paranoid reaction, thinking abnormal, hypesthesia. Rare: abnormal electroencephalogram, abnormal gait, antisocial reaction, brain edema, choreoathetosis, circumoral paraesthesia, confusion, delirium, delusions, diplopia, drug dependence, dysarthria, dyskinesia, dystonia, euphoria, fasciculations, grand mal convulsion, hostility, hyperalgesia, hypokinesia, hysteria, libido increased, manic depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, psychosis, psychotic depression, reflexes increased, stupor, torticollis, withdrawal syndrome.

Infrequent: arthralgia, arthritis, traumatic fracture. Rare: arthrosis, bone disorder, bursitis, cartilage disorder, myositis, osteoporosis, tetany.

Infrequent: abortion{*Incidence corrected for gender.}, amenorrhea*, breast pain*, cystitis, dysmenorrhea*, dysuria, menorrhagia*, nocturia, polyuria, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, vaginitis*. Rare: Breast atrophy*, cervix disorder*, endometrial disorder*, female lactation*, hematuria, kidney calculus, kidney function abnormal, kidney pain, mastitis*, nephritis, oliguria, salpingitis*, spermatogenesis arrest* urethritis, urinary casts, urine abnormality, uterine neoplasm*, vaginal moniliasis*.

Frequent: cough increased, rhinitis. Infrequent: asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu, sinusitis. Rare: hiccup, lung fibrosis, sputum increased, stridor, trachea disorder, voice alteration.

Frequent: weight gain, weight loss, increases in cholesterol levels. Infrequent: edema, hyperglycemia, peripheral edema, thirst. Rare: alkaline phosphatase increased, bilirubinemia, cachexia, dehydration, gout, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia (predominantly in the elderly) which is sometimes due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), non-protein nitrogen (NPN) increased, obesity, AST increased, ALT increased.

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 Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age); Action and Clinical Pharmacology and Dosage and Administration).

PAXIL is indicated for the symptomatic treatment of obsessive-compulsive disorder (OCD). The obsessions or compulsions must be experienced as intrusive, markedly distressing, time-consuming, or interfering significantly with the person's social or occupational functioning.

The effectiveness of PAXIL in long-term use (i.e. more than 8 weeks for GAD and 12 weeks for other indications) has not yet been established in controlled trials for OCD, panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder and post-traumatic stress disorder. Therefore, the physician who elects to use PAXIL for extended periods in these indications should periodically re-evaluate the long-term usefulness of the drug for individual patients (see Dosage and Administration, Dosing Considerations).

PAXIL is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

PAXIL is indicated for the symptomatic treatment of post-traumatic stress disorder (PTSD).

PTSD as defined by DSM-IV requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to clues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.

A diagnosis of PTSD requires that the symptoms are present for at least one month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

PAXIL is indicated for the symptomatic treatment of panic disorder, with or without agoraphobia.

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (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.

PAXIL is indicated for the symptomatic relief of anxiety causing significant distress in patients with Generalized Anxiety Disorder (GAD).

PAXIL (paroxetine hydrochloride) is indicated for symptomatic relief of Major Depressive Disorder (MDD).

Clinical trials have provided evidence that continuation treatment with PAXIL in patients with moderate to moderately severe depressive disorder is effective for at least 6 months.

PAXIL 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, or social life, or causes marked distress.

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, tachychardia, hyperhydrosis, mydriasis, convulsion, paraethesia, 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 and ECG changes have also been reported.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

No specific antidote is known. Treatment should consist of those general measures employed in the management of overdose with any antidepressant. Establish and maintain an airway; ensure adequate oxygenation and ventilation.

Activated charcoal effectively prevents gastrointestinal absorption of paroxetine, and should be considered as the primary means to reduce paroxetine exposure. It is most effective when administered within one hour of ingestion; usual dose is 25 to 100 grams in adults as an aqueous slurry. During the first 24 hours after ingestion of the overdose, 20 to 30 grams of activated charcoal may be administered every 4 to 6 hours. Due to the large volume of distribution of PAXIL, 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.

In managing overdosage, consider the possibility of multiple drug involvement.

A specific caution involves patients taking or recently having taken PAXIL 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.

Each blue, film-coated, oval, biconvex tablet, with the product name engraved on one side and strength engraved on the other side, contains: paroxetine HCl USP equivalent to paroxetine free base 30 mg. Nonmedicinal ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate and titanium dioxide. Bottles of 30.

The 10, 20 and 30 mg tablets also contain one or more of the following: D&C Red No. 30 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

Each pink, bisected, film-coated, oval, biconvex tablet, with the product name engraved on one side and strength engraved on the other side, contains: paroxetine HCl USP equivalent to paroxetine free base 20 mg. Nonmedicinal ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate and titanium dioxide. Bottles of 100 and 500. Blister cards of 30, cartons of 6.

Each yellow, bisected, film-coated, oval, biconvex tablet, with the product name engraved on one side and strength engraved on the other side, contains: paroxetine HCl USP equivalent to paroxetine free base 10 mg. Nonmedicinal ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate and titanium dioxide. Bottles of 30.

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.

If a patient becomes pregnant while taking PAXIL, or intends to become pregnant, she should be informed of the current estimate of increased risk to the fetus with PAXIL 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 behavioral therapy. Treatment with PAXIL 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 PAXIL treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Warnings and Precautions, Discontinuation of Treatment with PAXIL; Adverse Reactions, Adverse Events following Discontinuation of Treatment (or Dose Reduction) and Dosage and Administration, Discontinuation of Treatment).

Post-marketing reports indicate that some neonates exposed to PAXIL, 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, hypoglycemia, 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 Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with PAXIL during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration, Special Patient Populations, Treatment of Pregnant Women).

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, Laboratory Changes—Cholesterol and Warnings and Precautions, Endocrine and Metabolism).

These data should be taken into consideration when treating patients with underlying cardiac risk factors.

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occured in association with treatment of PAXIL, 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 PAXIL 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 PAXIL should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John's wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see Contraindications and Drug Interactions).

There have been several reports of abnormal bleeding (mostly ecchymosis) associated with paroxetine treatment, including a report of impaired platelet aggregation. While a causal relationship to paroxetine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.

Skin and mucous membrane bleedings (including upper gastrointestinal bleeding) have been reported following treatment with paroxetine. Paroxetine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti-inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

As with other antidepressants, PAXIL should be used with caution in patients with epilepsy.

In one epidemiological case-control study on persistent pulmonary hypertension (PPHN) with n=377 infants with PPHN and n=836 matched control infants, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. The study was too small to determine relative risks among the specific SSRIs. This information is considered to be preliminary at this time. The absolute risk of PPHN in the general population is reported to be 1-2 per 1000 (see Adverse Reactions, Post-Market Adverse Drug Reactions).

The efficacy and safety of the concurrent use of PAXIL and ECT have not been studied.

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 PAXIL, consideration should be given to switching to other treatment options. Treatment with PAXIL 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 Warnings and Precautions, Special Populations)

Post-marketing reports indicate that some neonates exposed to PAXIL, 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 PAXIL during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Warnings and Precautions, Special Populations; Dosage and Administration, Special Patient Populations, Treatment of Pregnant Women).

Clinical experience with PAXIL in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using PAXIL in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

PAXIL is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). See also Indications, Pediatrics (<18 years of age) and Dosage and Administration, Special Patient Populations, Pediatrics).

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 behavioral 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 Drug Reactions, Clinical Trial Adverse Drug Reactions, Pediatrics).

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.

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 also Drug Interactions, Tamoxifen). The clinical significance of this in terms of efficacy of tamoxifen is unclear.

Pharmacokinetic studies of PAXIL 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. PAXIL should be used with caution and dosages restricted to the lower end of the range in patients with clinically significant hepatic impairment (see Dosage and Administration, Special Patient Populations and Actions and Clinical Pharmacology, Hepatic Insufficiency).

During clinical testing in a patient population comprised primarily of unipolar depressed patients, approximately 1% of PAXIL-treated patients 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, PAXIL 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.

Administration of PAXIL to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults. (see Action and Clinical Pharmacology). Elderly patients should be initiated and maintained at the lowest daily dose of paroxetine which is associated with clinical efficacy (see Dosage and Administration).

Evaluation of approximately 800 elderly patients (≥65 years) treated with PAXIL (10-40 mg daily) in worldwide premarketing clinical trials revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. 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.

Patients currently taking PAXIL 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.

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 PAXIL does not affect them adversely.

The following additional precautions are listed alphabetically.

Since PAXIL 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 and Administration, Special Patient Populations and Actions and Clinical Pharmacology, Renal Insufficiency).

When discontinuing treatment, regardless of the indication for which PAXIL is being prescribed, 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, Adverse Events following Discontinuation of Treatment (or Dose Reduction), Post-Marketing]. 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 and Administration).

Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when PAXIL was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

PAXIL has 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 PAXIL.

During clinical trials, the overall incidence of seizures was 0.15% in patients treated with PAXIL. 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.

As with other SSRIs, PAXIL can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.

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. Not withstanding, 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 PAXIL 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 Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-Harm ).

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, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

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.

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.

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.

PAXIL has 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.

The results from a multiple dose pharmacokinetic study in subjects with severe hepatic dysfunction suggest that the clearance of paroxetine is markedly reduced in this patient group (see Table 4). 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 and Administration, Special Patient Populations).

In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half-life were observed relative to younger adult controls (Table 4). Elderly patients should, therefore, be initiated and maintained at the lowest daily dosage of paroxetine which is associated with clinical efficacy (see Dosage and Administration).

Owing to the extensive distribution of paroxetine into the tissues, less than 1% of the total drug in the body is believed to reside in the systemic circulation.

At therapeutic concentrations, the plasma protein binding of paroxetine is approximately 95%. After the administration of a single 50 mg oral dose to lactating women, the concentrations of paroxetine detected in breast milk were similar to those in plasma.

No clear dose relationship has been demonstrated for the antidepressant effects of paroxetine at doses above 20 mg/day. The results of fixed-dose studies comparing paroxetine and placebo in the treatment of depression, panic disorder, generalized anxiety disorder and post-traumatic stress disorder revealed a dose dependency for some adverse events.

Paroxetine is well absorbed after oral administration. In healthy volunteers, the absorption of a single 30 mg oral dose of paroxetine was not appreciably affected by the presence or absence of food.

Both the rate of absorption and the terminal elimination half-life appear to be independent of dose. Steady-state plasma concentrations of paroxetine are generally achieved in 7 to 14 days. No correlation has been established between paroxetine plasma concentrations and therapeutic efficacy or the incidence of adverse reactions.

In healthy young volunteers receiving a 20 mg daily dose of paroxetine for 15 days, the mean maximal plasma concentration was 41 ng/mL at steady state (see Table 4). Peak plasma levels generally occurred within 3 to 7 hours.

Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant and anxiolytic action in the treatment of depression, obsessive-compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (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.

Following the single or multiple dose administration of paroxetine at doses of 20 to 50 mg, the mean elimination half-life value for healthy subjects appears to be about 24 hours, although a range of 3 to 65 hours has been reported.

Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in the faeces. Less than 2% of the dose is recovered in the form of the parent compound.

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 (2D₆). 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 Drug 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 3000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes.