PAXETIN TABLET

Description

THERAPEUTIC INDICATIONS: Treatment of – Major Depressive Episode – Obsessive Compulsive Disorder – Panic Disorder with and without agoraphobia – Social Anxiety Disorders/Social phobia – Generalised Anxiety Disorder – Post-traumatic Stress Disorder

POSOLOGY AND 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. 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 medicinal products, dosage should be reviewed and adjusted if necessary within 3 to 4 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.
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 recommended to minimise 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. 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. 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. 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.
General Information Withdrawal Symptoms Seen On Discontinuation Of Paroxetine Abrupt discontinuation should be avoided. 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 Populations: • Elderly 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 paroxetine found to be associated with increased risk for suicidal behaviour and hostility. In addition, efficacy has not been adequately demonstrated.
• 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 less than 30 ml/min) or in those with hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range.
CONTRAINDICATIONS: -Known hypersensitivity to paroxetine or any of the excipients. -Paroxetine 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.
-Treatment with paroxetine can be initiated: ● two weeks after discontinuation of an irreversible MAOI, or ● at least 24hrs after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid, methylthioniniun chloride(methylene blue)).
-At least one week should elapse between discontinuation of paroxetine and initiation of therapy with any MAOI. -Paroxetine 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. Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes, and sudden death. -Paroxetine should not be used in combination with pimozide.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE: – Antidepressant drugs (such as paroxetine) increase risk compared to placebo of suicidal thinking and behavior in children adolescents and young adults in short term studies of major depressive disorders (MMD) and (suicidality) other psychiatric disorders
– Infant born to mother who took selective serotonin reuptake inhibitors (SSRI) after the 20th week of pregnancy were more likely to have persistent pulmonary hypertension (PPHN) than infant born to mother who did not take antidepressants during pregnancy.
– The risk of major congenital malformation particularly cardiac malformation in infants born to women who take paroxetine during the first trimester may be approximately twice as high as for women taking other antidepressants.
– A life-threatening condition called serotonin syndrome can happen when medicines called selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, and medicines used to treat migraine headaches known as hydroxytryptamine receptor agonists (triptans), are used together.
– Serotonin syndrome is characterized by the development of at least three of the following clinical features after a recent change in a treatment regimen involving: agitation, ataxia, diarrhoea, fever, hyperreflexia, myoclonus, diaphoresis, shivering, changes in mental statusmental status.
– 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.

Use in children and adolescents under 18 years of age Paroxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed among children and adolescents treated with antidepressants. 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.
Akathisia/psychomotor restlessness The use of paroxetine has been associated with the development of akathisia, which is characterized 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. 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. Diabetes In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted. Epilepsy As with other antidepressants, paroxetine should be used with caution in patients with epilepsy. Seizures Overall the incidence of seizures is less than 0.1% in patients treated with paroxetine. The drug should be discontinued in any patient who develops seizures.
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 haemorrhage have been reported. Elderly patients may be at an increased risk. -Caution is advised in patients taking SSRI’s 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 TCA’s, acetylsalicylic acid, NSAID’s, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding. Interaction with tamoxifen Paroxetine, a potent inhibitor of CYP2D6, may lead to reduce concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, paroxetin should whenever possible be avoided during tamoxifen treatment.

Withdrawal symptoms seen on discontinuation of paroxetine treatment -Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. 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. 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 they have been very rare 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.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION: Serotonergic drugs As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5 HT associated effects. Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L tryptophan, triptans, tramadol, linezolid, 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. Pimozide Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated. 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). Fosamprenavir/ritonavir: 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. clomipramine, nortriptyline, and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine), 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 most active forms of tamoxifen, i.e endoxifen, has been reported the literature. Reduced afficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen can’t be excluded, co-administration with potent CYP2D6 inhibitors (including paroxetine) shuld whenever possible be avoided.
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. 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. -Caution is advised in patients taking SSRI’s, concomitantly with oral anticoagulants, drugs known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCA’s, acetylsalicylic acid, NSAID’s, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding.
PREGNANCY AND LACTATION: Fertility Animals data have shown that paroxetine may affect sperm quality.
Impact on human fertility has not been observed so far.

Pregnancy -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. -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. Lactation Small amounts of paroxetine are excreted into breast milk. Since no effects are anticipated, breast feeding can be considered. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: -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. UNDESIRABLE EFFECTS: 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. Blood and lymphatic system disorders Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis). Very rare: thrombocytopenia. Immune system disorders Very rare: allergic reactions (including urticaria and angioedema). Endocrine disorders Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Metabolism and nutrition disorders Common: increases in cholesterol levels, decreased appetite. 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. Frequency not known: suicidal ideation and suicidal behaviour. Cases of suicidal ideation and suicidal behaviours have been reported during paroxetine therapy or early after treatment discontinuation. 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 disorder 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. 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 have 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 and 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), photosensitivity reactions. Renal and urinary disorders Uncommon: urinary retention, urinary incontinence. Reproductive system and breast disorders Very common: sexual dysfunction. Rare: hyperprolactinaemia/galactorrhoea. Very rare: priapism. Musculoskeletal and connective tissue disorders Rare: arthralgia, myalgia An increased risk of bone fractures in patients receiving SSRIs and TCAs who are 50 years of age and older. The mechanism leading to this risk is unknown. General disorder and 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 should be carried out. Adverse Events in Paediatrics -Increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly occurred in 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 occurred 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 occurred 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. OVERDOSE: Symptoms and Signs -A wide margin of safety is evident from available overdose information on paroxetine. -Fever and involuntary muscle contractions occur. 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 occasionally occur and, very rarely with a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol. Treatment -No specific antidote is known. -The treatment should consist of those general measures employed in the management of overdose with any antidepressant. 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. PHARMACOLOGICAL PROPERTIES: Pharmacodynamic Properties: Pharmacotherapeutic group: Antidepressants-selective serotonin reuptake inhibitors. 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 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 demonstrates lack of CNS depressant and hypotensive properties. Pharmacodynamic Effects -Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol. -Paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature. -Paroxetine is well tolerated by the cardiovascular system. Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after. -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 Higher frequency of suicidal behaviour in young adults (aged 18 24 years) with psychiatric disorders treated with paroxetine. In the older age, no such increase. In adults with major depressive disorder (all ages), there was an increase in the frequency of suicidal behaviour in patients treated with paroxetine; all of the events were suicide attempts. However, the majority of these attempts for paroxetine were in younger adults. Dose response Up-titrating the dose might be beneficial for some patients. Adverse Events In Paediatrics -Increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly occurred in 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 are: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations). -Symptoms occurred during the taper phase or upon discontinuation of paroxetine: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain. -Bleeding related adverse events, predominantly of the skin and mucous membranes occurred in paroxetine treated patients Pharmacokinetic Properties: 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. Metabolism -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 1 day. Special Patient Populations Elderly 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. PACKING: Paxetin 20 mg: A carton box containing one (Al/Colourless transparnet PVC) strip of 10 film coated tablets and a pamphlet. Paxetin 40 mg: A carton box containing one (Al/Opaque white PVC) strip of 10 film coated tablets and a pamphlet. STORAGE: Keep at a temperature not exceeding 30C, in dry place. Keep out of reach of children.