Apo-Paroxetine

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

In order to achieve the recommended doses other strengths are available.

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 Apo-Paroxetine

Abrupt discontinuation should be avoided. The taper phase regimen used in clinical trials involved decreasing the daily dose by 10 mg at weekly intervals. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Special populations:

Elderly

Increased plasma concentrations of Apo-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)

Apo-Paroxetine should not be used for the treatment of children and adolescents as controlled clinical trials have found Apo-Paroxetine to be associated with increased risk for suicidal behaviour and hostility. In addition, in these trials efficacy has not been adequately demonstrated.

Children aged below 7 years

The use of Apo-Paroxetine has not been studied in children less than 7 years. Apo-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 Apo-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.

Method of administration

It is recommended that Apo-Paroxetine is administered once daily in the morning with food.

The tablet should be swallowed rather than chewed.

Apo-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 Apo-Paroxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure.

Treatment with Apo-Paroxetine can be initiated:

- two weeks after discontinuation of an irreversible MAOI, or

- at least 24 hrs after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (methylene blue; a preoperative visualising agent which is a reversible non-selective MAOI)).

At least one week should elapse between discontinuation of Apo-Paroxetine and initiation of therapy with any MAOI.

Apo-Paroxetine should not be used in combination with thioridazine because, as with other drugs which inhibit the hepatic enzyme CYP450 2D6, Apo-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.

Apo-Paroxetine should not be used in combination with pimozide.

Treatment with Apo-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 Apo-Paroxetine should be increased gradually until an optimal response is reached.

Paediatric population

Apo-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 in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Apo-Paroxetine is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Akathisia/psychomotor restlessness

The use of Apo-Paroxetine has been associated with the development of akathisia, which is characterised by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Serotonin Syndrome/Neuroleptic Malignant Syndrome

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of Apo-Paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with Apo-Paroxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Apo-Paroxetine should not be used in combination with serotonin-precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome.

Mania

As with all antidepressants, Apo-Paroxetine should be used with caution in patients with a history of mania. Apo-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. Additionally, there have been studies suggesting that an increase in blood glucose levels may occur when Apo-Paroxetine and pravastatin are co-administered.

Epilepsy

As with other antidepressants, Apo-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 Apo-Paroxetine. The drug should be discontinued in any patient who develops seizures.

Electroconvulsive therapy (ECT)

There is little clinical experience of the concurrent administration of Apo-Paroxetine with ECT.

Glaucoma

As with other SSRIs, Apo-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 Apo-Paroxetine.

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Other haemorrhagic manifestations e.g. gastrointestinal and gynaecological haemorrhage have been reported. Elderly patients may be at an increased risk for non-menses related events of bleeding.

Caution is advised in patients taking SSRIs concomitantly with oral anticoagulants, drugs known to affect platelet function or other drugs that may increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding.

Interaction with tamoxifen

Apo-Paroxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, Apo-Paroxetine should whenever possible be avoided during tamoxifen treatment.

Withdrawal symptoms seen on discontinuation of Apo-Paroxetine treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. In clinical trials, adverse events seen on treatment discontinuation occurred in 30% of patients treated with Apo-Paroxetine compared to 20% of patients treated with placebo. The occurrence of withdrawal symptoms is not the same as the drug being addictive or dependence producing.

The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.

Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that Apo-Paroxetine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.

Clinical experience has shown that therapy with Apo-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 Apo-Paroxetine does not increase the mental and motor skill impairments caused by alcohol, the concomitant use of Apo-Paroxetine and alcohol is not advised.

Some of the adverse drug reactions listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to <1/100), rare (> 1/10,000 to <1/1,000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (including ecchymosis and gynaecological bleeding)

Very rare: thrombocytopenia

Immune system disorders

Very rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema)

Endocrine disorders

Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Common: decreased appetite, increases in cholesterol levels

Uncommon: Altered glycaemic control has been reported in diabetic patients

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

Not known: aggression, suicidal ideation and suicidal behaviour

Cases of aggression were observed in post marketing experience. Cases of suicidal ideation and suicidal behaviours have been reported during Apo-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

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 Apo-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

Hepatobiliary disorders

Rare: elevation of hepatic enzymes

Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure)

Elevation of hepatic enzymes has been reported. Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure) have also been received very rarely. Discontinuation of Apo-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), urticaria, photosensitivity reactions

Musculoskeletal and connective tissue disorders

Rare: arthralgia, myalgia

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Renal and urinary disorders

Uncommon: urinary retention, urinary incontinence

Reproductive system and breast disorders

Very common: sexual dysfunction

Rare: hyperprolactinaemia/galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia, amenorrhoea, menstruation delayed and menstruation irregular)

Very rare: priapism

General disorders and administration site conditions

Common: asthenia, body weight gain

Very rare: peripheral oedema

WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF Apo-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 Apo-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 Apo-Paroxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

ADVERSE EVENTS FROM PAEDIATRIC CLINICAL TRIALS

The following adverse events were observed:

Increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Increased hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age.

Additional events that were seen are: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations), bleeding related adverse events, predominantly of the skin and mucous membranes.

Events seen after discontinuation/tapering of Apo-Paroxetine are: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

Symptoms

A wide margin of safety is evident from available overdose information on Apo-Paroxetine.

Management

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 Apo-Paroxetine. Supportive care with frequent monitoring of vital signs and careful observation is indicated. Patient management should be as clinically indicated.

Pharmacotherapeutic group: Antidepressants, selective serotonin reuptake inhibitors, ATC code: N06AB05.

Mechanism of action

Apo-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.

Apo-Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants.

Apo-Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties.

In accordance with this selective action, in vitro studies have indicated that, in contrast to tricyclic antidepressants, Apo-Paroxetine has little affinity for alpha1, alpha2 and beta-adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties.

Pharmacodynamic effects

Apo-Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol.

As with other selective 5-HT uptake inhibitors, Apo-Paroxetine causes symptoms of excessive 5-HT receptor stimulation when administered to animals previously given monoamine oxidase (MAO) inhibitors or tryptophan.

Behavioural and EEG studies indicate that Apo-Paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature.

Animal studies indicate that Apo-Paroxetine is well tolerated by the cardiovascular system. Apo-Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects.

Studies indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, Apo-Paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.

In the treatment of depressive disorders, Apo-Paroxetine exhibits comparable efficacy to standard antidepressants.

There is also some evidence that Apo-Paroxetine may be of therapeutic value in patients who have failed to respond to standard therapy.

Morning dosing with Apo-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 Apo-Paroxetine therapy.

Adult suicidality analysis

A Apo-Paroxetine specific analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (aged 18 - 24 years) treated with Apo-Paroxetine compared with placebo (2.19% vs 0.92%).).

Dose response

In the fixed dose studies there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, there are some clinical data suggesting that up-titrating the dose might be beneficial for some patients.

Long-term efficacy

The long-term efficacy of Apo-Paroxetine in depression has been demonstrated in a 52 week maintenance study with relapse prevention design: 12% of patients receiving Apo-Paroxetine (20-40 mg daily) relapsed, versus 28% of patients on placebo.

The long-term efficacy of Apo-Paroxetine in treating obsessive compulsive disorder has been examined in three 24 week maintenance studies with relapse prevention design. One of the three studies achieved a significant difference in the proportion of relapsers between Apo-Paroxetine (38%) compared to placebo (59%).

The long-term efficacy of Apo-Paroxetine in treating panic disorder has been demonstrated in a 24 week maintenance study with relapse prevention design: 5% of patients receiving Apo-Paroxetine (10-40 mg daily) relapsed, versus 30% of patients on placebo. This was supported by a 36 week maintenance study.

The long-term efficacy of Apo-Paroxetine in treating social anxiety disorder and generalised anxiety disorder and Post-traumatic Stress Disorder has not been sufficiently demonstrated.

Adverse events from paediatric clinical trials

In short-term (up to 10-12 weeks) clinical trials in children and adolescents, the following adverse events were observed in Apo-Paroxetine treated patients at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Increased hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age. Additional events that were more often seen in the Apo-Paroxetine compared to placebo group were: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations).

In studies that used a tapering regimen, symptoms reported during the taper phase or upon discontinuation of Apo-Paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain.

In five parallel group studies with a duration of eight weeks up to eight months of treatment, bleeding related adverse events, predominantly of the skin and mucous membranes, were observed in Apo-Paroxetine treated patients at a frequency of 1.74% compared to 0.74% observed in placebo treated patients.

Absorption

Apo-Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Due to first-pass metabolism, the amount of Apo-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 Apo-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

Apo-Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate that only 1% of the Apo-Paroxetine in the body resides in the plasma.

Approximately 95% of the Apo-Paroxetine present is protein bound at therapeutic concentrations.

No correlation has been found between Apo-Paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).

Biotransformation

The principal metabolites of Apo-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 Apo-Paroxetine's therapeutic effects.

Metabolism does not compromise Apo-Paroxetine's selective action on neuronal 5-HT uptake.

Elimination

Urinary excretion of unchanged Apo-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 Apo-Paroxetine represents less than 1% of the dose. Thus Apo-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 Apo-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 Apo-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.

Toxicology studies have been conducted in rhesus monkeys and albino rats; in both, the metabolic pathway is similar to that described for humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies of up to one year duration at doses that were 6 times higher than the recommended range of clinical doses.

Carcinogenesis: In two-year studies conducted in mice and rats, Apo-Paroxetine had no tumorigenic effect.

Genotoxicity: Genotoxicity was not observed in a battery of in vitro and in vivo tests.

Reproduction toxicity studies in rats have shown that Apo-Paroxetine affects male and female fertility by reducing fertility index and pregnancy rate. In rats, increased pup mortality and delayed ossification were observed. The latter effects were likely related to maternal toxicity and are not considered a direct effect on the foetus/neonate.

Not applicable

No special requirements.