Paroxetine 30 mg Tablets

Each film-coated tablet contains 30 mg paroxetine (as paroxetine hydrochloride anhydrous 33.3mg).

For a full list of excipients, see section 6.1.

Film-coated tablet

A blue, oval, convex tablet with a pressure sensitive score, encoded PX 30.

The tablet can be divided into equal halves if required.

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

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 (OCD)

The recommended dose is 40 mg daily. Patients should start on 20 mg/day and the dose may be increased gradually in 10 mg increments to the recommended dose. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 60 mg/day.

Patients with OCD should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer. (see section 5.1)

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 (see section 5.1)

SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA

The recommended dose is 20 mg daily.If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day.Long-term use should be regularly evaluated (see section 5.1).

GENERALISED ANXIETY DISORDER

The recommended dose is 20 mg daily.If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day.Long-term use should be regularly evaluated (see section 5.1).

POST-TRAUMATIC STRESS DISORDER

The recommended dose is 20 mg daily.If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day.Long-term use should be regularly evaluated (see section 5.1).

GENERAL INFORMATION

WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINE

Abrupt discontinuation should be avoided (see sections 4.4 and 4.8). When stopping treatment with paroxetine the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and 4.8). 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 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 (below 18 years)

Paroxetine should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).

•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.

Known hypersensitivity to paroxetine or to any of the excipients.

Paroxetine is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). 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).

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 medicinal products, which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma levels of thioridazine (see section 4.5). 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 (see section 4.5.).

Use in children and adolescents

If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for appearance of suicidal symptoms.

In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8).

Monoamine oxidase inhibitors (MAOIs)

Suicide/suicidal thoughts or clinical worsening

Other psychiatric conditions for which 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, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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

Serotonin syndrome/Neuroleptic malignant syndrome

(See sections 4.3 and 4.5).

Mania

Renal/hepatic impairment

Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see section 4.2).

Diabetes

Epilepsy

Seizures

ECT

Glaucoma

Cardiac Conditions

Hyponatraemia

Haemorrhage

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

Alcohol

Withdrawal symptoms seen on discontinuation of paroxetine treatment

Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that paroxetine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see section 4.2 “Withdrawal Symptons Seen on Discontinuation of Paroxetine”).

Serotonergic drugs

As with other SSRIs, co-administration with serotonergic medicinal products (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, lithium and St. John's Wort – Hypericum perforatum – preparations) may lead to an incidence of 5HT associated effects (serotonin syndrome: see section 4.3 and 4.4).

Caution should be advised and a closer clinical monitoring is required when these drugs are combined with paroxetine.

Pimozide

Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) when coadministered with paroxetine. While the mechanism of this interaction is currently unknown, due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see section 4.3).

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 active substances metabolised by this enzyme. These include certain tricyclic antidepressants (e.g. clomipramine, nortriptyline, and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see section 4.3), 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.

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). Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).

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.

Alcohol

As with other psychotropic medicinal products patients should be advised to avoid alcohol use while taking paroxetine.

Oral anticoagulants

A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants can lead to an increased anticoagulant activity and haemorrhagic risk. Therefore, paroxetine should be used with caution in patients who are treated with oral anticoagulants. (see section 4.4).

NSAIDs and acetylsalicylic acid, and other antiplatelet agents

A pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid can lead to an increased haemorrhagic risk (see section 4.4).

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

Pregnancy

Some epidemiological studies suggest a small increased risk of cardiovascular malformation (e.g. ventricular (majority) and atrial septum defects) associated with the use of paroxetine during the first trimester. The mechanism is unknown. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is less then 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population. Available data do not suggest an increase of the overall rate of congenital malformation.

Paroxetine should only be used during pregnancy when strictly indicated. The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant.

Abrupt discontinuation should be avoided during pregnancy (see “Withdrawal symptoms seen on discontinuation of Paroxetine”, section 4.2).

New-born infants should be observed if maternal use of paroxetine continues into the later stages of pregnancy, particularly the third trimester.

The following symptoms may occur in the new-born infants 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.

Animal studies showed reproductive toxicity, but did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Section 5.3).

Lactation

Small amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 ng/ml) or very low (<4 ng/ml). No signs of drug effects were observed in these infants. Nevertheless, paroxetine should not be used during lactation unless the expected benefits to the mother justify the potential risks for the infant.

Paroxetine has no or negligible influence on the ability to drive and use machines.

Clinical experience has shown that therapy with paroxetine is not associated with impairment of cognitive or psychomotor function. However, as with all psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery.

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

Blood and lymphatic system disorders

Very rare: thrombocytopenia

Immune system disorders

Endocrine disorders

Metabolism and nutrition disorders

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

Uncommon: confusion, hallucinations

Rare: manic reactions, anxiety, depersonalisation, panic attacks

Frequency not known: cases of suicidal ideation and suicidal behaviours have been reported during paroxetine therapy or early after treatment discontinuation (see section 4.4).

These symptoms may also be due to the underlying disease.

Nervous system disorders

Uncommon: extrapyramidal disorders

Rare: psychomotor restlessness/akathisia (see section 4.4), convulsions

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 medicinal products.

Eye disorders

Very rare: acute glaucoma

Cardiac disorders

Rare: bradycardia

Vascular disorders

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

Gastrointestinal disorders

Common: constipation, diarrhoea, dry mouth

Very rare: gastrointestinal bleeding

Hepato-biliary disorders

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

Uncommon: skin rashes, pruritus

Very rare: photosensitivity reactions

Renal and urinary disorders

Reproductive system and breast disorders

Rare: hyperprolactinaemia/galactorrhoea

Very rare: priapism

Musculoskeletal disorders

General disorder and administration site conditions

Very rare: peripheral oedema

WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINE TREATMENT

Discontinuation of paroxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions.

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 (see sections 4.2 and 4.4).

Adverse events from paediatric clinical trials

In short-term (up to 10-12 weeks) clinical trials in children and adolescents, the following adverse events were observed in paroxetine treated patients at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo 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 paroxetine compared to placebo group were: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations).

In studies that used a tapering regimen, symptoms reported during the taper phase or upon discontinuation of paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain (see section 4.4).

Symptoms and Signs

A wide margin of safety is evident from available overdose information on paroxetine.

Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned under section 4.8, vomiting, dilated pupils, fever, blood pressure changes, headache, involuntary muscle contractions, agitation, anxiety and tachycardia have been reported. Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely 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. Where appropriate, the stomach should be emptied either by the induction of emesis, lavage or both. Following evacuation, 20 to 30 g of activated charcoal may be administered every 4 to 6 h during the first 24 h after ingestion. Supportive care with frequent monitoring of vital signs and careful observation is indicated.

Pharmacotherapeutic group: Antidepressants – selective serotonin reuptake inhibitors

ATC code: N06A B05

Mechanism of action

Paroxetine is a potent and selective inhibitor of 5hydroxytryptamine (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 disorderand panic disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones.

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

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

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

Pharmacodynamic effects

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

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

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

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

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

In the treatment of depressive disorders, paroxetine exhibits comparable efficacy to standard antidepressants.

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

Morning dosing with paroxetine does not have any detrimental effect on either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy.

Dose response

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

Long-term efficacy

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

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

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

The long-term efficacy of paroxetine in treating social anxiety disorder and generalised anxiety disorder and post-traumatic stress disorderhas not been sufficiently demonstrated.

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 nonlinear kinetics. However, the non-linearity is generally small and is confined to those subjects who achieve low plasma levels at low doses.

Steady state systemic levels are attained by 7 to 14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy.

Distribution

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

Approximately 95% of the paroxetine present is protein bound at therapeutic concentrations.

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

Transfer to human breast milk, and to the foetuses of laboratory animals, occurs in small amounts.

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.

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 oneyear 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, paroxetine had no tumorigenic effect.

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

Reproduction toxicity studies in rats have shown that paroxetine affects male and female fertility. 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.

Tablet core

Mannitol

Cellulose, microcrystalline

Copovidone

Sodium starch glycollate (Type A)

Silica, colloidal anhydrous

Magnesium stearate

Tablet-coating

Hypromellose

Talc

Titanium dioxide (E171)

Ferric oxide (E172)

Indigotine (E132)

Not applicable.

3 years

Do not store above 30º C.

Blister (Al/PVC) or polyethylene tablet container and screw cap.

Pack sizes:

7, 10, 14, 20, 28, 30, 50, 60, 100 and 250 tablets.

Not all pack sizes or pack types may be marketed.

No special requirements.

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire

GU35 9QE

PL 04416/0688

06/12/2007

06/2008