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Data Sheet

AROPAX™ Tablets

Paroxetine

Presentation

AROPAX TABLETS: White, film coated, modified oval, biconvex tablets containing 22.8mg paroxetine hydrochloride equivalent to 20mg paroxetine free base.

The tablet has the product name and strength engraved on one side and a breakline on the reverse to enable the tablets to be broken in half if required.

Uses

Actions

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 and Panic Disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones.

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

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

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

Pharmacodynamic effects

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

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

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

Animal studies indicate that paroxetine is well tolerated by the cardiovascular system.

Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects.

Studies indicate that, in contrast to antidepressants, which inhibit the uptake of nor-adrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.

Pharmacokinetics

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 7-14 days after starting treatment 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 in the plasma 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

About 64% of the dose is excreted in the urine; urinary excretion of unchanged paroxetine is generally less than 2% of the dose. About 36% of the dose is excreted in the faeces, probably via the bile; faecal excretion of 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 and hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.

Indications

Depression:

Depression of all types, including reactive and severe depression and depression accompanied by anxiety.

AROPAX is indicated for the prevention of relapse and also recurrence of further depressive episodes.

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

In general, improvement in patients starts after one week but does not become superior to placebo until the second week of therapy.

AROPAX, in addition to its significant antidepressant effects, also improves associated symptoms of anxiety.

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

Morning dosing with AROPAX 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 AROPAX therapy.

Where it is clinical practice to co-prescribe short-acting hypnotics with antidepressants, no additional adverse events have been recorded.

AROPAX is effective in improving depression and suicidal ideation concurrently during the first few weeks of therapy.

Long term treatment with AROPAX has shown that efficacy is maintained for periods of at least one year.

Controlled clinical studies failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children with Major Depressive Disorder (see Adverse Effects).

Obsessive Compulsive Disorder:

AROPAX is indicated for the treatment of Obsessive Compulsive Disorder (OCD).

In a placebo-controlled trial, the efficacy of AROPAX in the treatment of OCD has been maintained for at least 1 year.

Panic Disorder:

AROPAX is indicated for the treatment of Panic Disorder with and without agoraphobia.

The combination of AROPAX and cognitive-behavioural therapy has been shown to be significantly more effective than cognitive-behavioural therapy alone in the treatment of Panic Disorder.

In a placebo-controlled trial, the efficacy of AROPAX in the treatment of Panic Disorder has been maintained for up to 1 year.

Social Anxiety Disorder/Social Phobia:

AROPAX has been shown to be effective in the treatment of Social Anxiety Disorder/Social Phobia.

Generalised Anxiety Disorder:

AROPAX has been shown to be effective in the treatment of Generalised Anxiety Disorder.

In a placebo-controlled trial, the efficacy of AROPAX in the treatment of Generalised Anxiety Disorder has been maintained for up to 32 weeks.

Posttraumatic Stress Disorder:

AROPAX has been shown to be effective in the treatment of Posttraumatic Stress Disorder.

Dosage and Administration

It is recommended that paroxetine is administered once daily in the morning with food. The tablet should be swallowed rather than chewed.

Depression:

The recommended dose is 20mg daily. Some patients not responding to a 20mg dose may benefit from dose increases, in 10mg/day increments, up to a maximum of 50mg/day. It is recommended that AROPAX is administered once daily with food. Based on observed beneficial effects on sleep it is recommended that the dose be taken in the morning. If, however, a patient experiences unacceptable daytime somnolence with AROPAX, consideration should be given to dosing at bedtime. The tablet should be swallowed rather than chewed.

As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within 2 to 3 weeks of initiation of therapy and thereafter as judged clinically appropriate. Dose changes should occur at intervals of at least one week.

Patients with depression should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months.

Controlled clinical studies in children aged 7 to 17 years failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children with Major Depressive Disorder (see Adverse Effects).

Obsessive Compulsive Disorder:

The recommended dose is 40mg (2 tablets) daily. Patients should start on 20mg and the dose can be increased weekly in 10mg increments. Some patients will benefit from having their dose increased up to a maximum of 60mg/day.

It is recommended that AROPAX is administered once daily with food. The tablet should be swallowed rather than chewed.

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 40mg daily. Patients should be started on 10mg/day and the dose increased weekly in 10mg increments according to patient's response. Some patients may benefit from having their dose increased up to a maximum of 60mg/day.

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.

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 20mg daily. Some patients not responding to a 20mg dose may benefit from having dose increases in 10mg increments as required, up to a maximum of 50mg/day according to the patient's response.

Generalised Anxiety Disorder:

The recommended dose is 20mg daily. Some patients not responding to a 20mg dose may benefit from having dose increases in 10mg increments as required, up to a maximum of 50mg/day according to the patient's response.

Posttraumatic Stress Disorder:

For the majority of patients, the recommended starting and maintenance dose is 20mg daily. However, some patients not responding to a 20mg dose may benefit from having dose increases in 10mg increments as required, up to a maximum of 50mg/day according to the patient's response.

The use of AROPAX beyond 12 weeks has not been investigated in clinical trials.

Populations

Elderly: Increased plasma concentrations of AROPAX occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects.

Children: The efficacy of paroxetine in children under the age of 18 years has not been established. Controlled clinical studies in depression failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children under the age of 18 years with depression (see Adverse Effects).

Renal/Hepatic Impairment: Increased plasma concentrations of AROPAX occur in patients with severe renal impairment (creatinine clearance <30mL/min) or hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range.

Discontinuation Of Paroxetine

As with other psychoactive medications, abrupt discontinuation should generally be avoided (see Warnings and Precautions & Adverse Effects sections). The taper phase regimen used in recent clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for one week before treatment was stopped. 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.

Contraindications

Known hypersensitivity to paroxetine and excipients.

Paroxetine should not be used in combination with monoamine oxidase (MAO) inhibitors or within 2 weeks of terminating treatment with MAO inhibitors. Likewise, MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with paroxetine (see Interactions)

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 (see Interactions). Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes, and sudden death.

Warnings and Precautions

MAO INHIBITORS: Treatment with paroxetine should be initiated cautiously at least 2 weeks after terminating treatment with MAO inhibitors and dosage of paroxetine should be increased gradually until optimal response is reached (see Contraindications and Interactions).

As with other SSRI's, paroxetine should be used with caution in patients already receiving neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination.

MANIA: As with all antidepressants, paroxetine should be used with caution in patients with a history of mania.

TRYPTOPHAN: As adverse experiences have been reported when tryptophan was administered with another selective 5-HT re-uptake inhibitor, paroxetine should not be used in combination with tryptophan medication. (See Interactions).

CARDIAC CONDITIONS: The usual precautions should be observed in patients with cardiac conditions.

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.

Paroxetine should be discontinued in any patient who develops seizures.

SUICIDE/SUICIDAL IDEATION AND PSYCHIATRIC DISORDERS: The possibility of a suicide attempt is an inherent component of major depressive disorder and may persist 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. Other psychiatric conditions for which paroxetine is prescribed can also be associated with an increased risk of suicidal behaviour. 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.

ECT: There is little clinical experience of the concurrent administration of paroxetine with ECT.

GLAUCOMA: As with other SSRI's, paroxetine infrequently causes mydriasis and should be used with caution in patients with narrow angle glaucoma.

Hyponatraemia has been reported rarely, predominantly in the elderly. The hyponatraemia generally reverses on discontinuation of paroxetine.

Skin and mucous membrane bleedings have been reported following treatment with paroxetine. Paroxetine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding, and in patients with a known tendency for bleeding or those with predisposing conditions.

SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINE TREATMENT: Some patients may experience symptoms on discontinuation of paroxetine, particularly if treatment is stopped abruptly (see Adverse Effects). It is therefore advised that the dose should be gradually tapered when discontinuing treatment (see Dosage and Administration).

Pregnancy and Lactation

Although animal studies have not shown any teratogenic or selective embryotoxic effects, the safety of paroxetine in human pregnancy has not been established and it should not be used during pregnancy or by nursing mothers unless the potential benefit outweighs the possible risk.

Effects on Ability to Drive and Use Machines

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

Although paroxetine does not increase the mental and motor skill impairments caused by alcohol, the concomitant use of paroxetine and alcohol is not advised.

Other: Preclinical Safety Data

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

Adverse Effects

Some of the adverse experiences listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports. The frequencies of common and uncommon events were generally determined from pooled safety data from a clinical trial population of >8000 paroxetine-treated patients and are quoted as excess incidence over placebo. Rare and very rare events were generally determined from post-marketing data and refer to reporting rate rather than true frequency.

Blood & 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 & nutrition disorders

Common: 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.
Uncommon: confusion.
Rare: manic reactions.

Nervous system disorders

Common: dizziness, tremor.
Uncommon: extrapyramidal disorders.
Rare: convulsions.
Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering tachycardia and tremor).

Reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication. In addition, akathisia has been rarely reported.

Eye disorders

Common: blurred vision.
Very rare: acute glaucoma.

Cardiac disorders

Uncommon: sinus tachycardia

Vascular disorders

Uncommon: transient increases or decreases in blood pressure.

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, dry mouth.

Hepato-biliary disorders

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

Elevation of hepatic enzymes has been reported. Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice, and/or liver failure) have also been received very rarely. Discontinuation of paroxetine should be considered if there is prolonged elevation of liver function test results.

Skin & subcutaneous tissue disorders

Common: sweating.
Uncommon: skin rashes.
Very rare: photosensitivity reactions.

Renal & urinary disorders

Uncommon: urinary retention.

Reproductive system & breast disorders

Very common: sexual dysfunction.

Rare: hyperprolactinaemia / galactorrhoea.

General disorders & administration site conditions

Common: asthenia.
Very rare: peripheral oedema.

Symptoms seen on discontinuation of paroxetine treatment

Common: Dizziness, sensory disturbances, sleep disturbances, anxiety.
Uncommon: Agitation, nausea, sweating.

As with many psychoactive medicines, discontinuation of paroxetine (particularly when abrupt) may lead to symptoms such as dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances, agitation or anxiety, nausea and sweating. In the majority of patients, these events are mild to moderate and are self-limiting. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when paroxetine treatment is no longer required, gradual discontinuation by dose tapering be carried out (see Dosage and Administration & Warnings and Precautions).

Adverse Events from Paediatric Clinical Trials

In paediatric clinical trials the following adverse events were reported at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: decreased appetite, tremor, sweating, hyperkinesia, hostility, agitation, emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder).

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: nervousness, dizziness, nausea, emotional lability and abdominal pain.

Interactions

Interactive Effects on Paroxetine

Clinical studies have shown the absorption and pharmacokinetics of paroxetine to be unaffected or only marginally affected (i.e. at a level which warrants no change in dosing regimen) by:

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolising enzymes. For example, cimetidine, a known drug metabolising enzyme inhibitor can increase the bioavailability of paroxetine.

When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor (eg sodium valproate), consideration should be given to using 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, phenytoin). Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).

Interactive Effects of Paroxetine on Other Drugs

CYP2D6: 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. amitriptyline, nortriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine), risperidone, Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol.

CYP3A4: An in vivo interaction study involving the co-administration under steady state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. A similar in vivo interaction study revealed no effect of paroxetine on alprazolam pharmacokinetics and vice-versa. Concurrent administration of paroxetine with terfenadine, alprazolam and other drugs that are CYP3A4 substrates would not be expected to cause a hazard.

SSRI Class Interactions

As with other SSRIs, co-administration with serotonergic drugs [e.g. MAO inhibitors (see Contraindications), L-tryptophan] may lead to an incidence of 5HT associated effects (Serotonergic Syndrome; see Adverse Effects). The risk of using paroxetine in combination with other CNS active drugs has not been systematically evaluated. Consequently caution is advised if concomitant administration is required.

Overdosage

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 "Adverse effects", 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 2000mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol.

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 30g of activated charcoal may be administered every 4 to 6 hours during the first 24 hours after ingestion. Supportive care with frequent monitoring of vital signs and careful observation is indicated.

Pharmaceutical Precautions

Incompatibilities

There are no known incompatibilities with paroxetine tablets. The tablet should be swallowed whole, not chewed.

Shelf Life

2 years when stored below 30°C.

Special Precautions for Storage

Tablets: Store in a dry place at a temperature not exceeding 30°C.

Medicines Classification

Prescription Only Medicine

Package Quantities

AROPAX, 20mg: 30 tablet packs (blisters in strips containing 10 tablets).

Name and Address

GlaxoSmithKline NZ Limited
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown Auckland
NEW ZEALAND

Phone: (09) 367 2900
Facsimile: (09) 367 2506

Date of Preparation

Issue number: 17

Issue date: 5 June 2003

AROPAX™ is a trademark of the GlaxoSmithKline group of companies.

Ref: MDS Version 023

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