AROPAX

paroxetine

Presentation

AROPAX TABLETS

White, film coated, modified oval, biconvex tablets containing paroxetine hydrochloride equivalent to 20 mg 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.

Clinical Particulars

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

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

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.

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.

Posology and method of administration

Depression

The recommended dose is 20 mg 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.

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 depression or OCD should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months for depression and for OCD can be 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.

It is generally recommended that a course of antidepressant drug treatment should continue for a sufficient period, often for several months. This period may be several months for depression and for Panic Disorder can be 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.

Elderly

Increased plasma concentrations of AROPAX occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects. Dosing should commence at the adult starting dose and may be increased by 10 mg increments up to 40 mg daily, according to the patient's response.

Children

The use of AROPAX in children is not recommended as safety and efficacy have not been established in this population.

Renal/Hepatic Impairment

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

Discontinuation of Treatment

Discontinuation effects have been noted 1 to 4 days after abrupt cessation. AROPAX should not normally be discontinued abruptly. When AROPAX is to be discontinued, the dose should be tapered. As with many psychoactive medicines, abrupt discontinuation may lead to symptoms such as dizziness, sensory disturbances, sleep disturbances, tremor, agitation or anxiety, nausea and sweating.

Contraindications

Known hypersensitivity to paroxetine and excipients.

Concomitant use in patients taking monoamine oxidase inhibitors. (see Special Warnings and Special Precautions for Use)

Special Warnings and Special Precautions for Use

MAO Inhibitors

As with most antidepressants, paroxetine should not be used in combination with MAO inhibitors or within 2 weeks of terminating treatment with MAO inhibitors. Hereafter treatment should be initiated cautiously and dosage increased gradually until optimal response is reached.

MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with paroxetine.

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 with Other Medicaments and Other Forms of Interaction).

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.

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 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 and may be associated with the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). 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.

Interaction with Other Medicaments and Other Forms of Interaction

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:

• food
• antacids
• digoxin
• propranolol
• alcohol: paroxetine does not increase the impairment of mental and motor skills caused by alcohol, however, the concomitant use of paroxetine and alcohol is not advised.
• lithium: although there is no PK interaction, since there is limited experience in patients, the concurrent administration of paroxetine and lithium should be undertaken with caution.
• drug metabolising enzymes

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

Interactive Effects of Paroxetine on Other Drugs

Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

anticonvulsants:

carbamazepine, phenytoin, sodium valproate. Concomitant administration showed no effect on pharmacokinetic/dynamic profile in epileptic patients.

P450 isoenzymes

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) and Type 1c antiarrhythmics (e.g. propafenone and flecainide).

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. Concurrent administration of paroxetine with terfenadine 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 [eg MAO inhibitors (see Special Warnings and Special Precautions for Use), L-tryptophan] may lead to an incidence of 5HT associated effects (Serotonergic Syndrome; see Undesirable 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.

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.

Undesirable Effects

Adverse experiences with paroxetine are generally mild in nature and do not affect the patient's life-style. Adverse experiences may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.

The most commonly observed adverse events associated with the use of paroxetine in clinical trials were: nausea, somnolence, sweating, tremor, asthenia, dry mouth, insomnia, sexual dysfunction , dizziness, constipation, diarrhoea and decreased appetite.

Paroxetine is less likely than tricyclic antidepressants to be associated with dry mouth, constipation and somnolence.

The following adverse events have been reported rarely; dizziness, rash, acute glaucoma, urinary retention, peripheral oedema, sinus tachycardia, thrombocytopenia, serotonergic syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor), symptoms suggestive of hyperprolactinaemia/ galactorrhoea and hyponatraemia (predominantly in the elderly) which is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

Post-marketing reports of allergic reactions (such as angioedema, urticaria and skin rashes) have been received very rarely.

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

Rarely, abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis) has been reported following paroxetine treatment.

Manic reactions have been reported very rarely.

Blurred vision has been reported.

Occasional reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.

As with many psychoactive medicines, abrupt discontinuation may lead to symptoms such as dizziness, sensory disturbances, sleep disturbances, agitation or anxiety, nausea and sweating.

As with other SSRIs, transient increases or decreases in blood pressure have been reported following treatment with paroxetine, usually in patients with pre-existing hypertension or anxiety.

As with other SSRIs, confusion, convulsions and photosensitivity reactions have been reported rarely.

Overdose

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 "Undesirable 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 2000 mg 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 alone or in conjunction with other psychotropic drugs, with or without alcohol.

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 grams 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.

Pharmacological Properties

Pharmacodynamic Properties

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.

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.

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.

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.

Pharmacokinetic Properties

Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. 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.

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

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

Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. Partial aturation 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.

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.

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

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.

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.

Pharmaceutical Particulars

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.

Package Quantities

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

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