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 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 Pharmacodynamic Properties)   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 Pharmacodynamic Properties)   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 Pharmacodynamic Properties).   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 Pharmacodynamic Properties).   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 Pharmacodynamic Properties).   General Information Withdrawal Symptoms Seen On Discontinuation Of Paroxetine Abrupt discontinuation should be avoided (see section 4.4 Special Warnings and Special Precautions for Use and section 4.8 Undesirable Effects). 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 (7-17 years) Paroxetine should not be used for the treatment of children and adolescents as controlled clinical trials have found paroxetine to be associated with increased risk for suicidal behaviour and hostility. In addition, in these trials efficacy has not been adequately demonstrated (see section 4.4 Special Warnings and Special Precautions for use and section 4.8 Undesirable Effects).   • Children aged below 7 years The use of paroxetine has not been studied in children less than 7 years. Paroxetine should not be used, as long as safety and efficacy in this age group have not been established.   • Renal/hepatic impairment Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or in those with hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range.

 

Known hypersensitivity to paroxetine or any of the excipients. Paroxetine is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). In exceptional circumstances, linezolid (an antibiotic which is a reversible non-selective MAOI) can be given in combination with paroxetine provided that there are facilities for close observation of symptoms of serotonin syndrome and monitoring of blood pressure (see section 4.5). Treatment with paroxetine can be initiated: - Two weeks after discontinuation of an irreversible MAOI, or - At least 24hrs after discontinuation of a reversible MAOI (e.g. moclobemide, linezolid, methylthioninium chloride (methylene blue). At least one week should elapse between discontinuation of paroxetine and initiation of therapy with any MAOI. Paroxetine should not be used in combination with thioridazine, because, as with other drugs which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma levels of thioridazine (see section 4.5 Interactions with other medicinal products and other forms of interaction). 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 Interactions with other medicinal products and other forms of interaction).

Treatment with paroxetine should be initiated cautiously two weeks after terminating

treatment with an irreversible MAOI or 24 hours after terminating treatment with a

reversible MAO inhibitor. Dosage of paroxetine should be increased gradually until an

optimal response is reached (see section 4.3 Contraindications and section 4.5 Interactions

with other medicinal products and other forms of interaction).

Use in children and adolescents under 18 years of age

Paroxetine should not be used in the treatment of children and adolescents under the age of

18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility

(predominantly aggression, oppositional behaviour and anger) were more frequently 

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 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. 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 (see also section 5.1).

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 paroxetine has been associated with the development of akathisia, which is

characterized by an inner sense of restlessness and psychomotor agitation such as an

inability to sit or stand still usually associated with subjective distress. This is most likely to

occur within the first few weeks of treatment. In patients who develop these symptoms,

increasing the dose may be detrimental.

Serotonin Syndrome/Neuroleptic Malignant Syndrome

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndromelike

events may occur in association with treatment of 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 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.

Paroxetine should not be used in combination with serotonin-precursors (such as Ltryptophan,

oxitriptan) due to the risk of serotonergic syndrome.

(See Sections 4.3 Contraindications and 4.5 Interactions with other medicinal products and

other forms of interaction).

Mania

As with all antidepressants, paroxetine should be used with caution in patients with a history

of mania. Paroxetine should be discontinued in any patient entering a manic phase.

Renal/hepatic impairment

Caution is recommended in patients with severe renal impairment or in those with hepatic

impairment. (see section 4.2 Posology and Method of Administration)

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or

oral hypoglycaemic dosage may need to be adjusted.

Epilepsy

As with other antidepressants, paroxetine should be used with caution in patients with

epilepsy.

Seizures

Overall the incidence of seizures is less than 0.1% in patients treated with paroxetine. The

drug should be discontinued in any patient who develops seizures.

ECT

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

Glaucoma

As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in

patients with narrow angle glaucoma or history of glaucoma.

Cardiac Conditions

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

Hyponatraemia

Hyponatraemia has been reported rarely, predominantly in the elderly. Caution should also

be exercised in those patients at risk of hyponatraemia e.g. from concomitant medications

and cirrhosis. The hyponatraemia generally reverses on discontinuation of paroxetine.

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymoses and

purpura with SSRIs. Other haemorrhagic manifestations e.g. gastrointestinal haemorrhages

have been reported. Elderly patients may be at an increased risk.

Caution is advised in patients taking SSRI's concomitantly with oral anticoagulants, drugs

known to affect platelet function or other drugs that may increase risk of bleeding (e.g.

atypical antipsychotics such as clozapine, phenothiazines, most TCA's, acetylsalicylic acid,

NSAID's, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or

conditions which may predispose to bleeding.

Interaction with tamoxifen

Paroxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen,

one of the most important active metabolites of tamoxifen. Therefore, paroxetine should

whenever possible be avoided during tamoxifen treatment (see section 4.5).

Withdrawal symptoms seen on discontinuation of paroxetine treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if

discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials adverse

events seen on treatment discontinuation occurred in 30% of patients treated with 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 paroxetine should be gradually

tapered when discontinuing treatment over a period of several weeks or months, according

to the patient's needs (see "Withdrawal Symptoms Seen on Discontinuation of Paroxetine",

Section 4.2 Posology and Method of Administration).

Serotonergic drugs

As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of

5-HT associated effects (serotonin syndrome: see Section 4.4 Special Warnings and Special

Precautions for Use). Caution should be advised and a closer clinical monitoring is required

when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid,

methylthioninium chloride (methylene blue), SSRIs, lithium, pethidine and St. John's Wort –

Hypericum perforatum – preparations) are combined with paroxetine. Caution is also

advised with fentanyl used in general anaesthesia or in the treatment of chronic pain.

Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of

serotonin syndrome (see Section 4.3 Contraindications).

Pimozide

Increased pimozide levels of on average 2.5 times have been demonstrated in a study of a

single low dose pimozide (2 mg) when co-administered with 60 mg paroxetine. This may be

explained by the known CYP2D6 inhibitory properties of paroxetine. 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 Contraindications).

Drug metabolising enzymes

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or

inhibition of drug metabolising enzymes.

When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor,

consideration should be given to using paroxetine doses at the lower end of the range.

No initial dosage adjustment is considered necessary when the drug is to be co-administered

with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin,

phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage

adjustment (either after initiation or following discontinuation of an enzyme inducer) should

be guided by clinical effect (tolerability and efficacy).

Fosamprenavir/ritonavir:

Co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20

mg daily in healthy volunteers for 10 days significantly decreased plasma levels of

paroxetine by approximately 55%. The plasma levels of fosamprenavir/ritonavir during coadministration

of paroxetine were similar to reference values of other studies, indicating that

paroxetine had no significant effect on metabolism of fosamprenavir/ritonavir. There are no

data available about the effects of long-term co-administration of paroxetine and

fosamprenavir/ritonavir exceeding 10 days.

Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of

procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.

Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration

does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients.

CYP2D6 inhibitory potency of paroxetine

As with other antidepressants, including other SSRIs, paroxetine inhibits the hepatic

cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma

concentrations of co-administered drugs metabolized 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 Contraindications),

risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide)

and metoprolol. It is not recommended to use paroxetine in combination with metoprolol

when given in cardiac insufficiency, because of the narrow therapeutic index of metoprolol

in this indication.

Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75%

reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has

been reported in the literature. Reduced afficacy of tamoxifen has been reported with

concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of

tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including

paroxetine) should whenever possible be avoided (see section 4.4).

Alcohol

As with other psychotropic drugs patients should be advised to avoid alcohol use while

taking paroxetine.

Oral anticoagulants

A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur.

Concomitant use of paroxetine and oral anticoagulants can lead to an increased

anticoagulant activity and haemorrhagic risk. Therefore, paroxetine should be used with

caution in patients who are treated with oral anticoagulants. (see section 4.4 Special

Warnings and Special Precautions for use)

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 Special warnings and Special Precautions for use)

Caution is advised in patients taking SSRI's, concomitantly with oral anticoagulants, drugs

known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics

such as clozapine, phenothiazines, most TCA's, acetylsalicylic acid, NSAID's, COX-2

inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding.

Fertility

Animal data have shown that paroxetine may affect sperm quality (see section 5.3). In vitro

data with human material may suggest some effect on sperm quality, however, human case

reports with some SSRIs (including paroxetine) have shown that an effect on sperm quality

appears to be reversible.

Impact on human fertility has not been observed so far.

Pregnancy

Some epidemiological studies suggest an increased risk of congenital malformations,

particularly cardiovascular (e.g. ventricular 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 than 2/100 compared with an expected rate for such defects of approximately 1/100 in the

general population. 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 Posology and Method of Administration).

Neonates 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 neonate after maternal paroxetine use in later stages

of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding

difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness,

irritability, lethargy, constant crying, somnolence and difficulty in sleeping. These symptoms

could be due to either serotonergic effects or withdrawal symptoms. In a majority of instances

the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late

pregnancy, may have an increased risk of persistent pulmonary hypertension of the newborn

(PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general

population 1 to 2 cases of PPHN per 1000 pregnancies occur.

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 Preclinical Safety Data).

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), and

no signs of drug effects were observed in these infants. Since no effects are anticipated, breastfeeding

can be considered.

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.

 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), including isolated reports.

Blood and lymphatic system disorders

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (mostly

ecchymosis).

Very rare: thrombocytopenia.

Immune system disorders

Very rare: allergic reactions (including urticaria and angioedema).

Endocrine disorders

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

Metabolism and nutrition disorders

Common: increases in cholesterol levels, decreased appetite.

Rare: hyponatraemia.

Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to

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

Psychiatric disorders

Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).

Uncommon: confusion, hallucinations.

Rare: manic reactions, anxiety, depersonalisation, panic attacks, akathisia (see section 4.4).

Frequency not known: suicidal ideation and suicidal behaviour.

Cases of suicidal ideation and suicidal behaviours have been reported during paroxetine

therapy or early after treatment discontinuation (see section 4.4).

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 (see section 4.4 Special Warnings and Special Precautions for Use).

Very rare: acute glaucoma.

Ear and labyrinth disorders

Frequency not known: tinnitus.

Cardiac disorders

Uncommon: sinus tachycardia.

Rare: bradycardia.

Vascular disorders

Uncommon: transient increases or decreases in blood pressure, postural hypotension.

Transient increases or decreases of blood pressure have been reported following treatment

with paroxetine, usually in patients with pre-existing hypertension or anxiety.

Respiratory, thoracic and mediastinal disorders

Common: yawning.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, diarrhoea, vomiting, dry mouth.

Very rare: gastrointestinal bleeding.

Hepato-biliary disorders

Rare: elevation of hepatic enzymes.

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

failure).

Elevation of hepatic enzymes 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 and subcutaneous tissue disorders

Common: sweating.

Uncommon: skin rashes, pruritus

Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-

Johnson syndrome and toxic epidermal necrolysis), photosensitivity reactions.

Renal and urinary disorders

Uncommon: urinary retention, urinary incontinence.

Reproductive system and breast disorders

Very common: sexual dysfunction.

Rare: hyperprolactinaemia/galactorrhoea.

Very rare: priapism.

Musculoskeletal and connective tissue disorders

Rare: arthralgia, myalgia

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.

General disorder and administration site conditions

Common: asthenia, body weight gain

Very rare: peripheral oedema.

Withdrawal Symptoms Seen On Discontinuation Of Paroxetine Treatment

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.

Uncommon: agitation, nausea, tremor, confusion, sweating, emotional instability, visual

disturbances, palpitations, diarrhoea, irritability.

Discontinuation of paroxetine (particularly when abrupt) commonly leads to withdrawal

symptoms. Dizziness, sensory disturbances (including paraesthesia, electric shock sensations

and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea,

tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability,

irritability, and visual disturbances have been reported.

Generally these events are mild to moderate and are self-limiting; however, in some patients

they may be severe and/or prolonged. It is therefore advised that when paroxetine treatment is

no longer required, gradual discontinuation by dose tapering should be carried out (see

section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and

Special Precautions for use).

Adverse Events From Paediatric Clinical Trials

The following adverse events were observed:

Increased suicidal related behaviours (including suicide attempts and suicidal thoughts), selfharm

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 paroxetine are: emotional lability (including

crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness,

dizziness, nausea and abdominal pain (see section 4.4 Special Warnings and Special

Precautions for use).

See section 5.1 for more information on paediatric clinical trials.

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 "Undesirable Effects", fever and involuntary muscle

contractions 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. Administration of 20-30 g activated charcoal may be

considered if possible within a few hours after overdose intake to decrease absorption of

paroxetine. Supportive care with frequent monitoring of vital signs and careful

observation is indicated. Patient management should be as clinically indicated.

Pharmacotherapeutic group: Antidepressants – selective serotonin reuptake inhibitors,

ATC code: N06AB05

Mechanism of Action

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin)

uptake and its antidepressant action and effectiveness in the treatment of OCD, Social

Anxiety disorder/Social Phobia, General Anxiety Disorder, Post-traumatic Stress Disorder

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

brain neurones.

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

antidepressants.

Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have

indicated only weak anticholinergic properties.

In accordance with this selective action, in 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. 

Adult suicidality analysis

A 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 paroxetine compared with placebo (2.19% vs 0.92%). In the older age

groups, no such increase was observed. In adults with major depressive disorder (all

ages), there was an increase in the frequency of suicidal behaviour in patients treated with

paroxetine compared with placebo (0.32% vs 0.05%); all of the events were suicide

attempts. However, the majority of these attempts for paroxetine (8 of 11) were in

younger adults (see also section 4.4).

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

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 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, and 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 Special Warnings and Special Precautions for

use). In five parallel group studies with duration of eight weeks up to eight months of

treatment, bleeding related adverse events, predominantly of the skin and mucous

membranes, were observed in paroxetine treated patients at a frequency of 1.74%

compared to 0.74% observed in placebo treated patients.

Absorption

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

first-pass metabolism, the amount of paroxetine available to the systemic circulation is

less than that absorbed from the gastrointestinal tract. Partial saturation of the first-pass

effect and reduced plasma clearance occur as the body burden increases with higher

single doses or on multiple dosing. This results in disproportionate increases in plasma

concentrations of paroxetine and hence pharmacokinetic parameters are not constant,

resulting in non-linear kinetics. However, the non-linearity is generally small and is

confined to those subjects who achieve low plasma levels at low doses.

Steady state systemic levels are attained by 7 to 14 days after starting treatment with

immediate or controlled release formulations and pharmacokinetics do not appear to

change during long-term therapy.

Distribution

Paroxetine is extensively distributed into tissues and pharmacokinetic calculations

indicate that only 1% of the paroxetine in the body resides in the plasma. Approximately

95% of the paroxetine present is protein bound at therapeutic concentrations. No

correlation has been found between paroxetine plasma concentrations and clinical effect

(adverse experiences and efficacy).

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 feces, 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 overlap 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, 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.

-Lactose Monohydrate                                   

-Croscarmellose Sodium

-Colloidal Silicon Dioxide    

-Sodium Stearyl Fumarate

-Povidone K-30

-Opadry

-Simethicone Emulsion

Not applicable.

3 years.

Store below 30°C.

Does not use beyond the expiry date or if the product shows any sign of deterioration.

Three Aluminum – PVC/PVDC blisters of 10 tablets each, packed in a printed carton with a folded leaflet.

No special requirements.