Consumer medicine information

Paxtine

Paroxetine

BRAND INFORMATION

Brand name

Paxtine

Active ingredient

Paroxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Paxtine.

What is in this leaflet

This leaflet answers some common questions about PAXTINE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking PAXTINE against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What PAXTINE is used for

This medicine contains the active ingredient paroxetine.

This medicine belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRI) antidepressants. They are thought to work by their action on brain chemicals called amines which are involved in controlling mood.

Depression is longer lasting or more severe than the 'low moods' that everyone has from time to time. It is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional and physical symptoms. You may feel low in spirit, lose interest in your usual activities, be unable to enjoy life, have a poor appetite or over eat, have disturbed sleep, often waking up early, low energy and feel guilty over nothing.

PAXTINE may be used to treat irrational fears or obsessional behaviour. These can also be due to chemical imbalance in parts of the brain.

PAXTINE may be used to help prevent panic attacks.

PAXTINE may be used to treat patients who may avoid and/or are fearful of social situations.

Your doctor may decide that you should continue to use PAXTINE for some time, even when you have overcome your problem. This should prevent the problem from returning.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Before you take PAXTINE

Antidepressants can increase suicidal thoughts and actions in some children and adolescents younger than 18 years of age.

Suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal.

Antidepressants are used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and the risks of not treating it. You should discuss all treatment choices with your doctor, not just the use of antidepressants.

Patients (and caregivers of patients) need to monitor for any worsening of their condition and/or the emergence of thoughts of suicide or suicidal behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present (see Use in Children and Adolescents below).

When you must not take it

Do not take PAXTINE if you have an allergy to:

  • any medicine containing paroxetine
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant or intend to become pregnant. Studies show that use of paroxetine in early pregnancy (first 13 weeks) may be associated with an increased risk of some birth defects in babies.

If you become pregnant or intend to become pregnant while taking paroxetine, you should make an appointment to see your doctor and have your treatment reviewed.

It is important that you do not stop taking paroxetine suddenly. Paroxetine is a medicine that can have withdrawal side effects if stopped suddenly (see Unwanted Effects That May Occur on Stopping Treatment below).

If you have taken PAXTINE before and became unwell after taking it, tell your doctor or pharmacist before you take the first dose.

Do not take this medicine if you are taking any other medications for the treatment of depression or have done so in the last 14 days. Taking PAXTINE with another antidepressant may cause a serious reaction.

You must not take PAXTINE for 14 days after stopping monoamine oxidase inhibitor drugs (MAOIs). Taking PAXTINE with a MAOI may cause a serious reaction.

Examples of MAOIs are phenelzine and tranylcypromine. Another MAOI includes the antibiotic linezolid.

Do not take this medicine if you are taking or have recently taken (within the last two weeks) a medicine called methylthioninium chloride (methylene blue).

Do not take this medicine if you are taking:

  • thioridazine
  • pimozide

Taking PAXTINE together with either of the above medicines, which are medicines used to treat schizophrenia, can lead to serious side effects.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are over 65 years of age be aware as PAXTINE may cause a reduction in the amount of sodium within your blood. This can lead to sleepiness and muscle weakness. If you experience these symptoms, tell your doctor or pharmacist as soon as possible.

Medicines like PAXTINE may affect your sperm. Fertility in some men may be reduced while taking this medicine.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • liver problems
  • heart problems
  • epilepsy
  • mania
  • glaucoma (raised pressure in the eye)
  • problems with blood clotting
  • other psychiatric conditions (bipolar disorder)
  • diabetes

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking PAXTINE.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and PAXTINE may interfere with each other. These include:

  • medicines used to treat depression, anxiety, schizophrenia or attention-deficit hyperactivity disorder (ADHD) including tryptophan, St John's Wort (hypericum perforatum), perphenazine, risperidone, lithium or atomoxetine
  • medicines used in anaesthesia or to treat pain or chronic pain, such as tramadol or fentanyl
  • medicines used to control epilepsy (known as anticonvulsants), such as phenytoin, carbamazepine, phenobarbital (phenobarbitone)
  • medicines used to treat migraine attacks such as sumatriptan
  • medicines used to thin blood (anti-coagulants) such as warfarin, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs)
  • certain medicines used to treat Parkinson's disease such as selegiline and procyclidine
  • medicines used to lower blood pressure or treat heart conditions, such as metoprolol or flecainide
  • cimetidine, a medicine used to treat stomach ulcers
  • medicine to treat or prevent breast cancer such as tamoxifen
  • medicines used to treat HIV infection such as a combination of fosamprenavir and ritonavir
  • medicines used for anaesthesia, such as mivacurium and suxamethonium

These medicines may be affected by PAXTINE or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take PAXTINE

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

The usual dose of PAXTINE for depression and social anxiety disorder/social phobia is one 20 mg tablet per day.

To treat obsessions and compulsions or panic attacks, the usual dose of PAXTINE is two 20 mg tablets (40 mg) per day.

Your doctor may start you on a lower dose (half a tablet) and increase the dose slowly over several weeks. This may require you to break the tablet in half.

How to take it

Take the tablets with a full glass of water or another liquid.

Do not crush or chew the tablets.

PAXTINE tablets can be divided in half along the breakline if required.

When to take it

Take your medicine in the morning, preferably with food.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Like other drugs of this class, PAXTINE will not relieve your symptoms immediately. People generally start feeling better in a few weeks.

Occasionally, the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide.

It is possible that these symptoms may continue or increase until the full antidepressant effect of your medicine becomes apparent.

Tell your doctor immediately or go to your nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time.

Tell your doctor if you experience any worsening of your depression/ other symptoms at any time during your treatment.

Stopping treatment

Do not stop taking your medicine even if you begin to feel better.

Your doctor may decide that you should continue to use PAXTINE for some time, even when you have overcome your problem.

For best effect, PAXTINE must be taken regularly.

Your doctor will tell you when and how PAXTINE should be stopped. Treatment is usually stopped by slowly reducing the dosage over a period of several weeks. When you stop treatment with this medicine, especially if this is done suddenly, you may experience unwanted symptoms.

Use in children and adolescents

PAXTINE is not recommended for use in children and adolescents under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established and there are possible unwanted effects.

Information from clinical trials has suggested that young adults, particularly those with depression, may be at an increased risk of suicidal behaviour (including suicide attempts) when treated with PAXTINE, especially during initial treatment (generally the first one to two months).

The majority of attempted suicides in clinical trials in depression involved patients aged 18 to 30 years.

Family and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or non-psychiatric) need to monitor them for the emergence of agitation, irritability, unusual changes in behaviour, as well as the emergence of thoughts of suicide, and to report such symptoms immediately to their doctor.

It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.

Use in pregnancy

If you take PAXTINE near the end of your pregnancy, there may be an increased risk of heavy vaginal bleeding shortly after birth, especially if you have history of bleeding disorders. Your doctor or midwife should be aware that you are taking PAXTINE so they can advise you.

If you forget to take it

Skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much PAXTINE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking PAXTINE

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PAXTINE.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working and change your treatment unnecessarily.

Tell your doctor if you feel the tablets are not helping your condition.

If you are being treated for depression, discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness or bursts of unusual energy or anger. This will help your doctor to determine the best treatment for you.

Persons taking PAXTINE may be more likely to think about killing themselves or actually trying to do so, especially when PAXTINE is first started or the dose is changed. People close to persons taking PAXTINE can help by paying attention to changes in user's moods or actions.

Contact your doctor right away if someone using PAXTINE talks about or shows signs of killing him or herself. If you are taking PAXTINE yourself and you start thinking about killing yourself, tell your doctor about this side effect right away.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may want to do some blood tests and check your heart and blood pressure from time to time. This helps to prevent unwanted side effects.

Things you must not do

Do not stop taking PAXTINE without your doctor's permission. Suddenly stopping PAXTINE may cause symptoms like dizziness, trouble sleeping, shaking, feeling anxious, nausea, sweating or tinnitus.

Do not take PAXTINE to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how PAXTINE affects you. Tests have shown that PAXTINE does not have a marked effect on driving ability. However, this medicine may cause drowsiness, dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking moderate amounts of alcohol is unlikely to affect your response to PAXTINE, however it is best to avoid alcohol while you are taking this medicine.

There is an increased risk of breaking a bone in people taking medicines like PAXTINE. This risk is greatest during the early stages of treatment.

When your doctor decides that you should stop taking PAXTINE, the dose will be reduced slowly or the time between doses increased over 1 or 2 weeks. Some people may have symptoms such as dizziness, anxiety, sleep disturbances, pins and needles, electric shock sensations or feeling sick and sweating if this medicine is stopped, particularly if stopped suddenly.

Although PAXTINE is not recommended for children under 18 years of age, additional symptoms have been experienced by children whilst stopping treatment including abdominal pain, nervousness and mood changes.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PAXTINE.

This medicine helps most people who take it, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

MILD EFFECTS

Tell your doctor if you notice any of the following and they worry you:

  • feeling sick, dry mouth, constipation, decreased appetite, diarrhoea
  • vomiting
  • dizziness, drowsiness or difficulty getting to sleep
  • impaired sexual function
  • weakness
  • feeling sweaty or shaky
  • bruising
  • abnormal dreams (including nightmares)
  • weight gain

MORE SERIOUS EFFECTS

Tell your doctor as soon as possible if you notice any of the following:

  • muscle spasms or twitches

If any of the following happen, stop taking PAXTINE and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • allergic reaction including, swelling of limbs, face, lips, mouth or throat which may cause difficulty swallowing or breathing
  • skin rash, which may blister, and looks like small targets (central dark spots surround by a paler area, with a dark ring around the edge) called erythema multiforme
  • a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals or on much of the body surface (Stevens-Johnson syndrome or toxic epidermal necrolysis)
  • sudden onset of prolonged muscular spasm, affecting the eyes, head, neck and body
  • sudden increase in body temperature, severe convulsions
  • fast heart beat, sweating, muscle spasm, racing thoughts, restlessness

Other rare events that have been reported with PAXTINE use include:

  • blurred vision
  • abnormal liver function
  • low levels of sodium in the blood, especially in older people
  • bleeding disorders, including nose bleeds and gastrointestinal bleeding which occurs very rarely
  • hormone disturbances
  • mood of excitement, over-activity and uninhibited behaviour
  • confusion
  • seizures
  • rash caused by light
  • itchy rash, hives, swelling of the face, lips, mouth, tongue or throat
  • akathisia (restlessness or difficulty keeping still, caused by medicines to treat mental disorders)
  • irresistible urge to move the legs (Restless Legs Syndrome)
  • menstrual period disorder (including heavy periods, bleeding between periods and absence of periods
  • severe allergic reactions
  • heavy vaginal bleeding shortly after birth

Unwanted effects that may occur on stopping treatment may include:

  • dizziness
  • sensory disturbances such as pins and needles, burning sensations and electric shock-like sensations
  • sleep disturbances, including intense dreams
  • agitation or anxiety
  • feeling sick
  • shaking or tremors
  • confusion
  • headache
  • sweating
  • diarrhoea

These are likely to occur in the first few days of stopping treatment or, very rarely, if you miss a dose. They are more likely to occur if you stop taking PAXTINE suddenly.

Always consult your doctor before stopping your medicine.

For most patients, symptoms go away on their own within a few weeks. However, if you feel that the unwanted symptoms are too severe, tell your doctor who will suggest how to manage stopping treatment more slowly.

Additional symptoms that have been experienced by children and adolescents under the age of 18 years whilst stopping treatment include changing emotions (thoughts of suicide, attempting suicide, mood changes and feeling tearful), abdominal pain and nervousness.

Tell your doctor immediately if you notice any of the following:

  • wheezing, swelling of the lips/ mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting. These could be a symptom of an allergic reaction.

Although this medicine is not recommended for children and adolescents below 18 years of age, the most common side effects 18 are:

  • decreased appetite
  • tremor (uncontrollable trembling)
  • sweating
  • hyperactivity
  • hostile/unfriendly behaviour
  • agitation
  • changing emotions, including crying, changes in mood, trying to harm themselves, thoughts of suicide and attempting suicide

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people.

After taking PAXTINE

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store PAXTINE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

PAXTINE is a white, round film-coated tablet marked P/2 and G.

Each pack contains 30 tablets.

Ingredients

PAXTINE contains 20 mg of paroxetine as the active ingredient.

The tablets also contain the following inactive ingredients:

  • calcium hydrogen phosphate
  • colloidal anhydrous silica
  • magnesium stearate
  • methacrylic acid copolymer (Trade Name: Eudragit E 100)
  • purified talc
  • sodium starch glycollate
  • titanium dioxide (171)

PAXTINE also contains sulfites. This medicine does not contain sucrose, lactose, gluten or tartrazine.

Manufacturer

PAXTINE is made in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in November 2023.

Australian Registration Number:
AUST R 227120

PAXTINE® is a Viatris company trade mark

PAXTINE_cmi\Nov23/00

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Paxtine

Active ingredient

Paroxetine

Schedule

S4

 

1 Name of Medicine

Paroxetine hydrochloride.

2 Qualitative and Quantitative Composition

Each Paxtine tablet contains 20 mg of paroxetine (as hydrochloride) as the active ingredient.

Excipients of known effect.

Sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Paxtine 20 mg.

White, round film-coated tablet marked P/2 and G.

4 Clinical Particulars

4.1 Therapeutic Indications

Paxtine is indicated for the treatment of:
Major depression and prevention of relapse of depressive symptoms.
Obsessive compulsive disorder (OCD) and prevention of relapse of OCD.
Panic disorder and prevention of relapse of panic disorder.
Social anxiety disorder/ social phobia.

4.2 Dose and Method of 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 of paroxetine is 20 mg (1 tablet) daily. Many patients will respond to a 20 mg daily dose. Patients not responding to a 20 mg dose may benefit from dose increases in 10 mg/day increments, up to a maximum of 50 mg/day according to the patient's response.
As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within 2 or 3 weeks of initiation of therapy and thereafter as judged clinically appropriate. Dose changes should occur at intervals of at least 1 week.
It is generally recommended that a course of antidepressant drug treatment should continue for a sufficient period, often for several months. There is no body of evidence available to answer the question of how long the patient treated with paroxetine should remain on it. It is generally agreed that acute episodes of depression require several months or longer of sustained drug therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain or sustain euthymia is unknown.
Systematic evaluation of paroxetine hydrochloride has shown that efficacy was maintained for periods up to one year.

Obsessive compulsive disorder.

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

Maintenance therapy.

Long-term maintenance of efficacy was demonstrated in a 6 month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Patients with OCD should be treated for a sufficient period to ensure that they are free from symptoms.

Panic disorder.

The recommended dose is 40 mg daily (2 tablets). Patients should be started on 10 mg/day and the dose increased weekly in 10 mg increments according to patient's response. Some patients may benefit from having their dose increased up to a maximum of 60 mg/day.
A low starting dose and slow dosage increase reduce the risk of an initial transient increase in anxiety which is generally recognised to occur early in the treatment of this disorder.

Maintenance therapy.

Long-term maintenance of efficacy was demonstrated in two studies, the first a 3 month relapse prevention trial and the second a 36 week extension study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). In the relapse prevention trial patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo. Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Social anxiety disorder/ social phobia.

The recommended dose is 20 mg (1 tablet) daily. Some patients may benefit from having their dose increased up to a maximum of 50 mg/day. Patients should start on 20 mg and, according to the patient's response, the dose can be increased weekly in 10 mg increments. The lowest dose of paroxetine studied in clinical trials (20 mg) produced a statistically significant superior response to placebo.

Use in the 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 and may be increased up to 40 mg daily. Dosing should not exceed 40 mg daily.
Elderly patients should be initiated and maintained at the lowest daily dosage of paroxetine that is associated with clinical efficacy.

Use in children and adolescents (< 18 years).

Paroxetine is not indicated for use in children or adolescents aged < 18 years. Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy, and do not support the use of paroxetine in the treatment of depression in this population (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use). The safety and efficacy of paroxetine in children aged < 7 years has not been studied.

Use in renal/hepatic impairment.

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

Discontinuation of treatment.

As with other psychoactive medications, abrupt discontinuation should generally be avoided (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). The taper phase regimen used in the recent clinical trials involved a decrease in the daily dose by 10 mg/day at weekly intervals.
Recent clinical trials supporting the various approved indications for paroxetine employed a taper phase regimen, rather than an abrupt discontinuation of treatment. The taper phase regimen used in 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 1 week before treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: abnormal dreams, paraesthesia and dizziness. In the majority of patients, these events were mild and moderate and were self limiting, and did not require medical intervention.
Also, during paroxetine marketing there have been spontaneous reports of adverse events upon discontinuation (particularly when abrupt), such as dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances, tremor, agitation or anxiety, nausea and sweating. Similar events have been reported for other selective serotonin reuptake inhibitors.
Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine is being prescribed. Paroxetine should not normally be discontinued abruptly. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 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.

Prolonged treatment.

The physician who elects to use paroxetine for extended period should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

4.3 Contraindications

Paxtine is contraindicated in persons who are known to be hypersensitive to paroxetine or any of its components of the formulation (see Section 6.1 List of Excipients).
Paxtine should not be used in combination with monoamine oxidase (MAO) inhibitors (including linezolid, an antibiotic which is a reversible nonselective MAO inhibitor) and methylthioninium chloride (methylene blue) 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 Section 4.4 Special Warnings and Precautions for Use).
Paxtine should not be used in combination with thioridazine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Paxtine should not be used in combination with pimozide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide attempts is inherent in depression and may persist until significant remission occurs. The risk must be considered in all depressed patients.
Young adults, especially those with major depression disorder (MDD), may be at increased risk for suicidal behaviour during treatment with paroxetine, especially during initial treatment (generally the first one to two months). An analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (prospectively defined as aged 18-24 years) treated with paroxetine compared with placebo (17/776 (2.19%) versus 5/542 (0.92%)), although this difference was not statistically significant. In the older age groups (aged 25-64 years and ≥ 65 years), no such increase was observed.
In adults with MDD (all ages), there was a statistically significant increase in the frequency of suicidal behaviour in patients treated with paroxetine compared with placebo (11/3455 (0.32%) versus 1/1978 (0.05%); all of the events were suicide attempts). However, the majority of these attempts for paroxetine (8 of 11) were in younger adults aged 18-30 years. These MDD data suggest that the higher frequency observed in the younger adult population across psychiatric disorders may extend beyond the age of 24.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications and this risk may persist until significant remission occurs. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including the development of new symptoms) and/or the emergence of suicidal ideation/ behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognised that the onset of some symptoms, such as agitation, akathisia or mania, could be related either to the underlying disease state or the drug therapy (see Section 4.4 Special Warnings and Precautions for Use, Akathisia, Mania and bipolar disorder; Section 4.8 Adverse Effects (Undesirable Effects)). Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analysis of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials but there were signals of risk arising from the trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
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 comorbid 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.
Additionally, patients with a history of suicidal behaviour or thoughts, young adults and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment are at a greater risk of suicidal thoughts or suicide attempts. All patients should be monitored for clinical worsening (including development of new symptoms) and suicidality throughout treatment, and especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases.
Family and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Paxtine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Akathisia.

Rarely, the use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterised by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.

Monoamine oxidase inhibitors (MAOIs).

Treatment with paroxetine should be initiated cautiously at least 2 weeks after terminating treatment with MAO inhibitors (see Section 4.3 Contraindications) and dosage increased gradually until optimal response is reached.

Diabetes.

In patients with diabetes, treatment with an SSRI may alter glycaemic control (hypoglycaemia or hyperglycaemia). Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Tricyclic antidepressants (TCAs).

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism via the cytochrome P450 enzyme 2D6. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine.

Serotonin syndrome/ neuroleptic malignant syndrome.

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of 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 L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Serotonergic drugs).

Mania and bipolar disorder.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/ manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk of bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that paroxetine is not approved for use in treating bipolar depression. As with all antidepressants, paroxetine should be used with caution in patients with a history of mania.

Tamoxifen.

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/ mortality, may be reduced when coprescribed with paroxetine as a result of paroxetine's irreversible inhibition of CYP2D6 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

Bone fracture.

Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association with fractures. The risk occurs during treatment and is greatest in the early stages of therapy. The possibility of fracture should be considered in the care of patients treated with paroxetine.

Oral anticoagulants.

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Warfarin.

Tryptophan.

As adverse experiences have been reported when tryptophan was administered with another selective 5HT uptake inhibitor, paroxetine should not be used in combination with tryptophan medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cardiac conditions.

The usual precautions should be observed in patients with cardiac conditions. There is limited experience concerning the use of paroxetine in patients with recent myocardial infarction or unstable heart disease.

Epilepsy.

As with other antidepressants, paroxetine should be used with caution in patients with epilepsy or a history of convulsive disorders.

Seizure.

Overall, the incidence of seizures is < 0.1% in patients treated with paroxetine. The drug should be discontinued in any patient who develops seizures.

Electroconvulsive therapy (ECT).

The efficacy and safety of the concurrent use of paroxetine and ECT have not been studied.

Glaucoma.

As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.

Hyponatraemia.

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

Cognitive and motor performance.

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

Alcohol.

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

Bleeding.

Bleeding abnormalities of the skin and mucous membranes have been reported with the use of SSRIs (including purpura, ecchymoses, haematoma, epistaxis, vaginal bleeding and gastrointestinal bleeding). This risk may be potentiated by concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other medicines that affect coagulation. SSRIs/SNRIs may increase the risk of postpartum haemorrhage. Paroxetine should, therefore, be used with caution in patients concomitantly treated with medicines that increase the risk of bleeding or in patients with a past history of abnormal bleeding or those with predisposing conditions. Pharmacological gastroprotection should be considered for high risk patients.

Sexual dysfunction.

Selective serotonin reuptake inhibitors (SSRIs)/ serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of long-lasting sexual dysfunction where symptoms have continued despite discontinuation of SSRIs/SNRIs.

Discontinuation of treatment.

Discontinuation symptoms have been reported with SSRI antidepressants, including paroxetine, when they have been discontinued, particularly when treatment has been stopped abruptly (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). It is, therefore, advised that the dose should be gradually tapered when discontinuing treatment (see Section 4.2 Dose and Method of Administration).

Symptoms seen on discontinuation of paroxetine treatment in adults.

In clinical trials in adults, 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 discontinuation symptoms is not the same as the drug being addictive or dependence producing as with a substance of abuse.
Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea 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 to 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 Dose and Method of Administration, Discontinuation of treatment).

Symptoms seen on discontinuation of paroxetine treatment in children and adolescents.

In clinical trials in children and adolescents, adverse events seen on treatment discontinuation occurred in 32% of patients treated with paroxetine compared to 24% of patients treated with placebo. Events reported upon discontinuation of paroxetine at a frequency of at least 2% of patients and which occurred at a rate at least twice that of placebo were: emotional lability (including suicidal ideation, suicide attempt, mood changes and tearfulness), nervousness, dizziness, nausea and abdominal pain (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic and renal impairment.

Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Increased plasma concentrations of paroxetine occur in elderly subjects, but the range of concentrations overlap with that observed in younger subjects (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Paroxetine is not indicated for use in children or adolescents aged < 18 years.
Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of depression in this population.
The safety and efficacy of paroxetine in children aged < 7 years has not been studied.
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. In clinical trials of paroxetine in children and adolescents, adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in patients treated with paroxetine compared to those treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The absorption and pharmacokinetics of paroxetine are not affected by food or antacids. Paroxetine has little or no effect on the pharmacokinetics of digoxin, propranolol and warfarin.

Pimozide.

Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with paroxetine. This is 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).

Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin, etc.).

Serotonin release by platelets plays an important role in haemostasis. There is an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of abnormal bleeding. Concurrent use of an NSAID, aspirin or warfarin potentiates this risk. Thus, patients should be cautioned about using such medicines concurrently with Paxtine.

Warfarin.

A double blind parallel group study was performed in which healthy male volunteers were given daily doses of warfarin until a stable prothrombin time (measured as an INR) was achieved. There was no clinically or statistically significant change in INR in subjects who were then dosed with paroxetine or placebo, in addition to warfarin, for 28 days.
The following tabulated results of this study show that the healthy volunteers who received paroxetine had no significant differences in coagulation factors or the prothrombin time, measured as an INR. This suggests that paroxetine has no effect on warfarin metabolism and, therefore, it would not be expected that patients receiving warfarin therapy would develop an overdosage effect when they start therapy with paroxetine. With respect to platelet function, the overall screening tests and the bleeding time were unchanged after paroxetine therapy. Pharmacokinetic analysis has shown that there appears to be no effect of paroxetine on plasma concentrations of either warfarin enantiomer and no difference in warfarin concentrations between paroxetine dosed and placebo dosed subjects. (See Table 1.)

Drugs affecting hepatic metabolism.

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 whereas phenytoin, a known drug metabolising enzyme inducer, can decrease it. Coadministration of a single 30 mg dose of paroxetine to subjects receiving chronic daily dosing with 300 mg phenytoin, is associated with decreased paroxetine AUC and half-life of approximately 30% and an increased incidence of adverse events.
When paroxetine is to be coadministered 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 coadministered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital (phenobarbitone), phenytoin, sodium valproate). Coadministration of paroxetine with other anticonvulsants may also be associated with an increased incidence of adverse effects. Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).

Anticonvulsants (carbamazepine, phenytoin, sodium valproate).

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

Fosamprenavir/ ritonavir.

Coadministration of fosamprenavir/ ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Drugs metabolised by cytochrome P450 2D6.

As with other antidepressants, including other selective serotonin reuptake inhibitors (SSRIs), paroxetine inhibits the specific hepatic cytochrome P450 enzyme 2D6 (CYP2D6). Inhibition of CYP2D6 may lead to enhanced plasma levels of those coadministered drugs which are metabolised to a significant extent by this isoenzyme, although the clinical significance of the interaction will depend on the therapeutic window of the affected drug.
Therefore, coadministration of paroxetine with certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), phenothiazines (e.g. perphenazine and promethazine), risperidone, atomoxetine and type 1C antiarrhythmics (e.g. flecainide) and metoprolol should be approached with caution (dose adjustment of concomitant medicines should be considered).
Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see Section 4.4 Special Warnings and Precautions for Use).
Pharmacokinetic interactions with tricyclic antidepressants (TCAs) have been reported for all SSRIs. As for other SSRIs, dosing of paroxetine with tricyclic antidepressants is not recommended as TCA plasma levels may be elevated to levels at which there may be an increased risk of TCA related adverse events in some patients which can be serious. Concomitant therapy has not been evaluated for safety and efficacy.
The effects of concomitant administration of paroxetine with neuroleptics and antiarrhythmics have not been studied. Coadministration may lead to pharmacokinetic interactions and should therefore be approached with caution because of the potential increased risk of serious adverse events in some patients, e.g. symptoms suggestive of neuroleptic malignant syndrome.

Neuromuscular blockers.

SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.

Thioridazine.

Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes and sudden death. As with other drugs which inhibit the hepatic enzyme CYP450 2D6 (including other antidepressants), paroxetine can elevate plasma levels of thioridazine. Therefore, paroxetine should not be administered with thioridazine (see Section 4.3 Contraindications).

Drugs metabolised by cytochrome P450 3A4.

An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no significant effect of paroxetine on terfenadine pharmacokinetics. Paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance when it is administered with terfenadine or other drugs that are CYP3A4 substrates.

Procyclidine.

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

Psychotropic agents.

A study of the interaction between paroxetine and diazepam showed no alteration in the pharmacokinetics of paroxetine that would warrant changes in the dose of paroxetine for patients receiving both drugs.
Experience in a limited number of healthy subjects has shown that paroxetine does not increase the sedation and drowsiness associated with haloperidol, amobarbital (amylobarbitone) or oxazepam when given in combination.

SSRIs/SNRIs.

SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

Serotonergic drugs.

As with other SSRIs, coadministration with serotonergic drugs may lead to an incidence of 5HT associated effects (serotonin syndrome) (see Section 4.4 Special Warnings and Precautions for Use). Caution should be advised, and a closer clinical monitoring is required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, SSRIs, lithium, fentanyl and St. John's wort (Hypericum perforatum) preparations) are combined with paroxetine. Concomitant use of paroxetine and MAO inhibitors (including linezolid, an antibiotic which is a reversible nonselective MAO inhibitor) and methylthioninium chloride (methylene blue) is contraindicated (see Section 4.3 Contraindications).
Symptoms may include agitation, confusion, diaphoresis, hallucinations, hyper-reflexia, myoclonus, shivering, tachycardia and tremor. 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.

Lithium.

In a study in depressed patients stabilised on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, since there is limited experience in patients, the concurrent administration of paroxetine and lithium should be undertaken with caution.

Alcohol.

See Section 4.4 Special Warnings and Precautions for Use.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality. This effect appears to be reversible following discontinuation of treatment. Changes in sperm quality may affect fertility in some men.
Serotonergic compounds are known to affect reproductive function in animals. Impaired reproductive function (i.e. reduced pregnancy rate, increased pre- and post-implantation losses, decreased viability of pups) was found in the reproduction studies in rats at paroxetine doses of 13 mg/kg and above. Vacuolation of epididymal tubular epithelium and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis occurred in male rats at doses of 25 mg/kg/day in toxicity studies.
(Category D)
Paroxetine should not be used in pregnancy.
The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant. If a decision is taken to discontinue paroxetine treatment in a pregnant woman, the prescriber should see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Discontinuation of treatment.
Epidemiological studies have shown infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations.
A recent retrospective US epidemiological study of 3,581 pregnant women exposed to paroxetine or other antidepressants during the first trimester of pregnancy showed an increased risk of major congenital malformations overall for paroxetine compared to other antidepressants (odds ratio 2.20; 95% confidence interval 1.34-3.63). There was also an increased risk of cardiovascular malformations for paroxetine compared to other antidepressants (odds ratio 2.08; 95% confidence interval 1.03-4.23). These figures excluded women exposed to both antidepressants and teratogenic drugs. The majority of cardiovascular malformations were ventricular septal defects.
The prevalence of congenital malformations as a whole and cardiovascular malformation alone in the infants of women taking paroxetine and excluding women taking teratogenic drugs as well were 4% (23 cases out of 527 infants) and 2% (11 cases out of 589 infants), respectively. These rates compare with those in the general population of 3% for all congenital malformation and 1% for cardiovascular malformation (Centres for Disease Control and Prevention, USA and Metropolitan Atlanta Birth Congenital Defects Program Data (MACDP)).
A separate study based on the Swedish Medical Birth Register evaluated 4,291 infants born to mothers exposed to SSRIs in early pregnancy. Of these infants, 2.9% were reported to have a congenital malformation, which does not differ from the rate in the unexposed. The rate of congenital malformation in infants whose mothers had been exposed to paroxetine (n = 708) was 3.4%.
There have been reports of premature birth in pregnant women exposed to paroxetine or other SSRIs, although a causal relationship with drug therapy has not been established.
Neonates should be observed if maternal use of paroxetine continues into the later stages of pregnancy. There have been reports of complications in neonates exposed to paroxetine or other SSRIs late in the third trimester of pregnancy; however, a causal association with drug therapy has not been confirmed. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, somnolence and constant crying. In some neonates the complications have resulted in prolonged hospitalisation, respiratory support and tube feeding. In some instances the reported symptoms were described as neonatal withdrawal symptoms. In a majority of instances the complications were reported to have arisen either immediately or soon (< 24 hours) after delivery.
Epidemiological studies have shown that the use of SSRIs (including paroxetine) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The risk of PPHN among infants born to women who used SSRIs late in pregnancy was estimated to be 4 to 5 times higher than the rate of 1 to 2 per 1000 pregnancies observed in the general population.
Reproduction studies performed in rats and rabbits at oral doses of up to 43 and 5 mg/kg, respectively, have revealed no evidence of teratogenic effects. Studies in rats have shown increased pre- and post-implantation losses and decreased postnatal survival at dose levels producing maternal toxicity. Animal reproduction studies are not always predictive of human response.
 The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in plasma. Neonatal mortality was increased in the offspring of rats receiving oral paroxetine 13 and 43 mg/kg/day during pregnancy and lactation. The risk to the infant by paroxetine administration to lactating women is unknown. Therefore, this drug should not be used by lactating women unless the potential benefit outweighs the possible risk.

4.7 Effects on Ability to Drive and Use Machines

Cognitive and motor performance.

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 or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Adverse experiences with paroxetine are generally mild in nature and do not affect the patient's lifestyle. Adverse experiences may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. 13% of paroxetine (n = 2,963) treated patients in worldwide short-term clinical trials for depression discontinued treatment due to an adverse experience, compared to 5% receiving placebo (n = 554). In addition, 11.8% (64/542) and 9.4% (44/462) of paroxetine patients withdrew from worldwide trials in obsessive compulsive disorder (OCD) (versus placebo, 21/265, 7.9%) and panic disorder (versus placebo, 32/324, 9.9%), respectively.
The most commonly observed adverse events associated with the use of paroxetine in clinical trials and not seen at an equivalent incidence among placebo treated patients 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 were observed during the clinical trial programs for depression, OCD and panic disorder. All adverse experiences are included in the list except those reported in terms so general as to be uninformative and those experiences for which the drug cause was remote. It should however be noted that causality has not necessarily been established, and that patients enrolled in the clinical trials may have been generally healthier than the general patient population.
Events are listed within body systems and categorised by frequency according to the following definitions: very common: > 1/10, common: > 1/100 and < 1/10, uncommon: > 1/1000 and < 1/100, rare: > 1/10,000 and < 1/1000 and very rare: < 1/10,000.

Body as a whole.

Common: headache, asthenia, abdominal pain, fever, chest pain, trauma, back pain, malaise, pain.
Uncommon: allergic reaction, chills[2][4], face oedema, infection[2], moniliasis, neck pain, overdose.
Rare: abnormal laboratory value, abscess, adrenergic syndrome, cellulitis, chills and fever, cyst, hernia, intentional overdose, neck rigidity, pelvic pain, peritonitis, substernal chest pain, ulcer.

Cardiovascular.

Common: palpitation, vasodilatation, postural hypotension, hypertension, syncope, tachycardia.
Uncommon: bradycardia, conduction abnormalities, abnormal electrocardiogram, hypotension, migraine[2], ventricular extrasystoles.
Rare: angina pectoris, arrhythmia, atrial arrhythmia, atrial fibrillation, bundle branch block, cerebral ischaemia, cerebrovascular accident, congestive heart failure, extrasystoles, low cardiac output, myocardial infarct, myocardial ischaemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis[5], thrombosis, varicose vein, vascular headache.

Gastrointestinal.

Common: nausea, dry mouth, constipation, diarrhoea, appetite decrease, flatulence, vomiting, oropharynx disorder, dyspepsia, increased appetite; gastrointestinal disorder[3], tooth disorder[3], stomatitis[3].
Uncommon: bruxism, buccal cavity disorders, dysphagia, eructation, gastroenteritis, gastrointestinal flu, glossitis, increased salivation, liver function tests abnormal[2], mouth ulceration, rectal haemorrhage.
Rare: aphthous stomatitis, bloody diarrhoea, bulimia, colitis, duodenitis, oesophagitis, faecal impaction, faecal incontinence, gastritis, gingivitis[2], haematemesis, hepatitis, ileus, jaundice, melaena, peptic ulcer, salivary gland enlargement, stomach ulcer, stomatitis, tongue oedema, tooth caries, tooth malformation[5].

Haematological/ lymphatic.

Uncommon: anaemia, leukopenia, lymphadenopathy, purpura, white blood cell abnormality.
Rare: eosinophilia, iron deficiency anaemia, leukocytosis, lymphoedema, lymphocytosis, microcytic anaemia, monocytosis, normocytic anaemia.

Endocrine.

Rare: diabetes mellitus, hyperthyroidism, hypothyroidism, thyroiditis.

Metabolic/ nutritional.

Common: weight gain[3][5], weight loss[3], increase in cholesterol levels.
Uncommon: oedema, hyperglycaemia, peripheral oedema, thirst.
Rare: alkaline phosphatase increased[2], bilirubinaemia, dehydration, gout, hyperphosphataemia[5], hypocalcaemia, hypoglycaemia, hypokalaemia, hyponatraemia, obesity, AST increased, ALT increased.

Musculoskeletal.

Common: myopathy, myalgia, myasthenia.
Uncommon: arthralgia[2], arthritis, traumatic fracture.
Rare: arthrosis, bursitis, cartilage disorder, myositis, osteoporosis, tetany.

Nervous system.

Common: somnolence, insomnia, dizziness, tremor, headache, nervousness, anxiety, paraesthesia, libido decreased, agitation, drugged feeling, myoclonus, CNS stimulation, confusion, concentration impaired, depression, emotional lability, vertigo, abnormal dreams (including nightmares)[3], hyperesthesia[2].
Uncommon: abnormal thinking[2], akinesia, alcohol abuse, amnesia[2], ataxia, convulsion, depersonalisation[2], hallucinations, hyperkinesia[2], hypertonia[2], incoordination, lack of emotion, manic reaction, paranoid reaction.
Rare: abnormal electroencephalogram, abnormal gait, antisocial reaction, choreoathetosis, circumoral paraesthesia, delirium, delusions, diplopia, drug dependence, dysarthria, dyskinesia, dystonia, euphoria, fasciculations, grand mal convulsions, hostility[2], hyperalgesia, hypokinesia, hysteria, libido increased, manic depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, psychosis, psychotic depression, reflexes increased, restless legs syndrome (RLS), stupor, withdrawal syndrome.

Respiratory.

Common: respiratory disorder, yawning, pharyngitis, cough increased, rhinitis.
Uncommon: asthma, bronchitis, dyspnoea, epistaxis, hyperventilation, pneumonia, respiratory flu, sinusitis[2].
Rare: emphysema[5], hiccup, lung fibrosis, pulmonary oedema[5], sputum increased, voice alteration.

Dermatological.

Common: sweating, rash, pruritus, sweat gland disorder[3].
Uncommon: acne, alopecia, dry skin, ecchymosis, eczema, furunculosis, herpes simplex, urticaria.
Rare: angioedema, contact dermatitis, erythema nodosum, herpes zoster, hirsutism[5], maculopapular rash, photosensitivity, skin discolouration, skin ulcer.
Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).

Special senses.

Common: blurred vision, abnormal vision[3], taste perversion.
Uncommon: abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis media, tinnitus[2], keratoconjunctivitis[3].
Rare: amblyopia, specified cataract, conjunctival oedema, corneal lesion, corneal ulcer, exophthalmos, eye haemorrhage, glaucoma, hyperacusis, otitis externa, photophobia, retinal haemorrhage, taste loss, anisocoria, deafness.

Urogenital.

Common: abnormal ejaculation[1], urinary frequency, female/ male genital disorder[1], urination impaired, impotence[1].
Uncommon: abortion[1], amenorrhoea[1], breast pain[1], cystitis, dysmenorrhoea[2][1], dysuria, menorrhagia[1], nocturia, polyuria, urinary incontinence, urinary retention, urinary tract infection[2][4], urinary urgency, vaginitis[2][1].
Rare: breast atrophy[1], female lactation[1], haematuria, kidney calculus, abnormal kidney function, kidney pain, mastitis[1], nephritis, oliguria, urethritis, urine abnormality, vaginal moniliasis[1].
Key to symbols:
[1] = Incidence corrected for gender.
[2] = Adverse experiences reported more frequently in OCD versus depression clinical trials.
[3] = Adverse experiences reported in OCD clinical trials.
[4] = Adverse experiences reported more frequently in panic versus depression clinical trials.
[5] = Adverse experiences reported in panic clinical trials.

Post-marketing experience.

Adverse events occurring during postmarketing surveillance:

Blood and lymphatic system disorders.

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes.
Very rare: thrombocytopenia.

Immune system disorders.

Very rare: severe allergic reactions (including anaphylactoid reactions, and angioedema).

Endocrine disorders.

Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Common: increases in cholesterol levels, decreased appetite.
Rare: hyponatraemia.
Hyponatraemia has been reported rarely, predominantly in the elderly, and in some cases may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders.

Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).
Uncommon: confusion, hallucinations.
Rare: manic reactions.
These symptoms may be due to the underlying disease.

Nervous system disorders.

Common: dizziness, tremor, headache.
Uncommon: extrapyramidal disorders.
Rare: convulsions, akathisia, restless legs syndrome (RLS).
Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering tachycardia and tremor).
Reports of extrapyramidal disorders including orofacial 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 Precautions for Use).
Very rare: acute glaucoma.

Cardiac disorders.

Uncommon: sinus tachycardia.

Vascular disorders.

Uncommon: postural hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Gastrointestinal disorders.

Very common: nausea.
Common: constipation, diarrhoea, vomiting, dry mouth.
Very rare: gastrointestinal bleeding.

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

Common: sweating.
Uncommon: skin rashes.
Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, photosensitivity reactions.

Renal and urinary disorders.

Uncommon: urinary retention, urinary incontinence.

Reproductive system and breast disorders.

Very common: sexual dysfunction.
Rare: hyperprolactinaemia/ galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia and amenorrhoea).
Unknown: postpartum haemorrhage (this event has been reported for the therapeutic class of SSRIs/SNRIs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, SSRIs/SNRIs).

General disorders and administration site conditions.

Common: asthenia, bodyweight gain.
Very rare: peripheral oedema.

Discontinuation symptoms.

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.
Uncommon: agitation, nausea, tremor, confusion, sweating, diarrhoea.
As with many psychoactive medicines, discontinuation of paroxetine (particularly when abrupt) may lead to symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), tremor, agitation or anxiety, nausea, headache, confusion, diarrhoea 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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

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: emotional lability (including self harm, suicidal thoughts, attempted suicide, crying and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with major depressive disorder. Hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age.
In studies that used a tapering regimen (daily dose decreased by 10 mg/day at weekly intervals to a dose of 10 mg/day for one week), 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, nervousness, dizziness, nausea and abdominal pain.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose with paroxetine (up to 2000 mg) alone and in combination with other drugs has been reported. Events such as coma, convulsions or ECG changes have occasionally been reported. Fatalities have been reported when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol or, in isolated cases, when taken alone.
As with all overdose attempts, the possibility of multiple drug ingestion should be borne in mind.

Symptoms.

Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned in Adverse Effects (Undesirable Effects)), sedation, blood pressure changes, involuntary muscle contractions and facial flush have been reported.

Treatment.

No specific antidote is known. Treatment should consist of those general measures employed in the management of overdose with any antidepressant.
Supportive care with frequent monitoring of vital signs and careful observation is indicated. Patient management should be as clinically indicated, or as recommended by the national poisons centre, where available.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5HT, serotonin) uptake and its antidepressant action and efficacy in the treatment of obsessive compulsive disorder (OCD), panic disorder and social anxiety disorder/ social phobia is thought to be related to its specific inhibition of 5HT uptake in brain neurones.
In vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for α1-, α2- and β-adrenoreceptors, dopamine (D2), 5HT1-like, 5HT2 and histamine (H1) receptors. This lack of interaction with postsynaptic receptors in vitro is substantiated by in vivo studies which demonstrate a lack of CNS depressant and hypotensive properties. Paroxetine has a low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties.
Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, it is most unlikely that they contribute to paroxetine's therapeutic effect.
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 inhibitors (MAOIs) or tryptophan. Behavioural and electroencephalographic (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.
Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol.
Animal studies indicate that paroxetine is well tolerated by the cardiovascular system, and in healthy subjects paroxetine produces no clinically significant changes in blood pressure, heart rate and electrocardiograph (ECG).
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.
In general, improvement in patients starts after one week but does not become superior to placebo until the second week of therapy. Paroxetine is effective in improving depression and suicidal ideation concurrently during the first few weeks of 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. Where it is clinical practice to co-prescribe short acting hypnotics with antidepressants, no additional adverse events have been recorded.
Paroxetine, in addition to its significant antidepressant effects, can improve associated symptoms of anxiety.

Clinical trials.

Relapse prevention of depression.

A study of depressed outpatients who had responded to paroxetine (Hamilton depression score total < 8) during an initial eight week open treatment phase and were then randomised to continuation on paroxetine or placebo for one year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%).

Obsessive compulsive disorder.

The effectiveness of paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12 week placebo controlled studies (studies 1 and 2). The results of a third placebo controlled study (study 3) support the effectiveness of paroxetine in the treatment of OCD.
Study 1 was a dose ranging study which originally consisted of 348 patients with OCD and compared placebo, 20 mg, 40 mg or 60 mg daily. Of these 348 patients, 338 had at least one postbaseline efficacy evaluation and were included in the intent to treat (ITT) population for efficacy analyses. Paroxetine 40 mg and 60 mg/day were significantly superior to placebo (p < 0.001) in the treatment of OCD as assessed by the primary efficacy variable mean change from baseline in the Yale-Brown Obsessive Compulsive Disorder (YBOCS) total score. Significant improvement was noted from week 6 onwards.
Studies 2 and 3 were flexible dose studies comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In study 2, conducted in 399 patients, 391 had at least one postbaseline efficacy evaluation and were included in the intent to treat (ITT) population for efficacy analyses. Paroxetine was significantly more effective than placebo as assessed by the primary efficacy variables mean change from baseline in YBOCS total score (p = 0.002). In addition, the efficacy of paroxetine was comparable to that of clomipramine in this study. In study 3, conducted in 241 patients, 232 had at least one postbaseline efficacy evaluation and were included in the intent to treat (ITT) population for efficacy analyses. There was a numerically better response in paroxetine treated patients compared to placebo in the mean change from baseline in YBOCS total score, the magnitude of which was comparable to that in study 2, though this did not reach statistical significance.

Relapse prevention of obsessive compulsive disorder.

A study of OCD outpatients who had responded to paroxetine during an initial 6 month open treatment phase and were then randomised to continuation on paroxetine or placebo for 6 months, demonstrated a significantly lower relapse rate for patients taking paroxetine (38%) compared to those on placebo (59%). The risk ratio assessment conducted in this study showed that patients randomised to placebo were 2.7 times more likely to experience a relapse compared to those patients who continued on paroxetine treatment (p = 0.001).

Panic disorder.

The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in four multicentre, placebo controlled studies of adult outpatients. Patients in all studies had panic disorder (Diagnostic and Statistical Manual, 3rd Edition, DSM III-R) with or without agoraphobia. The studies were conducted over 10 to 12 weeks. Two of these studies also had an active comparator (clomipramine or alprazolam) arm.
In all four studies, patients received either paroxetine 10 to 60 mg/day (n = 469), clomipramine 10 to 150 mg/day (n = 121), alprazolam 1 to 6 mg/day (n = 77) or placebo (n = 324). These studies indicated that paroxetine was superior to placebo and comparable with active comparator.

Relapse prevention of panic disorder.

The efficacy of paroxetine in preventing relapse of panic disorder was demonstrated in a 12 week double blind relapse prevention study. Patients (n = 43) who were responders during the 10 week double blind phase and a 3 month double blind extension phase were rerandomised to either paroxetine (10, 20, or 40 mg/day) or placebo. 33 paroxetine treated patients treated with paroxetine and 37 placebo treated patients remained on study at week 12. Patients treated with paroxetine were significantly less likely to relapse than patients receiving placebo (5% versus 30%; p = 0.002).
Benefit in maintenance treatment was demonstrated in a 36 week extension study which compared paroxetine 20 to 60 mg/day (n = 68) to clomipramine 50 to 150 mg/day (n = 63) or placebo (n = 45). Patients who had satisfactorily completed the 12 week double blind phase, continued on the same medication for a further 36 weeks. By week 36, 50 paroxetine patients remained on the study, 43 clomipramine patients and 27 placebo patients remained on study. Maintenance of efficacy of paroxetine was significantly superior to placebo in two out of three primary efficacy variables (p < 0.05), and comparable with clomipramine.

Social anxiety disorder/ social phobia.

The effectiveness of paroxetine in the treatment of social anxiety disorder/ social phobia was demonstrated in three 12 week, multicentre, double blind, randomised parallel group, placebo controlled clinical trials (2 flexible dose, 1 dose ranging). Patients received paroxetine 20 to 60 mg/day (n = 522) or placebo (n = 339). These studies indicated that paroxetine was statistically superior to placebo according to either the Liebowitz Social Anxiety Scale (LSAS) or the Clinical Global Impression (CGI) scale.
In the fixed dose study, no statistically significant differences in efficacy were observed between the groups treated with 20, 40 and 60 mg/day paroxetine.
Patients in all studies had a primary diagnosis of social anxiety disorder/ social phobia according to DSM-IV. A number of exclusion criteria excluded patients from entering the trials, e.g. any other AXIS 1 disorder as a primary diagnosis in the last 6 months.

5.2 Pharmacokinetic Properties

Absorption.

Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. As a consequence, 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 dosing 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. These properties are a consequence of the fact that one of the enzymes that metabolises paroxetine is the readily saturable cytochrome P450 enzyme 2D6 (CYP2D6). However, because this enzyme becomes saturated early on following commencement of paroxetine treatment, the non-linearity observed during a subsequent dose increase is generally small and is confined to those subjects who achieve low plasma levels at low doses.

Distribution.

Paroxetine is distributed throughout the body including the central nervous system. Approximately 95% of the paroxetine present in the plasma is protein bound at therapeutic concentrations.

Metabolism.

Paroxetine is extensively metabolised after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than one-fiftieth the potency of the parent compound at inhibiting serotonin uptake.
The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. At steady state, when CYP2D6 is essentially saturated, paroxetine clearance is governed by alternate P450 isoenzymes which, unlike CYP2D6, are not saturable at clinical doses (as evidenced by linear pharmacokinetics in CYP2D6 deficient individuals).
Because of the involvement of CYP2D6 in the metabolic clearance of paroxetine, considerable variation can occur in the plasma concentrations achieved between individuals. However, no correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy). 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.

Excretion.

Approximately 64% of the dose is excreted in the urine; urinary excretion of unchanged paroxetine is generally less than 2% of 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. However, because of the reduction in plasma clearance which occurs on multiple dosing (nonlinear kinetics: see Section 5.2 Pharmacokinetic Properties, Absorption). Seven to fourteen days are required for the achievement of steady state. Thereafter, pharmacokinetics do not appear to change during long-term therapy. Considerable variation can occur in the plasma concentrations achieved between individuals, possibly due to variable first-pass effect and variability in clearance.
A bioequivalence study comparing Paxtine, and the brand leader Aropax tablets, in thirty six young adult volunteers showed that there was no statistically significant difference between the two formulations with respect to the rate or extent of absorption of paroxetine. The results for the 90% CI for the ratio of mean Cmax values was 0.978 to 1.117, whilst the 90% CI for the ratio of AUC0-t was 1.000 to 1.139. These results for the two formulations were within the bioequivalence acceptance limits.

5.3 Preclinical Safety Data

Genotoxicity.

In two year studies conducted in mice and rats, paroxetine had no tumourigenic effect and no genotoxicity effects were observed in a battery of in vitro and in vivo tests.

Carcinogenicity.

In two year studies conducted in mice and rats, paroxetine had no tumorigenic effect.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets contain the following excipients: calcium hydrogen phosphate, colloidal anhydrous silica, magnesium stearate, methacrylic acid copolymer, purified talc, sodium starch glycollate and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Container type: blister pack (PVC/PVDC).
Pack size: 30 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 227120 - Paxtine paroxetine 20 mg (as hydrochloride) tablet blister pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Paroxetine hydrochloride anhydrous is a white to off white crystalline powder, with a melting point of 118°C to 120.5°C, and solubility of 6.53 mg/mL in water. Paroxetine is an orally administered antidepressant with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic or other available antidepressant agents.
Chemical name: (3S, 4R)-(-)-4-(4'-fluorophenyl)- 3-[3',4'-(methylenedioxy)-phenoxy] methylpiperidine hydrochloride.
Molecular formula: C19H20FNO3.HCl.
Molecular weight: 365.83.

CAS number.

78246-49-8.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes