Consumer medicine information

Aropax

Paroxetine

BRAND INFORMATION

Brand name

Aropax

Active ingredient

Paroxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aropax.

SUMMARY CMI

AROPAX®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using AROPAX?

AROPAX contains the active ingredient paroxetine (as hydrochloride hemihydrate).

AROPAX is used to treat depression, panic attack prevention, anxiety and other illnesses by helping to control mood.

For more information, see Section 1. Why am I using AROPAX? in the full CMI.

2. What should I know before I use AROPAX?

Do not use if you have ever had an allergic reaction to AROPAX or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use AROPAX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with AROPAX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use AROPAX?

  • The usual dose of AROPAX for depression, social anxiety disorder/social phobia, generalised anxiety disorder or post-traumatic stress disorder is one 20 mg tablet per day.
  • To treat obsessions and compulsions or panic attacks, the usual dose of AROPAX is two 20 mg tablets per day.
  • AROPAX tablets can be broken in half but should not be chewed.
  • AROPAX should be taken in the morning, preferably with food.

More instructions can be found in Section 4. How do I use AROPAX? in the full CMI.

5. What should I know while using AROPAX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using AROPAX.
  • Take AROPAX with a full glass of water or another liquid.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Driving or using machines
  • Be careful driving or operating machinery until you know how AROPAX affects you.
  • AROPAX may cause drowsiness, dizziness or lightheadedness in some people.
Drinking alcohol
  • Although drinking moderate amounts of alcohol is unlikely to affect your response to AROPAX, it is best to avoid alcohol while you are taking this medicine.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them. Keep the pack in a cool dry place.
  • Do not leave it in the car on a hot day. Do not store medicine in the bathroom or near a sink.

For more information, see Section 5. What should I know while using AROPAX? in the full CMI.

6. Are there any side effects?

Like other medicines, AROPAX can cause some side effects. If they occur, they are most likely to be minor and temporary.

Mild side effects can include feeling sick, dry mouth, constipation, decreased appetite, diarrhea, vomiting, drowsiness, dizziness, difficulty in getting to sleep, impaired sexual function, weakness, feeling sweaty or shaky, bruising, abnormal dreams (including nightmares), weight gain.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI



FULL CMI

AROPAX®

Active ingredient(s): paroxetine (as hydrochloride hemihydrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using AROPAX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using AROPAX.

Where to find information in this leaflet:

1. Why am I using AROPAX?
2. What should I know before I use AROPAX?
3. What if I am taking other medicines?
4. How do I use AROPAX?
5. What should I know while using AROPAX?
6. Are there any side effects?
7. Product details

1. Why am I using AROPAX?

AROPAX contains the active ingredient.

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

AROPAX is used to treat:

  • Depression which 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 part of the brain that affects your whole body and can cause emotional and physical symptoms. You may feel low in spirit, lose interest in usual activities, have poor appetite, disturbed sleep, wake up early, have low energy and feel guilty over nothing.
  • Irrational fears or obsessional behaviour: These can also be due to chemical imbalance in parts of the brain.
  • Panic attacks: AROPAX may be used to help prevent panic attacks.
  • Patients who may avoid and/or are fearful of social situations.
  • Patients with excessive anxiety and worry, and who feel irritable, restless and/or tense in the muscles.
  • Repetitive and distressing recollections of a past traumatic event.

2. What should I know before I use AROPAX?

Warnings

In some children and adolescents, treatment with an antidepressant increases suicidal thinking or actions.

  • It is important to discuss all the risks of treating depression and also 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 Section 2. What should I know before I use AROPAX - Children and Adolescents).

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

Do not use AROPAX if:

  • you are allergic to paroxetine, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are pregnant or intend to become pregnant.
  • you have taken AROPAX before and became unwell, tell your doctor or pharmacist before taking the first dose.
  • you are taking any other medications for the treatment of depression or have done so in the last 2 weeks. Taking AROPAX with another antidepressant may cause a serious reaction.
  • You must not take AROPAX until 2 weeks after stopping monoamine oxidase inhibitor drugs (MAOIs). Examples of MAOIs are phenelzine and tranylcypromine. Another MAOI includes the antibiotic linezolid. There may be others so please check with your doctor. Taking AROPAX with a MAOI may cause a serious reaction.
  • you are taking or have recently taken (within the last two weeks) a medicine called methylthioninium chloride (methylene blue).
  • you are taking thioridazine for the treatment of schizophrenia.
  • you are taking pimozide.
  • the expiry date (EXP) printed on the pack has passed.
  • the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • you are allergic to foods, dyes, preservatives or any other medicines.
  • have any other medical conditions such as:
    - liver problems
    - heart problems
    - kidney problems
    - epilepsy
    - mania
    - raised pressure in the eye
    - problems with blood clotting
    - other psychiatric conditions (bipolar disorder)
    - diabetes
    - history of bleeding disorders, such as after childbirth
  • you are pregnant or intend to become pregnant.
  • you are breastfeeding or wish to breastfeed.
    Your doctor will discuss with you the possible risks and benefits of using AROPAX during breastfeeding.

The signs of an allergic reaction are wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Fertility

Medicines like AROPAX may affect your sperm. Fertility in some men may be reduced while taking AROPAX.

Elderly

Take special care with AROPAX if you are over 65 years of age as AROPAX may cause a reduction in the amount of sodium within your blood which can lead to sleepiness and muscle weakness. If you experience these symptoms, please consult your doctor as soon as possible.

Children and adolescents

AROPAX is not recommended for use in children and adolescents under 18 years.

  • The use of AROPAX is not recommended to treat depression in children and adolescents under 18, as the drug has not been shown to be effective in this age group 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 AROPAX, 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.

3. What if I am taking other medicines?

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

Some medicines may interfere with AROPAX and affect how it works. In particular tell your doctor if you are taking any of the following medicines which:

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect AROPAX.

4. How do I use AROPAX?

How much to use

  • The usual dose of AROPAX for depression, social anxiety disorder/social phobia, generalised anxiety disorder or post-traumatic stress disorder is one 20 mg tablet per day. Your doctor may increase the dose slowly over several weeks. This may require you to break the tablet in half.
  • To treat obsessions and compulsions or panic attacks, the usual dose of AROPAX is two 20 mg tablets 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.
  • Follow the instructions provided and use AROPAX until your doctor tells you to stop.

When to take AROPAX

  • AROPAX should be taken in the morning, preferably with food.

How to take AROPAX

  • Take AROPAX with a full glass of water or another liquid.
  • AROPAX tablets can be broken in half but should not be chewed.

Instructions for use:

  • An extra protective packaging layer is used for this medicine. Tablets will need to be firmly pushed out through the foil to remove them from the blister.

How long to take AROPAX

Keep taking your AROPAX for as long as your doctor tells you.

Your doctor may decide that you should continue to use AROPAX for some time, even when you have overcome your problem. For best effect AROPAX must be taken regularly.

Your doctor will tell you when and how AROPAX should be discontinued.

Your doctor will usually recommend that you stop treatment by slowly reducing the dosage over a period of several weeks. When you stop treatment with AROPAX, especially if this is done suddenly, you may experience unwanted symptoms. Please see the Section 6. Are there any side effects?

If you forget to use AROPAX

  • Do not take an extra dose. Wait until the next day and take your normal dose then.
  • Do not try to make up for the dose that you missed by taking more than one dose at a time.
  • If it is almost time for your next dose, 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 you missed.

If you use too much AROPAX

If you think that you have used too much AROPAX, you may need urgent medical attention.

If you take too much AROPAX, symptoms include sedation, blood pressure changes, involuntary muscle contractions and facial flush. It rarely can lead to seizures, heart rhythm changes and unconsciousness. For more information, see Section 6. Are there any side effects?

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using AROPAX?

Things you should do

Call your doctor straight away if you:

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

Like other drugs of this type, AROPAX will not relieve your symptoms straight away. People generally start feeling better in a few weeks or so. 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.

All thoughts of suicide must be taken seriously. Tell your doctor immediately or go to the nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time.

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

Tell your doctor or go to the hospital immediately if you experience symptoms of serotonin syndrome or neuroleptic malignant syndrome, which are rare life-threatening conditions. These symptoms include high body temperature, stiffness, involuntary muscle jerks, confusion, extreme agitation, delirium and coma.

Remind any doctor, dentist or pharmacist you visit that you are using AROPAX.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use AROPAX to treat any other complaints unless your doctor says to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how AROPAX affects you.

Tests have shown that AROPAX does not have a marked effect on driving ability. However, AROPAX may cause drowsiness, dizziness or lightheadedness in some people. Make sure you know how you react to AROPAX before you drive a car or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Although drinking moderate amounts of alcohol is unlikely to affect your response to AROPAX, it is best to avoid alcohol while you are taking this medicine.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them.
  • Keep the pack in a cool dry place.
  • Do not leave it in the car on a hot day.
  • Do not store medicine in the bathroom or near a sink.
    Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it, such as in a locked cupboard.

Stopping treatment

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

Your doctor may decide that you should continue to use AROPAX for some time, even when you have overcome your problem. For best effect AROPAX must be taken regularly.

Your doctor will tell you when and how AROPAX should be discontinued.

When your doctor decides that you should stop taking AROPAX the dose may 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 AROPAX is stopped, particularly if stopped suddenly.

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

Please see additional information under Section 6. Are there any side effects?

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • feeling sick, dry mouth, constipation, decreased appetite, diarrhoea
  • vomiting
  • drowsiness, dizziness, difficulty in getting to sleep
  • impaired sexual function. In some cases, these symptoms have continued after stopping treatment
  • weakness
  • feeling sweaty or shaky
  • bruising
  • abnormal dreams (including nightmares)
  • weight gain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • muscle spasms or twitches
Stop taking AROPAX and seek help if any of the following happens:
  • allergic reaction including swelling of limbs, face, lips, mouth or throat which may cause wheezing, difficulty swallowing or breathing
  • Lumpy rash
  • Hayfever
  • Fainting
  • 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 (Stevens-Johnson syndrome)
  • a widespread rash with blisters and skin peeling on much of the body surface (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
  • fainting
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Other rare events that have been reported with AROPAX 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.
  • heavy vaginal bleeding shortly after birth.
  • severe allergic reactions.

Unwanted effects that may occur on stopping treatment:

Symptoms 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
  • sweating
  • headache
  • diarrhoea.

These are likely to occur in the first few days of stopping treatment or very rarely if you miss a dose. However, they are more likely to occur if you stop taking AROPAX too quickly.

Therefore, always consult your doctor before stopping your medicine. For the majority of patients, symptoms go away on their own within a few weeks.

However, if you feel that the unwanted symptoms are too severe, see your doctor who will suggest how to manage stopping treatment more slowly.

Although AROPAX is not recommended for children under 18 years of age, the most common unwanted effects in children under 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.

Additional symptoms that have been experienced by children whilst stopping treatment are changing emotions (including thoughts of suicide, attempting suicide, mood changes and feeling tearful), abdominal pain and nervousness.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What AROPAX contains

Active ingredient
(main ingredient)		Paroxetine (as hydrochloride hemihydrate)
Other ingredients
(inactive ingredients)
  • opadry white YS-1R-7003 (PI 1625)
  • calcium hydrogen phosphate dihydrate
  • sodium starch glycollate
  • magnesium stearate.

Do not take this medicine if you are allergic to any of these ingredients.

AROPAX tablets do not contain sucrose, lactose or tartrazine.

What AROPAX looks like

AROPAX tablets are white, film-coated, oval shaped biconvex tablet, debossed with "20" on one side and a break bar on the other containing 20 mg of paroxetine.

Available in blister packs of 30 tablets.

(Aust R 57927)

Who distributes AROPAX

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia.

AROPAX® is a registered trademark of Aspen Global Incorporated.

This leaflet was prepared in September 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Aropax

Active ingredient

Paroxetine

Schedule

S4

 

1 Name of Medicine

Paroxetine hydrochloride hemihydrate.

2 Qualitative and Quantitative Composition

Aropax tablets contain 20 mg paroxetine (as hydrochloride hemihydrate) as the active ingredient. They also contain calcium hydrogen phosphate dihydrate, magnesium stearate, opadry white YS-1R-7003 (PI) and sodium starch glycollate as excipients.

3 Pharmaceutical Form

Aropax are white, film-coated oval shaped biconvex tablets, debossed with "20" on one side and a break bar on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Aropax is indicated for the treatment of:
major depression and for the prevention of relapse of depressive symptoms;
obsessive compulsive disorder and for the prevention of relapse of OCD;
panic disorder and for the prevention of relapse of panic disorder;
social anxiety disorder/ social phobia;
generalised anxiety disorder; and
post-traumatic stress disorder.

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 Aropax is 20 mg (1 Aropax 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 to 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 Aropax is 40 mg (2 Aropax 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 Aropax 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.

Generalised anxiety disorder.

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

Post-traumatic stress disorder.

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

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 which is associated with clinical efficacy.

Use in renal/ hepatic impairment.

Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min) 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 Aropax employed a taper phase regimen, rather than an abrupt discontinuation of treatment. The taper phase regimen used in GAD and PTSD 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 Aropax 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 Aropax marketing there have been spontaneous reports of adverse events upon discontinuation (particular 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 Aropax is being prescribed. Aropax 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

Aropax is contraindicated in persons who are known to be hypersensitive to paroxetine or any of its components (see Section 2 Qualitative and Quantitative Composition).
Aropax should not be used in combination with pimozide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Aropax should not be used in combination with MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective 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).
Aropax should not be used in combination with thioridazine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Identified precautions.

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 depressive disorder, 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 patients 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 Akathisia and Mania and bipolar disorder below; see 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 co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
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 non-psychiatric) 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 Aropax 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 co-administration of tricyclic antidepressants (TCAs) with Aropax 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 co-administered with Aropax.

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 co-prescribed 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 co-administration. 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 5-HT 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 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.

ECT.

The efficacy and safety of the concurrent use of Aropax 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.

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

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.

Haemorrhage.

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 non-steroidal 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 the symptoms have continued despite discontinuation of SSRIs/SNRI.

Discontinuation of treatment.

Discontinuation symptoms have been reported with SSRI antidepressants, including Aropax, when they have been discontinued, particularly when treatment has been stopped abruptly (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration). 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 (2-3 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 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 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.

See Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

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. 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 adolescent, 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 Aropax.

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 (see Table 1) 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.

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 experiences. 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 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 Aropax 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 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)).

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 doses of 13 mg paroxetine/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 consult 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. [Centers 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, hyper-reflexia, 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 paroxetine 13 and 43 mg/kg/day PO 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)

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 = 2963) 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 OCD (vs placebo, 21/265, 7.9%) and panic disorder (vs 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 programmes 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+**, face oedema, infection+, 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+, 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++, thrombosis, varicose vein, vascular headache.

Gastrointestinal.

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

Haematologic/ lymphatic.

Uncommon: anaemia, leukopenia, lymphadenopathy, purpura, WBC 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#++, weight loss#, increases in cholesterol levels. Uncommon: oedema, hyperglycaemia, peripheral oedema, thirst. Rare: alkaline phosphatase increased+, bilirubinaemia, dehydration, gout, hyperphosphataemia++, hypocalcaemia, hypoglycaemia, hypokalaemia, hyponatraemia, obesity, AST increased, ALT increased.

Musculoskeletal.

Common: myopathy, myalgia, myasthenia. Uncommon: arthralgia+, 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), hyperaesthesia+. Uncommon: abnormal thinking+, akinesia, alcohol abuse, amnesia+, ataxia, convulsion, depersonalisation+, hallucinations, hyperkinesia+, hypertonia+, 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+, 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+. Rare: emphysema++, hiccup, lung fibrosis, pulmonary edema++, sputum increased, voice alteration.

Dermatological.

Common: sweating, rash, pruritus, sweat gland disorder#. Uncommon: acne, alopecia, dry skin, ecchymosis, eczema, furunculosis, herpes simplex, urticaria. Rare: angioedema, contact dermatitis, erythema nodosum, herpes zoster, hirsutism++, 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#, taste perversion. Uncommon: abnormality of accommodation, conjunctivitis, ear pain, eye pain, mydriasis, otitis media, tinnitus+, keratoconjunctivitis#. 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*, urinary frequency, female/ male genital disorder*, urination impaired, impotence*. Uncommon: abortion*, amenorrhoea*, breast pain*, cystitis, dysmenorrhoea+*, dysuria, menorrhagia*, nocturia, polyuria, urinary incontinence, urinary retention, urinary tract infection+**, urinary urgency, vaginitis+*. Rare: breast atrophy*, female lactation*, haematuria, kidney calculus, abnormal kidney function, kidney pain, mastitis*, nephritis, oliguria, urethritis, urine abnormality, vaginal moniliasis*.
*Incidence corrected for gender.
+Adverse experiences reported more frequently in OCD vs depression clinical trials.
#Adverse experience reported in OCD clinical trials.
**Adverse experiences reported more frequently in panic vs depression clinical trials.
++Adverse experiences reported in panic clinical trials.
See Table 2.

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

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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 under 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacology.

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and efficacy in the treatment of OCD, panic disorder, social anxiety disorder/ social phobia, generalised anxiety disorder and post-traumatic stress disorder are thought to be related to its specific inhibition of 5-HT uptake in brain neurons.
In vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for α1, α2 and β-adrenoceptors, dopamine (D2), 5HT1-like, 5HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties. Paroxetine has 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 (MAO) inhibitors or tryptophan. Behavioural and EEG studies indicate that paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature.
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 ECG.
In the treatment of depressive disorders, Aropax 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. Aropax 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.
Aropax, 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 Aropax (HAM-D total score < 8) during an initial 8 week open treatment phase and were then randomised to continuation on Aropax or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking Aropax (15%) compared to those.

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 post-baseline 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 post-baseline 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 OCD.

A study of OCD outpatients, who had responded to Aropax during an initial 6 month open treatment phase and were then randomised to continuation on Aropax or placebo for 6 months, demonstrated a significantly lower relapse rate for patients taking Aropax (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 (DSM III-R) with or without agoraphobia. The studies were conducted over 10-12 weeks. Two of these studies also had an active comparator (clomipramine or alprazolam) arm.
In all four studies, patients received either paroxetine 10-60 mg/day (n = 469), clomipramine 10-150 mg/day (n = 121), alprazolam 1-6 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 re-randomised to either paroxetine (10, 20, or 40 mg/day) or placebo. Thirty three paroxetine treated patients 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% vs 30%; p = 0.002).
Benefit in maintenance treatment was demonstrated in a 36 week extension study which compared paroxetine 20-60 mg/day (n = 68) to clomipramine 50-150 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 the study. Maintenance of efficacy of paroxetine was significantly superior to placebo in 2 out of 3 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, multi-centre, double blind, randomised, parallel group, placebo controlled clinical trials (2 flexible dose, 1 dose ranging). Patients received paroxetine 20-60 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.

Generalised anxiety disorder.

The effectiveness of paroxetine in the treatment of generalised anxiety disorder (GAD) was demonstrated overall, in three 8 week, multicenter, placebo controlled studies of adult outpatients with generalised anxiety disorder (DSM-IV).
Study 1 was a fixed dose study and compared paroxetine 20 mg (n = 188) or 40 mg/day (n = 197) with placebo (n = 180). Paroxetine 20 mg and 40 mg were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items (20 mg: p < 0.001; 40 mg: p < 0.001), and the Clinical Global Impression (CGI) responder criterion (20 mg: p = 0.002; 40 mg: p < 0.001).
Two flexible dose studies were conducted comparing paroxetine 20 mg to 50 mg daily and placebo. In study 2, paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score (p = 0.008), both the HAM-A anxiety (p = 0.001) and tension items (p = 0.005), and the Clinical Global Impression (CGI) responder criterion (p = 0.007). Study 3 supports the use of paroxetine in the treatment of GAD. Paroxetine demonstrated statistical significance over placebo on a number of the secondary outcome measures, including the HAM-A anxiety item (p = 0.011) and the Clinical Global Impression (CGI) responder criterion (p = 0.011).
Study 4 was a long-term (up to 32 weeks) relapse prevention study comparing paroxetine 20-50 mg to placebo. Following an 8 week single blind treatment phase on paroxetine, patients who responded were randomised to either paroxetine or placebo in a 24 week double blind phase. Paroxetine was shown to be statistically superior to placebo in the proportion of patients relapsing during the double blind phase (10.9% versus 39.9%: p < 0.001).
In addition paroxetine demonstrated statistically superiority over placebo on the mean change from double blind baseline in the HAM-A (total, items 1 and 2: p < 0.001), HAD (p < 0.001) and SDS (p < 0.001) and in the proportion of responders (relative to single blind baseline) as measured by the CGI global improvement scale (88.0% paroxetine versus 50.7% placebo: p < 0.001). There was a high remission rate for paroxetine patients with many becoming effectively symptom free (73% in the retrospective analysis of HAM-A total score of ≤ 7 at week 32), whereas many patients who had switched to placebo deteriorated.

Post-traumatic stress disorder.

The effectiveness of paroxetine in the treatment of post-traumatic stress disorder (PTSD) was studied in three 12 week, multicentre, double blind, randomised, parallel group, placebo controlled clinical studies (2 flexible dose, 1 dose ranging, fixed dose) of adult outpatients with a primary diagnosis of post-traumatic stress disorder (DSM-IV). The efficacy of Aropax has not been evaluated in placebo controlled trials of more than 12 weeks duration.
Study 1 was a fixed dose study and compared paroxetine 20 mg/day (n = 183) or 40 mg/day (n = 182) with placebo (n = 186). Studies 2 and 3 were flexible dose studies in which patients received paroxetine 20-50 mg/day (n = 311) or placebo (n = 318).
All three studies indicated that paroxetine was statistically superior to placebo according to the Clinician Administered PTSD Scale Part 2 (CAPS 2), and two studies showed paroxetine superior to placebo according to the Clinical Global Impression (CGI) scale. In addition, paroxetine demonstrated statistical significance over placebo on a number of the secondary outcome measures in all three studies, including the Treatment Outcome PTSD Scale (TOP 8), the Davidson Trauma Scale (DTS), and the Sheehan Disability Scale (SDS).
In a pooled analysis of the pivotal studies, paroxetine was statistically superior over placebo in patients with or without comorbid depression. The majority of patients in these trials were women (Study 1: 68.4% (377/551), Study 2: 65.8% (202/307), Study 3: 53.7% (173/322).
The pooled analysis showed that paroxetine is effective in the treatment of PTSD in both males and females.

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 non-linear 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 CNS. 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 1/50 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 (non-linear kinetics: see Absorption), 7-14 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.

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.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

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 30°C.

6.5 Nature and Contents of Container

Available in Al laminated with PVC blister packs of 10 (sample pack) or 30 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Paroxetine hydrochloride hemihydrate is an odourless, off white powder, with a melting point range of 120°C to 138°C and solubility of 5.4 mg/mL in water.
Aropax (paroxetine hydrochloride hemihydrate) 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. It is the hemihydrated hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy)methyl]-piperidine hydrochloride hemihydrate. The molecular weight of paroxetine hydrochloride hemihydrate is 374.8 (329.4 as free base).

CAS number.

110429-35-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes