Consumer medicine information

Chemmart Paroxetine Tablets

Paroxetine

BRAND INFORMATION

Brand name

Chemmart Paroxetine

Active ingredient

Paroxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Chemmart Paroxetine Tablets.

What is in this leaflet

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

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

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

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

What this medicine is used for

Paroxetine is used to treat:

  • depression
  • Obsessive Compulsive Disorder (OCD)
  • panic disorder
  • social anxiety disorder or social phobia
  • generalised anxiety disorder
  • post-traumatic stress disorder.

It is also used to prevent the symptoms of depression, Obsessive Compulsive Disorder and panic disorder from coming back.

Paroxetine belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs).

How it works

Paroxetine is thought to work by acting on brain chemicals called amines which are involved in controlling mood. Paroxetine corrects the chemical imbalance and helps to relieve the symptoms of depression and stop them coming back.

Depression is longer lasting and/or more severe than the 'low moods' everyone has from time to time due to the stress of everyday life. It is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional and physical symptoms. You may feel low in spirit, not interested in usual activities, being unable to enjoy life, poor appetite or overeat, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing.

Paroxetine is thought to have a similar action when it used to for irrational fears, obsessional behaviour or panic attacks, and when it is used to treat patients who may avoid or are fearful of social situations, have excessive anxiety and worry, who feel irritable, restless and/or tense in the muscles, or who experience repeated and distressing recollections of a past traumatic event.

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

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

This medicine is not addictive

Paroxetine is not recommended for use in children under 18 years of age. It has been shown that the risk of serious side effects such as suicidal thoughts and actions is higher in this age group.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • paroxetine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine if you are taking other medicines called Monoamine Oxidase Inhibitors (MAOIs). MAOIs may be used for the treatment of depression (e.g. phenelzine, tranylcypromine, moclobemide), Parkinson's disease (e.g. selegiline), infections (e.g. linezolid), or diagnosis of certain conditions or treatment of certain blood disorders (e.g. methylene blue). Check with your doctor or pharmacist if you are taking any MAOIs.

Do not take paroxetine until 14 days after stopping any MAOI, and do not take MAOIs until 14 days after stopping paroxetine. Taking paroxetine with or within 14 days of taking MAOIs may cause a serious reaction with a sudden increase in body temperature, very high blood pressure and convulsions. Your doctor will know when it is safe to start paroxetine after the MAOI has been stopped.

Do not take this medicine if you are taking thioridazine or pimozide for the treatment of schizophrenia or other psychoses (disturbances in thinking, feelings and behaviours).

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

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

Before you start to take it

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

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

  • mania, hypomania, bipolar disorder, previous episodes of depression or other psychiatric conditions
  • epilepsy, fits or seizures
  • heart, liver or kidney problems
  • narrow-angle glaucoma (raised pressure in the eye)
  • problems with blood clotting or abnormal bleeding
  • diabetes
  • thoughts or actions relating to self-harm or suicide
  • intolerance to lactose. These tablets contain lactose.

Tell your doctor if you are pregnant or plan to become pregnant. Studies show that use of paroxetine in early pregnancy (first 13 weeks) may be associated with an increased risk of heart defects in babies. If you become pregnant or intend to become pregnant while taking this medicine, see your doctor for a review of your treatment immediately. It is important that you do not stop taking this medicine suddenly. Paroxetine can have withdrawal side effects if stopped suddenly.

If you are male, your chances of fathering a child may be reduced.

Tell your doctor if you are breastfeeding. Paroxetine passes into breast milk and it is not known if it affects babies. Your doctor will discuss with you the risks and benefits involved.

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

Taking other medicines

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

When taken with paroxetine, some medicines may increase the risk of having serious side effects. These serious side effects may be life-threatening. These include:

  • MAOIs (e.g. phenelzine, tranylcypromine, moclobemide, linezolid, selegiline, methylene blue)
  • thioridazine and pimozide.

Other medicines may interfere with paroxetine. These include:

  • tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine, desipramine)
  • other SSRIs (e.g. fluoxetine, citalopram, sertraline, fluvoxamine)
  • medicines used for treating disorders which affect the way you think, feel or act (e.g. perphenazine, risperidone, atomoxetine, lithium)
  • procyclidine, used to treat Parkinson's disease
  • some medicines used to control epilepsy or fits (e.g. phenytoin, carbamazepine, phenobarbital, sodium valproate)
  • metoprolol and flecainide, used to lower blood pressure or treat heart conditions
  • aspirin, non-steroidal antiinflammatory drugs (NSAIDs) and anti-coagulants (such as warfarin), which can thin the blood
  • cimetidine, used to treat stomach ulcers or reflux
  • some medicines used to treat migraines (e.g. sumatriptan, naratriptan, zolmitriptan)
  • St John's Wort (Hypericum perforatum) or L-tryptophan, contained in some multivitamin and herbal preparations
  • medicines used to relieve severe pain (e.g. fentanyl, tramadol)
  • tamoxifen, used to treat breast cancer
  • fosamprenavir and ritonavir, used to treat HIV infection
  • anaesthetic medicines (e.g. mivacurium, suxamethonium).

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

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

Other medicines not listed above may also interact with paroxetine.

How to take this medicine

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

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

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

If you have kidney or liver problems, then the doses may be lower.

For depression, social anxiety disorder/social phobia, generalised anxiety disorder or post-traumatic stress disorder:
The usual dose is one 20 mg tablet taken once a day. This dose may be increased slowly by your doctor if needed. This may require you to break the tablet in half. The dose should not go above 50 mg per day in adults, or 40 mg per day in elderly people.

For obsessions and compulsions or panic attacks:
The usual dose is two 20 mg tablets taken once a day. Your doctor should start you on a lower dose and increase the dose slowly over several weeks. This may require you to break the tablet in half. The dose should not go above 60 mg per day in adults, or 40 mg per day in elderly people.

How to take it

Swallow the tablets with a glass of water. The tablets should not be chewed.

When to take it

Take this medicine in the morning at about the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It should preferably be taken with food.

How long to take it for

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

Make sure you have enough to last over weekends and holidays.

Like other drugs of this type, this medicine 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 your medicine starts to work.

Make sure that you or anyone close to you or caring for you watch for these symptoms in the first few months or treatment or when changing the dose. 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.

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

Stopping Treatment

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

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

Your doctor will tell you when and how this medicine 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 this medicine, especially if this is done suddenly, you may experience unwanted side effects such as feeling dizzy, sick or anxious; sweating; pins and needles or electric shock feelings, or disturbed sleep.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of unwanted side effects.

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

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

If you take too much (overdose)

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

Symptoms of an overdose may include nausea, vomiting, tremor, dilated pupils, dry mouth, sedation, sweating, dizziness, confusion, headache, fast heartbeat and irritability.

While you are taking this medicine

Things you must do

People taking paroxetine may be more likely to think about killing themselves or actually try to do so, especially when paroxetine is first started or the dose is changed.

Tell your doctor immediately if you have thoughts about killing yourself, or if you are close to or care for someone using paroxetine who talks about or shows signs of killing him or herself. All mentions of suicide or violence must be taken seriously.

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. It is possible that these symptoms continue or get worse until the full antidepressant effect of the medicine becomes apparent. This is more likely to occur if you are a young adult, i.e. 18 to 24 years of age, and you have not used antidepressant medicines before.

If you or someone you know or care for demonstrates any of the following warning signs of suiciderelated behaviour while taking paroxetine, contact a doctor immediately, or even to go to the nearest hospital for treatment:

  • thoughts or talk of death or suicide
  • thoughts of talk of self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability or agitation.

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

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are a male and you and your partner have been unsuccessful whilst trying for a baby, tell your doctor. Some studies have shown that medicines such as paroxetine may affect sperm quality. However, the effect goes away if the medicine is stopped.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

If you have an accident, and/or break a bone, tell your doctor that you are taking paroxetine. Some antidepressant medicines have been associated with an increased risk of bone fracture.

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

Tell your doctor if you feel the tablets are not helping your condition. If you are being treated for depression, discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness, thoughts of suicide, bursts of unusual energy, anger or aggression, or if you become particularly agitated or restless.

This will help your doctor to determine the best treatment for you.

Things you must not do

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

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

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. This medicine may cause dizziness, drowsiness, light-headedness or problems concentrating in some people. If you have any of these symptoms, do not drive a car; operate machinery, or anything else that could be dangerous.

Be careful when drinking alcohol while you are taking paroxetine. If you drink alcohol, dizziness, drowsiness or impaired concentration may be worse, or your symptoms of depression or anxiety may become worse. Your doctor may suggest avoiding alcohol while you are being treated with this medicine.

You should wait at least 14 days after stopping paroxetine before starting any medicines known as monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine and moclobemide.

When your doctor decides that you should stop taking this medicine, the dose may be reduced slowly or the time between the doses increased over 1 to 2 weeks (see 'Stopping Treatment').

Side effects

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

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

If you are over 65 years of age you may have an increased chance of getting side effects.

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

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

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

  • gastrointestinal problems e.g. feeling or being sick, dry mouth, increased or decreased appetite, wind, indigestion, constipation or diarrhoea
  • weight gain or loss
  • teeth grinding
  • yeast infection of the mouth
  • drowsiness, dizziness, difficulty in getting to sleep; strange dreams
  • feeling nervous, anxious or agitated
  • sexual problems
  • headache, pain, weakness or apathy, back pain
  • feeling sweaty or shaky
  • bruising
  • mild rash, itching, excess sweating
  • sunburn-type rash following a short time in the sun
  • red bumps on the shins, rash following contact with certain materials
  • impaired concentration, confusion
  • changes in taste sensation
  • muscle weakness or muscle or joint or cartilage pain or inflammation
  • stiff or painful neck
  • burping or problems swallowing
  • sore throat, yawning, cough, stuffy nose
  • excess saliva
  • breast pain, missed or painful periods
  • acne, hair loss or excess growth, dry skin, unusual bruising, eczema, boils, cold sores

The above list includes the more common side effects of your medicine.

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

  • muscle spasms or twitches, facial twitching, feeling restless and needing to move often
  • Restless Legs Syndrome (leg discomfort in the calves, twitching, burning, tingling, feeling of insects crawling)
  • menstrual period disorder (including heavy periods, bleeding between periods and absence of periods
  • confusion, changing emotions or mood
  • low levels of sodium in the blood, especially if you are over 65 years of age. This may be felt as sleepiness and muscle weakness.
  • chills or fever
  • feeling dizzy or faint when standing up (due to low blood pressure)
  • high or low blood pressure
  • flushing
  • pain in the upper or lower abdomen
  • varicose veins, swollen veins
  • migraine or severe headache
  • shingles (painful skin rash with blisters), discoloured or ulcerated skin
  • abnormal breast milk production, infected breasts
  • problems with your eyesight or hearing
  • hormone disturbances
  • mood of excitement, over-activity and uninhibited behaviour
  • problems with urinating (frequent or painful urination or large amounts of urine produced, night time urination)
  • vaginal irritation or infection
  • diabetes or thyroid problems
  • changes in your blood which you may notice as feeling tired, weak, thirsty, easily bruised, or prone to infections

The above list includes serious side effects that may require medical attention.

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

  • sudden increase in body temperature, severe convulsions (fits)
  • yellowing of your skin or eyes. unusually dark urine or pale faeces, unexplained persistent nausea, stomach problems, loss of appetite or unusual tiredness or weakness (this may indicate liver problems)
  • sudden fever, hallucinations, loss of coordination, confusion and overactive reflexes
  • fast heartbeat, sweating, muscle spasm, racing thoughts, restlessness
  • seizures
  • thumping, fluttering, slow or irregular heartbeat, chest pain or left arm/neck pain, unconsciousness
  • thinking or acting strangely
  • thoughts of suicide and attempting suicide or self-harm
  • sudden weakness or numbness of the face, arms or legs, especially on one side, slurred speech
  • suddenly getting long-lasting muscle spasms, affecting the eyes, head, neck and body.
  • feeling out of sorts, with fever, headache and cough, then suddenly getting spots or blisters which quickly develop into large amounts of blistering or peeling skin
  • abnormal bleeding (including vaginal and gastrointestinal bleeding, nosebleed) or bruising, bloody diarrhoea, black tarry stools, vomiting blood
  • blood clots, swollen veins due to blood clots, coughing up blood
  • severe 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) (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)
  • kidney stones and/or kidney pain, blood in the urine
  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (symptoms of an allergic reaction).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Withdrawal Symptoms

Unwanted effects that may occur after paroxetine has been stopped suddenly include:

  • headache, dizziness, confusion
  • sensory disturbances such as pins and needles, burning sensations and electric shock-like sensations
  • feeling sick, diarrhoea
  • agitation or anxiety
  • sweating, shaking or tremors
  • disturbed sleep (including nightmares)
  • tinnitus (ringing or buzzing in the ears)

These are likely to occur within 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 paroxetine too quickly. Therefore, always consult your doctor before stopping your medicine.

For most people, the above side effects will disappear within a few weeks. However, if you feel that these effects are too severe, see your doctor who can suggest how to stop your medicine more gradually.

Although paroxetine is not recommended for children under 18 years of age, the most common unwanted effects in this age group are as follows:

  • decreased appetite
  • uncontrollable trembling or shaking
  • sweating
  • hyperactivity
  • abdominal (e.g. stomach) pain
  • hostile or unfriendly behaviour
  • trying to harm themselves
  • thinking about or trying to commit suicide
  • changing emotions or moods e.g. feeling tearful
  • feeling nervous or agitated.

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

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

Storage and Disposal

Storage

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

Keep your medicine in a cool, dry place where the temperature stays below 25°C. Protect from moisture.

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

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

Disposal

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

Product description

What it looks like

20 mg tablets:
White, oval, biconvex and film-coated, with a partial bisect and engraved "20" on one side. The other side is plain.

Blister pack of 30 tablets.

AUST R 83104

Ingredients

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

It also contains the following:

  • magnesium stearate
  • sodium starch glycollate
  • lactose
  • hydroxypropylcellulose
  • hypromellose
  • macrogol 8000
  • titanium dioxide.

This medicine does not contain gluten, sucrose, tartrazine and other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was prepared in September 2018.

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Chemmart Paroxetine

Active ingredient

Paroxetine

Schedule

S4

 

1 Name of Medicine

Paroxetine hydrochloride.

6.7 Physicochemical Properties

Paroxetine hydrochloride 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. It is the hydrochloride salt of a phenylpiperidine compound.
Paroxetine is an orally administered antidepressant with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic or other available antidepressant agents.
Chemical Name: (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl]-piperidine hydrochloride. Molecular Formula: C19H20FNO3.HCl. Molecular Weight: 365.83.

Chemical structure.


CAS number.

78246-49-8.

2 Qualitative and Quantitative Composition

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

Excipients with known effect.

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

3 Pharmaceutical Form

White, oval-shaped, biconvex, film-coated tablets, partial bisect and engraved "20" on one side, other side plain.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and efficacy in the treatment of obsessive compulsive disorder, panic disorder, social anxiety disorder/ social phobia, generalised anxiety disorder and post-traumatic stress disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones.
In vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for α1, α2 and β-adrenoceptors, dopamine (D2), 5-HT1-like, 5-HT2 and histamine (H1) receptors. This lack of interaction with postsynaptic 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 major metabolites of paroxetine are at most 1/50th of the parent compound, it is most unlikely that they contribute to the therapeutic effect of paroxetine.
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, paroxetine exhibits comparable efficacy to standard antidepressants. There is also some evidence that paroxetine may be of therapeutic value in patients who have failed to respond to standard therapy.
In general, improvement in patients starts after one week but does not become superior to placebo until the second week of therapy. Paroxetine is effective in improving depression and suicidal ideation concurrently during the first few weeks of therapy.
Morning dosing with paroxetine does not have any detrimental effect on either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy. Where it is clinical practice to coprescribe short acting hypnotics with antidepressants, no additional adverse events have been recorded.
Paroxetine, in addition to its significant antidepressant effects, can improve associated symptoms of anxiety.

Clinical trials.

Relapse prevention of depression.

A study of depressed outpatients who had responded to paroxetine (HAM-D total score < 8) during an initial 8 week open treatment phase and were then randomised to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%).

Obsessive compulsive disorder.

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

Relapse prevention of OCD.

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

Panic disorder.

The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in four multicentre, placebo controlled studies of adult outpatients. Patients in all studies had panic disorder (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 rerandomised to either paroxetine (10 mg/day, 20 mg/day 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, 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, multicentre, 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 mg/day, 40 mg/day 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, multicentre, placebo controlled studies of adult outpatients with generalised anxiety disorder (DSM-IV).
Study 1 was a fixed dose study and compared paroxetine 20 mg/day (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 the 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 20-50 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% vs. 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 paroxetine 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 nonlinear kinetics. These properties are a consequence of the fact that one of the enzymes that metabolises paroxetine is the readily saturable cytochrome P450 enzyme 2D6 (CYP2D6). However, because this enzyme becomes saturated early on following commencement of paroxetine treatment, the nonlinearity 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 1/50th the potency of the parent compound at inhibiting serotonin uptake.
The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. At steady state, when CYP2D6 is essentially saturated, paroxetine clearance is governed by alternate P450 isoenzymes which, unlike CYP2D6, are not saturable at clinical doses (as evidenced by linear pharmacokinetics in CYP2D6 deficient individuals).
Because of the involvement of CYP2D6 in the metabolic clearance of paroxetine, considerable variation can occur in the plasma concentrations achieved between individuals. However, no correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy). Increased plasma concentrations of paroxetine occur in elderly subjects and in those subjects with severe renal and hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.

Excretion.

Approximately 64% of the dose is excreted in the urine; urinary excretion of unchanged paroxetine is generally less than 2% of dose. About 36% of the dose is excreted in the faeces, probably via the bile; faecal excretion of unchanged paroxetine represents less than 1% of the dose. Thus, paroxetine is eliminated almost entirely by metabolism. Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine.
The elimination half-life is variable, but is generally about 1 day. However, because of the reduction in plasma clearance which occurs on multiple dosing (nonlinear kinetics, see 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 a 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Paroxetine is indicated for the treatment of:
major depression and for the prevention of relapse of depressive symptoms;
obsessive compulsive disorder (OCD) 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;
post-traumatic stress disorder.

4.3 Contraindications

Paroxetine is contraindicated in persons who are known to be hypersensitive to paroxetine or any of its components (see Section 6.1 List of Excipients).
Paroxetine should not be used in combination with pimozide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Paroxetine should not be used in combination with MAO inhibitors (including linezolid, an antibiotic which is a reversible nonselective MAO inhibitor and methylthioninium chloride (methylene blue)) with MAO inhibitors or within 2 weeks of terminating treatment. 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).
Paroxetine 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

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 and other psychiatric disorders. In clinical trials of paroxetine in children and adolescents, adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in patients treated with paroxetine compared to those treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

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 (MDD), may be at increased risk for suicidal behaviour during treatment with paroxetine, especially during initial treatment (generally the first 1-2 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 medication (see Akathisia, 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 4,400 children and adolescents with major depressive disorder (16 trials), obsessive compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from the trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Other psychiatric conditions for which paroxetine is prescribed can also be associated with an increased risk of suicidal behaviour. In addition, these conditions may be comorbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Additionally, patients with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts. All patients should be monitored for clinical worsening (including development of new symptoms) and suicidality throughout treatment, and especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases.
Family and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for paroxetine 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.

Renal impairment.

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

Hepatic impairment.

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

Diabetes.

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

Tricyclic antidepressants (TCAs).

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

Serotonin syndrome/ neuroleptic malignant syndrome.

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic medicines. 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 medicines).

Mania and bipolar disorder.

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

Tamoxifen.

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

Bone fracture.

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

Oral anticoagulants.

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

Tryptophan.

As adverse experiences have been reported when tryptophan was administered with another selective 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.

Seizures.

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

ECT.

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

Glaucoma.

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

Hyponatraemia.

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

Cognitive and motor performance.

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

Alcohol.

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

Bleeding.

Bleeding abnormalities of the skin and mucous membranes have been reported with the use of SSRIs (including purpura, haematoma, epistaxis, vaginal bleeding and gastrointestinal bleeding). This risk may be potentiated by concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other medicines that affect coagulation. 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.

Lactose.

Chemmart Paroxetine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, severe lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take this medicine.

Discontinuation of treatment.

Discontinuation symptoms have been reported with SSRI antidepressants, including paroxetine, when they have been discontinued, particularly when treatment has been stopped abruptly (see Section 4.8 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 medicine being addictive or dependence producing as with a substance of abuse.
Dizziness, sensory disturbances (including paraesthesia, tinnitus and electric shock sensations), 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 the elderly.

No data available.

Paediatric use.

Use in children and adolescents (< 18 years).

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

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 coadministered 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 the 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 medicines 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 paroxetine.

Warfarin.

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

Medicines 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 paroxetine is to be coadministered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, 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).

Medicines 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 medicines 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 medicines.
Therefore, coadministration of paroxetine with certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), phenothiazine neuroleptics (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 medicines which inhibit the hepatic enzyme CYP2D6 (including other antidepressants), paroxetine can elevate plasma levels of thioridazine. Therefore, paroxetine should not be administered with thioridazine (see Section 4.3 Contraindications).

Medicines 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 medicines 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 medicines.
Experience in a limited number of healthy subjects has shown that paroxetine does not increase the sedation and drowsiness associated with haloperidol, amylobarbitone or oxazepam, when given in combination.

Serotonergic medicines.

As with other SSRIs, coadministration with serotonergic drugs may lead to an incidence of 5-HT 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 see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Discontinuation of treatment.
Epidemiological studies have shown infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations.
A recent retrospective US epidemiological study of 3,581 pregnant women exposed to paroxetine or other antidepressants during the first trimester of pregnancy showed an increased risk of major congenital malformations overall for paroxetine compared to other antidepressants (odds ratio 2.20; 95% confidence interval 1.34-3.63). There was also an increased risk of cardiovascular malformations for paroxetine compared to other antidepressants (odds ratio 2.08; 95% confidence interval 1.03-4.23). These figures excluded women exposed to both antidepressants and teratogenic medicines. 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 medicines 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 these medicines 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 these medicines has not been confirmed. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, somnolence and constant crying. In some neonates the complications have resulted in prolonged hospitalisation, respiratory support and tube feeding. In some instances, the reported symptoms were described as neonatal withdrawal symptoms. In a majority of instances the complications were reported to have arisen either immediately or soon (< 24 hours) after delivery.
Epidemiological studies have shown that the use of SSRIs (including paroxetine) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The risk of PPHN among infants born to women who used SSRIs late in pregnancy was estimated to be 4 to 5 times higher than the rate of 1-2 per 1000 pregnancies observed in the general population.
Reproduction studies performed in rats and rabbits at oral doses of up to 43 mg/kg 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 mg/kg/day and 43 mg/kg/day PO during pregnancy and lactation. The risk to the infant by paroxetine administration to lactating women is unknown. Therefore, paroxetine should not be used by lactating women unless the potential benefit outweighs the possible risk.

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 treated patients (n = 2963) 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 programs for depression, OCD and panic disorder. All adverse experiences are included in the list except those reported in terms so general as to be uninformative and those experiences for which the association with the medicine 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; 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, thrombophlebitis1, 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 malformation1.

Haematological/ 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#1, weight loss#; increases in cholesterol levels.
Uncommon: oedema, hyperglycaemia, peripheral oedema, thirst.
Rare: alkaline phosphatase increased+, bilirubinaemia, dehydration, gout, hyperphosphataemia1, 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), hyperthesia+.
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: emphysema1, hiccup, lung fibrosis, pulmonary oedema1, 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, hirsutism1, 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*.
Key to symbols. *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 disorder vs. depression clinical trials.
1Adverse experiences reported in panic disorder clinical trials.

Adverse events occurring during postmarketing surveillance.

Blood and lymphatic system disorders.

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

Immune system disorders.

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

Endocrine disorders.

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

Metabolism and nutrition disorders.

Common: increases in cholesterol levels, decreased appetite.
Rare: hyponatraemia.
Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders.

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

Nervous system disorders.

Common: dizziness, tremor, headache.
Uncommon: extrapyramidal disorders.
Rare: convulsions, akathisia, restless legs syndrome (RLS).
Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor).
Reports of extrapyramidal disorders including orofacial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.

Eye disorders.

Common: blurred vision.
Uncommon: mydriasis (see Section 4.4 Special Warnings and Precautions for Use).
Very rare: acute glaucoma.

Cardiac disorders.

Uncommon: sinus tachycardia.

Vascular disorders.

Uncommon: postural hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: yawning.

Gastrointestinal disorders.

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

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

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

Renal and urinary disorders.

Uncommon: urinary retention, urinary incontinence.

Reproductive system and breast disorders.

Very common: sexual dysfunction.
Rare: hyperprolactinaemia/ galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia and amenorrhoea).

General disorders and administration site conditions.

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

Discontinuation symptoms.

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.
Uncommon: agitation, nausea, tremor, confusion, sweating, diarrhoea.
As with many psychoactive medicines, discontinuation of paroxetine (particularly when abrupt) may lead to symptoms such as dizziness, sensory disturbances (including tinnitus, paraesthesia and electric shock sensations), sleep disturbances (including intense dreams), tremor, agitation or anxiety, nausea, headache, confusion, diarrhoea and sweating. In the majority of patients, these events are mild to moderate and are self limiting. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when paroxetine treatment is no longer required, gradual discontinuation by dose tapering be carried out (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Adverse events from paediatric clinical trials.

In paediatric clinical trials the following adverse events were reported at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: emotional lability (including self harm, suicidal thoughts, attempted suicide, crying and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia and agitation. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with major depressive disorder. Hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children, less than 12 years of age.
In studies that used a tapering regimen (daily dose decreased by 10 mg/day at weekly intervals to a dose of 10 mg/day for one week), symptoms reported during the taper phase or upon discontinuation of paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability, nervousness, dizziness, nausea and abdominal pain.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquires/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Chemmart Paroxetine tablets are intended for oral administration.

Dosage.

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

Depression.

The recommended dose of paroxetine is 20 mg 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 medicines, 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 medicine 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 medicine therapy. Whether the dose of an antidepressant needed to induce remission is identical to the dose needed to maintain or sustain euthymia is unknown.
Systematic evaluation of paroxetine hydrochloride has shown that efficacy was maintained for periods up to one year.

Obsessive compulsive disorder.

The recommended dose of paroxetine is 40 mg 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. 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 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 in elderly patients 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 children and adolescents (< 18 years).

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

Renal impairment/ hepatic impairment.

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

Discontinuation of treatment.

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

Prolonged treatment.

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

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Overdose with paroxetine (up to 2000 mg) alone and in combination with other medicines have 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 medicines, 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, see Section 4.8 Adverse Effects (Undesirable Effects), sedation, involuntary muscle contractions and facial flush have been reported.

Treatment.

No specific antidote is known. Treatment should consist of those general measures employed in the management of overdose with any antidepressant. Supportive care with frequent monitoring of vital signs and careful observation is indicated. Patient management should be as clinically indicated, or as recommended by the national poisons centre, where available.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Magnesium stearate, sodium starch glycollate, lactose, hyprolose, hypromellose, Macrogol 8000 and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from moisture.

6.5 Nature and Contents of Container

Chemmart Paroxetine 20 mg tablets.

Blister pack (clear PVC, PVDC/aluminium) of 30 tablets.
AUST R 83104.

6.6 Special Precautions for Disposal

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

Summary Table of Changes