Consumer medicine information

APX-Quetiapine XR

Quetiapine

BRAND INFORMATION

Brand name

APX-Quetiapine XR

Active ingredient

Quetiapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APX-Quetiapine XR.

SUMMARY CMI

APX-QUETIAPINE XR

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking APX-QUETIAPINE XR, speak to your doctor or pharmacist.

1. Why am I taking APX-QUETIAPINE XR?

APX-QUETIAPINE XR contains the active ingredient quetiapine (as fumarate). APX-QUETIAPINE XR is taken to correct chemical imbalances in the brain. For more information, see Section 1. Why am I taking APX-QUETIAPINE XR? in the full CMI.

2. What should I know before I take APX-QUETIAPINE XR?

Do not take if you have ever had an allergic reaction to quetiapine (as fumarate) or any of the ingredients listed at the end of the CMI.

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

For more information, see Section 2. What should I know before I take APX-QUETIAPINE XR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APX-QUETIAPINE XR and affect how it works.

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

4. How do I take APX-QUETIAPINE XR?

  • Your doctor will tell you how many APX-QUETIAPINE XR tablets you will need to take each day and how long you need to take it.
  • Swallow APX-QUETIAPINE XR tablets whole with a full glass of water. It should be taken without food.

More instructions can be found in Section 4. How do I take APX-QUETIAPINE XR? in the full CMI.

5. What should I know while taking APX-QUETIAPINE XR?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking APX-QUETIAPINE XR.
  • Tell your doctor or mental health professional immediately, or go to the nearest hospital, if you have any suicidal thoughts or other mental/mood changes.
  • If you become pregnant while taking APX-QUETIAPINE XR, tell your doctor immediately.
Things you should not do
  • Do not stop taking APX-QUETIAPINE XR suddenly.
  • Do not take APX-QUETIAPINE XR to treat other complaints unless your doctor or pharmacist tells you to.
  • Do not give APX-QUETIAPINE XR to anyone else, even if they have the same symptoms or condition as yours.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how APX-QUETIAPINE XR affects you. It can make some people dizzy or sleepy.
Drinking alcohol
  • Combining APX-QUETIAPINE XR and alcohol can make you more sleepy or dizzy.
Looking after your medicine
  • Keep APX-QUETIAPINE XR in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while taking APX-QUETIAPINE XR? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with APX-QUETIAPINE XR. It is important to be aware of them so that you can identify any symptoms if they occur. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APX-QUETIAPINE XR

Active ingredient: Quetiapine (as fumarate)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking APX-QUETIAPINE XR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking APX-QUETIAPINE XR.

Where to find information in this leaflet:

1. Why am I taking APX-QUETIAPINE XR?
2. What should I know before I take APX-QUETIAPINE XR?
3. What if I am taking other medicines?
4. How do I take APX-QUETIAPINE XR?
5. What should I know while taking APX-QUETIAPINE XR?
6. Are there any side effects?
7. Product details

1. Why am I taking APX-QUETIAPINE XR?

APX-QUETIAPINE XR contains the active ingredient quetiapine (as fumarate). APX-QUETIAPINE XR belongs to a group of medicines called antipsychotics.

APX-QUETIAPINE XR helps to correct chemical imbalances in the brain. It is used to treat conditions such as:

  • Bipolar disorder, an illness in which there are sustained mood swings either up (mania) or down (depression). During mania, patients experience episodes of overactivity, elation or irritability. During depression, patients may feel depressed or guilty, lack of energy, lose their appetite and have trouble sleeping.
  • Recurrent major depressive disorder, an illness where 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 such as feeling low in spirit, loss of interest in activities, being unable to enjoy life, poor appetite or overeating, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing.
  • Generalised anxiety disorder, where patients have excessive anxiety and worry.
  • Schizophrenia, an illness with disturbances in thinking, feelings and behaviour.
  • APX-QUETIAPINE XR is available only with a doctor's prescription.

2. What should I know before I take APX-QUETIAPINE XR?

Warnings

Do not take APX-QUETIAPINE XR if:

  • You are allergic to quetiapine (as fumarate), or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin or you may feel faint.
    Always check the ingredients to make sure you can take APX-QUETIAPINE XR.
  • It is beyond expiry date which is printed on the pack.
  • The packaging is torn or shows signs of tampering.
  • You are pregnant or breastfeeding unless your doctor says so. Ask your doctor about the risks and benefits involved.

APX-QUETIAPINE XR is not recommended for use in children.

There is not enough information on its effects in children.

APX-QUETIAPINE XR, as with other anti-psychotic medicines, is recommended for use with caution in the elderly and is not approved for treatment of dementia and behavioural disturbances. In clinical studies with this group of medicines for the treatment of dementia and behavioural disturbances in the elderly, have suggested an increased risk of cardiovascular adverse events including stroke, and increased mortality risk for elderly patients has been reported.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking APX-QUETIAPINE XR, talk to your doctor or pharmacist.

Check with your doctor if you:

  • Have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
  • Have or have had any medical conditions, especially the following:
    - Heart or blood vessel problems or a family history of heart or blood vessel problems including high or low blood pressure, stroke, problems with your circulation or any condition that affects blood flow to the brain, problems with the way your heart beats or a history of heart attack.
    - Liver problems.
    - Diabetes (or a family history of diabetes). Patients with diabetes or who have a higher chance of diabetes should have their blood sugar checked before and during treatment with APX-QUETIAPINE XR.
    - Increased cholesterol levels.
    - Inflammation of pancreas.
    - Difficulty swallowing.
    - Epilepsy (seizures or fits).
    - Dementia or related behavioural disorders (especially in elderly patients).
    - Low white blood cell count.
    - Sleep apnoea, a condition where you stop breathing for short periods during your normal nightly sleep.
    - Urinary retention, a condition where you cannot completely empty your bladder.
    - An enlarged prostate.
    - A blockage in your intestines.
    - Increased pressure inside your eyes or glaucoma.
    - History of alcohol or drug abuse.

Tell your doctor or mental health professional if you have any mental/mood changes or suicidal thoughts.

Depression and other mental illnesses can increase the risk of suicide. It is important to discuss all the risks of treating depression and mental illness as well as the risks of not treating it. You should discuss all treatment choices with your doctor, not just the use of antidepressants.

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

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

Pregnancy and breastfeeding

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

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

Do not take APX-QUETIAPINE XR if you are pregnant or breastfeeding unless your doctor says so. Ask your doctor about the risks and benefits involved.

It is not known if APX-QUETIAPINE XR is safe for you to take it while you are pregnant.

Neonates exposed to antipsychotic drugs (including quetiapine) may experience agitation, hypertonia (high level muscle tone), hypotonia (decreased muscle tone), tremor, somnolence, respiratory distress and feeding disorder following delivery (extrapyramidal neurological disturbances and/or withdrawal symptoms). These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring.

However, if you need to take APX-QUETIAPINE XR during your pregnancy, the doctor will discuss the risks and benefits of taking it with you.

It is recommended that you do not breastfeed while taking APX-QUETIAPINE XR, as it may pass into breast milk.

Before your doctor starts you on APX-QUETIAPINE XR your doctor may want to take some tests (e.g. blood tests, blood pressure, weight or height measurements). These tests may help to prevent side effects.

Tell your doctor if you are lactose intolerant.

APX-QUETIAPINE XR tablets contain lactose monohydrate.

3. What if I am taking other medicines?

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

Some medicines may interfere with APX-QUETIAPINE XR and affect how it works.

Some medicines and APX-QUETIAPINE XR may interfere with each other. These include:

  • Medicines for high blood pressure (including diuretics or fluid tablets) or heart conditions.
  • Lorazepam, a medicine used to help you sleep.
  • Medicines used to treat anxiety, depression, mood swings, attention deficit hyperactivity disorder (ADHD) or other mood disorders.
  • Thioridazine, an antipsychotic medicine.
  • Medicines used to treat Parkinson's disease.
  • Stimulants such as amphetamines.
  • Medicines that have anti-cholinergic (muscarinic) effects.

These medicines may be affected by APX-QUETIAPINE XR or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Medicines that may increase the effect of APX-QUETIAPINE XR include:

  • Medicines for fungal infections such as ketoconazole.
  • Some antibiotics such as erythromycin.
  • Medicines for Human Immunodeficiency Virus (HIV).

Medicines that may reduce the effect of APX-QUETIAPINE XR include:

  • Phenytoin or carbamazepine, medicines used to treat epilepsy.
  • Some antibiotics such as rifampicin.
  • Glucocorticoids, medicines used to treat inflammation.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking APX-QUETIAPINE XR.

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

4. How do I take APX-QUETIAPINE XR?

How much to take

  • Your doctor will tell you how many tablets you will need to take each day and how long you need to take it. This depends on your condition and whether or not you are taking any other medicines.
  • APX-QUETIAPINE XR is usually started as a low dose that will be gradually increased by your doctor. Your doctor will recommend a dose especially for you. This will depend on various factors including your age, condition being treated, other medical conditions (e.g. liver problems), other medicines you are taking and how you may react to APX-QUETIAPINE XR. Your doctor will monitor your condition and may change your dose depending on how you respond to it. Your doctor will use the lowest dose for the least amount of time to keep you well.
  • Your doctor may have switched your treatment from Quetiapine immediate release tablets to APX-QUETIAPINE XR tablets. Your doctor will generally prescribe you a once daily dose of APX-QUETIAPINE XR, which is equivalent to your total daily dose of Quetiapine immediate release tablets. Your doctor will tell you how many tablets you will need to take each day.
  • Follow the instructions provided and take APX-QUETIAPINE XR until your doctor tells you to stop.

When to take it

  • APX-QUETIAPINE XR should be taken once a day, at approximately the same time each day.
  • Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

How to take it

  • Swallow your APX-QUETIAPINE XR tablets whole with a full glass of water. It should be taken without food.
  • Do not split, chew or crush the tablets.
  • If you split, chew or crush the tablets they will not work properly.

How long to take it

  • Continue taking APX-QUETIAPINE XR tablets for as long as your doctor tells you.
  • APX-QUETIAPINE XR helps control your condition but does not cure it. Therefore, you must take it every day.
  • Do not stop taking APX-QUETIAPINE XR unless your doctor tells you to, even if you feel better.

If you forget to take APX-QUETIAPINE XR

APX-QUETIAPINE XR should be taken regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember.

If it is almost time for 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 you missed.

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

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

If you take too much APX-QUETIAPINE XR

If you think that you have taken too much APX-QUETIAPINE XR, you may need urgent medical attention.

You should immediately:

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

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

You may need urgent medical attention.

If you take too many APX-QUETIAPINE XR tablets you may feel drowsy, sleepy, dizzy or have fast heartbeats.

APX-QUETIAPINE XR overdose may lead to gastric bezoar (tightly packed partially digested material in stomach) formation.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose.

There were cases reported of QT prolongation (abnormal electrocardiogram) with overdose.

There have been very rare reports of overdose of quetiapine alone resulting in death or coma.

5. What should I know while taking APX-QUETIAPINE XR?

Things you should do

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking it.

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are taking it.

Tell your doctor or mental health professional immediately, or go to the nearest hospital, if you have any of the following suicidal thoughts or other mental/mood changes:

  • Thoughts or talk of death or suicide.
  • Thoughts or talk of self-harm or harm to others.
  • Any recent attempts of self-harm.
  • Increase in aggressive behaviour, irritability or agitation.
  • Worsening of depression.

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. These symptoms may continue or get worse during the early stages of treatment until the effect of the medicine becomes apparent. All mentions of suicide or violence must be taken seriously.

If you become pregnant while taking APX-QUETIAPINE XR, tell your doctor immediately.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking APX-QUETIAPINE XR.

If you need to have any medical tests (including urine drug screening) while you are taking APX-QUETIAPINE XR, tell your doctor.

It may affect the results of some tests.

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Your doctor will check your progress and may want to take some tests (e.g. blood tests, blood pressure, weight or height measurements) from time to time. These tests may help to prevent side effects.

Call your doctor straight away if:

  • Your condition worsens or does not improve.

Remind any doctor, dentist or pharmacist you visit that you are taking APX-QUETIAPINE XR.

Things you should not do

  • Do not stop taking APX-QUETIAPINE XR suddenly.
  • Do not stop taking APX-QUETIAPINE XR, or change the dosage, even if you are feeling better, without checking with your doctor.
  • If you stop taking APX-QUETIAPINE XR suddenly, your condition may worsen or your chance of getting an unwanted side effect may increase. To prevent this, your doctor may gradually reduce the amount of APX-QUETIAPINE XR you take each day before stopping completely.
  • Do not give APX-QUETIAPINE XR to anyone else, even if their symptoms seem similar or they have the same condition as you.
  • Do not take APX-QUETIAPINE XR to treat any other complaints unless your doctor tells you to.
  • Do not take any medicines that cause drowsiness while you are taking APX-QUETIAPINE XR, unless recommended by your doctor.

Things to be careful of

  • Avoid getting over-heated or dehydrated, do not over-exercise. In hot weather stay inside in a cool place, stay out of the sun, do not wear too much or heavy clothing, drink plenty of water. Keep warm in cool weather.
  • APX-QUETIAPINE XR may affect the way your body reacts to temperature changes.
  • Avoid drinking large quantities of grapefruit juice. APX-QUETIAPINE XR may be affected by grapefruit juice. Talk to your doctor or pharmacist if you have any concerns.
  • Talk to your doctor or pharmacist about these things if you think they may bother you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APX-QUETIAPINE XR affects you.

It can make some people dizzy or sleepy. Make sure you know how you react to APX-QUETIAPINE XR before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or sleepy.

If it makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful when drinking alcohol while you are taking APX-QUETIAPINE XR.

Combining APX-QUETIAPINE XR and alcohol can make you more sleepy or dizzy. Your doctor may suggest you avoid alcohol while you are being treated with it.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they will not keep well.
  • Store below 25°C.
  • Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight, for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking APX-QUETIAPINE XR or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Getting rid of any unwanted medicine

If you no longer need to take APX-QUETIAPINE XR or it is out of date, take it to any pharmacy for safe disposal.

Do not take APX-QUETIAPINE XR after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • Feeling sleepy.
  • Weight gain, increased appetite.
  • Dry mouth.
  • Upset stomach, constipation, indigestion, vomiting (mainly in elderly or children).
  • Feeling weak.
  • Swelling of the hands, ankles or feet.
  • Runny or stuffy nose (particularly in children).
  • Blurred vision.
  • Abnormal dreams, nightmares.
  • Irritability.
  • Confusion.
  • Shortness of breath, difficulty in breathing and/or tightness in the chest.
  • Fast or irregular heartbeats (palpitations).
  • Muscle pain or swelling or weakness.
  • Headache.
  • Insomnia.
  • Diarrhoea.
These side effects are usually mild. Some of these side effects may go away after a while.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Difficulty swallowing.
  • Falling, feeling dizzy or faint on standing up.
  • Flat and red skin lesions or substantial hemorrhages under the skin (purpura).
  • Difficulty in speaking.
  • Rapid heartbeat.
  • Symptoms of high sugar levels in the blood (including passing large amounts of urine, excessive thirst, increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, irritable and generally unwell).
  • Breast enlargement, unusual secretion of breast milk.
  • Cutaneous vasculitis, with skin symptoms such as lesions, including palpable purpura (discolouration of skin, raised and can be felt), petechiae (tiny spots of bleeding under the skin), urticaria, ulcers, livedo reticularis (a type of skin disorder) and nodules.
These are serious side effects. You may need urgent medical attention.		Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
  • Abnormal muscle movements, including difficulty starting muscle movements, shaking, restlessness or muscle stiffness without pain.
  • Worm-like movements of the tongue or other uncontrolled movement of the tongue, mouth, cheeks or jaw which may progress to the arms and legs (a disorder called ‘tardive dyskinesia’).
  • A sudden increase in body temperature with sweating or a fast heartbeat.
  • Bleeding or bruising more easily than normal.
  • Very marked drowsiness.
  • Reduced consciousness.
  • Fits (seizures).
  • Long-lasting and painful erections.
  • Fainting (particularly in children).
  • Widespread skin rash that may include blistering or peeling of the skin, often accompanied by flu-like symptoms, fever, swelling of the face and/or swollen lymph nodes (painful, warm or red lump under your chin, on your neck, groin, armpit or behind your ear). These symptoms may also be associated with changes in your blood (e.g. white blood cell increase, as sometimes seen in allergic reactions) or liver function. These are some of the symptoms of potentially life-threatening conditions called Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systematic symptoms (DRESS).
  • Severe allergic reaction (may include severe difficulty in breathing, shock, swelling of the face, lips, tongue or other parts of the body, skin, rash, hayfever or may feel faint.
  • Signs of frequent infections such as fever, chills, sore throat or mouth ulcers.
  • Severe upper stomach pain, often with nausea and vomiting (particularly in patients with other risk factors such as gallstones, alcohol consumption and/or increased levels of certain fats within the blood). These are symptoms of pancreatitis.
  • Combination of fever, very marked drowsiness, muscle stiffness, marked increase in blood pressure or heartbeats and reduced consciousness (a disorder called ‘neuroleptic malignant syndrome’).
These are very serious side effects. Stop taking APX-QUETIAPINE XR if you develop these symptoms. You may need urgent medical attention or hospitalisation.

Occasionally, APX-QUETIAPINE XR may be associated with changes in your liver function or blood (e.g. blood fat levels such as cholesterol or triglycerides, blood sugar levels, blood pressure, thyroid hormone levels, white blood cells). These can only be found when your doctor does tests from time to time to check your progress.

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

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

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Reporting side effects

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

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

7. Product details

APX-QUETIAPINE XR is only available with a doctor's prescription.

What APX-QUETIAPINE XR contains

Active ingredient
(main ingredient)
  • Quetiapine (as fumarate)
Other ingredients
(inactive ingredients)
  • Lactose monohydrate
  • Microcrystalline cellulose
  • Magnesium oxide, light
  • Carrageenan
  • Povidone
  • Magnesium stearate
  • Macrogol 400
  • Titanium dioxide (E171)
  • Iron oxide red (50 mg tablet only)
  • Iron oxide yellow (50 mg tablet, 200 mg tablet and 300 mg tablet)
Potential allergensN/A

APX-QUETIAPINE XR contains sugars as lactose.

APX-QUETIAPINE XR does not contain gluten or sucrose.

Do not take APX-QUETIAPINE XR if you are allergic to any of these ingredients.

What APX-QUETIAPINE XR looks like

APX-QUETIAPINE XR 50 mg Tablet

Light pink to pink, capsule shaped, biconvex, coated tablet, plain on both sides. AUST R 199887.

APX-QUETIAPINE XR 150 mg Tablet

White to off-white, round, biconvex, coated tablet, plain on both sides. AUST R 199885.

APX-QUETIAPINE XR 200 mg Tablet

Yellow, capsule shaped, biconvex, coated tablet, plain on both sides. AUST R 199876.

APX-QUETIAPINE XR 300 mg Tablet

Pale yellow, capsule shaped, biconvex, coated tablet, plain on both sides. AUST R 199867.

APX-QUETIAPINE XR 400 mg Tablet

White to off-white, capsule shaped, biconvex, coated tablet, plain on both sides. AUST R 199869.

APX-QUETIAPINE XR is available in pack size of 60 tablets*.

*Not all strengths may be available.

Who distributes APX-QUETIAPINE XR

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in October 2024.

Published by MIMS December 2024

BRAND INFORMATION

Brand name

APX-Quetiapine XR

Active ingredient

Quetiapine

Schedule

S4

 

1 Name of Medicine

Quetiapine fumarate.

2 Qualitative and Quantitative Composition

APX-Quetiapine XR modified release tablets come in five strengths and contain quetiapine fumarate equivalent to 50 mg, 150 mg, 200 mg, 300 mg and 400 mg of quetiapine free base.

Excipients with known effect.

Contains sugars as lactose.
The tablets are gluten free.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APX-Quetiapine XR 50 mg.

Quetiapine (as fumarate) 50 mg modified release tablet; Light pink to pink, capsule shaped, biconvex, coated tablet, plain on both sides.

APX-Quetiapine XR 150 mg.

Quetiapine (as fumarate) 150 mg modified release tablet; White to off-white, round, biconvex, coated tablet, plain on both sides.

APX-Quetiapine XR 200 mg.

Quetiapine (as fumarate) 200 mg modified release tablet; Yellow, capsule shaped, biconvex, coated tablet, plain on both sides.

APX-Quetiapine XR 300 mg.

Quetiapine (as fumarate) 300 mg modified release tablet; Pale yellow, capsule shaped, biconvex, coated tablet, plain on both sides.

APX-Quetiapine XR 400 mg.

Quetiapine (as fumarate) 400 mg modified release tablet; White to off-white, capsule shaped, biconvex, coated tablet, plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

APX-Quetiapine XR is indicated for:

Bipolar disorder.

Maintenance treatment of bipolar I disorder, as monotherapy or in combination with lithium or sodium valproate, for the prevention of relapse/recurrence of manic, depressive or mixed episodes.
Treatment of depressive episodes associated with bipolar disorder (see Section 4.2 Dose and Method of Administration).
Treatment of acute mania associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate.
Efficacy of quetiapine modified release tablets in the treatment of bipolar disorder indications was established in part, on the basis of extrapolation from the established effectiveness of quetiapine immediate release tablets.

Schizophrenia.

Treatment of schizophrenia, prevention of relapse and maintenance of clinical improvement during continuation therapy.

Major depressive disorder.

Treatment of recurrent major depressive disorder (MDD) in patients who are intolerant of, or who have an inadequate response to alternative therapies.

Generalised anxiety disorder.

Treatment of generalised anxiety disorder (GAD).

4.2 Dose and Method of Administration

Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative equally effective but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory response should be sought. The need for continued treatment should be reassessed periodically.
APX-Quetiapine XR should be administered once daily, without food.
The tablets should be swallowed whole and not split, chewed or crushed.

Adults.

Bipolar disorder.

Maintenance treatment.

Patients who have responded to quetiapine modified release tablets for acute treatment of bipolar disorder should continue therapy at the same dose. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest possible dose needed to maintain remission.
For prevention of relapse/ recurrence of manic, depressive and mixed episodes in bipolar disorder, the usual effective dose is within the range of 300 to 800 mg/day (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The dose of APX-Quetiapine XR can be re-adjusted depending on the clinical response and tolerability of the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.
Bipolar depression. When treating depressive episodes in bipolar disorder, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist. APX-Quetiapine XR should be titrated as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). APX-Quetiapine XR can be titrated to 400 mg on Day 5 and up to 600 mg by Day 8.
Acute mania. APX-Quetiapine XR should be titrated as follows: 300 mg on Day 1, 600 mg on Day 2 and up to 800 mg after Day 2, alone or in combination with a mood stabiliser.
The dose should be adjusted within the usual effective dose range of 400 to 800 mg/day, depending on the clinical response and tolerability of the individual patient.
Schizophrenia. The daily dose at the start of therapy is 300 mg on Day 1, 600 mg on Day 2 and up to 800 mg after Day 2. The dose should be adjusted within the usual effective dose range of 400 to 800 mg/day, depending on the clinical response and tolerability of the individual patient. For maintenance therapy in schizophrenia no dosage adjustment is necessary. The safety of doses above 800 mg/day has not been evaluated.
Recurrent major depressive disorder. When treating recurrent MDD in patients who are intolerant of, or who have an inadequate response to alternative therapies, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist.
APX-Quetiapine XR should be administered once daily in the evening.
Initial dosing should begin at 50 mg on Day 1 and 2, increased to 150 mg on Day 3 and 4. The usual effective dose in MDD is 150 mg (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Further adjustments can be made upwards or downwards within the recommended dose range of 50 mg to 300 mg depending upon the clinical response and tolerability of the patient.
Patients who have not responded to quetiapine modified release tablets after 6 weeks treatment for MDD should have treatment re-evaluated (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
For maintenance therapy in MDD in patients who have responded to acute treatment, the effective dose during initial treatment should be continued. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest possible dose needed to maintain remission. The dose can be adjusted within the recommended dose range depending upon the clinical response and tolerability of the patient. Patients should be periodically reassessed to determine the need for maintenance treatment.
Generalised anxiety disorder. Initial dosing should begin at 50 mg on Day 1 and 2, increased to 150 mg on Day 3 and 4. Further adjustments can be made within the recommended dose range of 50 mg to 150 mg depending upon the clinical response and tolerability of the patient. Efficacy was demonstrated with quetiapine modified release tablets at doses ranging from 50 to 300 mg/day, however no additional benefit was seen with the 300 mg group compared to the 150 mg group (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Doses above 150 mg/day are not recommended.
For maintenance therapy in GAD the effective dose during initial treatment should be continued. The dose can be adjusted within the recommended dose range depending upon the clinical response and tolerability of the individual patient.

Switching from quetiapine immediate release tablets.

For more convenient dosing, patients who are currently being treated with divided doses of quetiapine immediate release tablets may be switched to quetiapine modified release tablets at the equivalent total daily dose taken once daily (see Section 5.1 Pharmacodynamic Properties, Clinical trials). For example - patients administered quetiapine immediate release 300 mg twice daily (total daily dose of 600 mg) would be switched to a dose of quetiapine modified release 600 mg once daily on the next calendar day. Individual dosage adjustments may be necessary.

Use in the elderly.

As with other antipsychotics, APX-Quetiapine XR should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly subjects when compared with younger patients. Elderly patients should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
In elderly patients with MDD, initial dosing should begin at 50 mg on Days 1-3, the dose can be increased to 100 mg on Day 4, 150 mg on Day 8 and then up to 300 mg depending on clinical response and tolerability.
In elderly patients with GAD, initial dosing should begin at 50 mg on Days 1-3, the dose can be increased to 100 mg on Day 4, 150 mg on Day 8. Further adjustments can be made within the recommended dose range of 50 mg to 150 mg depending on clinical response and tolerability.

Paediatric use (< 18 years of age).

The safety and efficacy of quetiapine modified release tablets have not been evaluated in patients under 18 years of age, however clinical trials have been conducted with quetiapine in children and adolescents 10 to 17 years of age with bipolar mania (as monotherapy), and 13 to 17 years of age with schizophrenia (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in renal impairment.

Dosage adjustment is not necessary.

Use in hepatic impairment.

Quetiapine is extensively metabolised by the liver. Therefore, APX-Quetiapine XR should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

4.3 Contraindications

APX-Quetiapine XR is contraindicated in patients who are hypersensitive to any component of this product.

4.4 Special Warnings and Precautions for Use

Concomitant cardiovascular illness.

Quetiapine should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or other conditions predisposing to hypotension (dehydration, hypovolaemia and treatment with antihypertensive medications).
Quetiapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies. Because of the risk of orthostatic hypotension with quetiapine, caution should be observed in cardiac patients.

Orthostatic hypotension.

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope has been commonly reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Orthostatic hypotension, dizziness and syncope may lead to falls (see Section 4.8 Adverse Effects (Undesirable Effects)). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

QT interval.

In clinical trials, quetiapine was not associated with a persistent increase in QTc intervals. However, in post marketing experience there were cases reported of QT prolongation with overdose (see Section 4.9 Overdose), in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients, including children and adolescents, with cardiovascular disease or family history of QT prolongation.
Particularly in the elderly, the use of quetiapine should be avoided in combination with neuroleptics and drugs that are known to prolong QTc including Class Ia antiarrhythmics (e.g. disopyramide) or Class III antiarrhythmics (e.g. amiodarone, sotalol), antipsychotic medications (e.g. ziprasidone, chlorpromazine, haloperidol), antibiotics (e.g. moxifloxacin, erythromycin), or any other class of medications known to prolong the QTc interval (e.g. citalopram, pentamidine, methadone). Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsades de pointes and/or sudden death, including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalaemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval (see Section 4.5).

Cardiomyopathy and myocarditis.

Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients with suspected cardiomyopathy or myocarditis, discontinuation of quetiapine should be considered.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life threatening adverse drug reactions that have been reported during quetiapine exposure. SCARs commonly present as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue quetiapine if severe cutaneous adverse reactions occur.

Seizures.

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). As with other antipsychotics, caution is recommended when treating patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Clinical worsening and suicide risk associated with psychiatric disorders.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. The risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. 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 MDD (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 taking a placebo. There was considerable variation in risk among the antidepressants but there was a tendency towards an increase for almost all antidepressants studied. This meta-analysis did not include trials involving quetiapine.
The risk of suicidality was most consistently observed in the MDD 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 MDD as well as for other indications, both psychiatric and non-psychiatric. 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.
Families and caregivers of patients being treated with antidepressants for MDD or for any other condition (psychiatric or non-psychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as 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. The possibility of a suicide attempt is inherent in schizophrenia; close supervision of high risk patients should accompany drug therapy.
Prescriptions for quetiapine should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risks factors for VTE should be identified before and during treatment with quetiapine and preventative measures undertaken.

Extrapyramidal symptoms (EPS).

In placebo controlled clinical trials of adult patients with schizophrenia, bipolar mania and maintenance treatment of bipolar disorder, the incidence of EPS was no different from that of placebo across the recommended therapeutic dose range. In short-term, placebo-controlled clinical trials of adult patients with bipolar depression, MDD and GAD, the incidence of EPS was higher in quetiapine treated patients than in placebo treated patients (see Section 4.8 Adverse Effects (Undesirable Effects) for rates of EPS observed in all indications and ages).

Class effect.

Akathisia has been reported in patients treated with quetiapine. The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

Tardive dyskinesia.

Quetiapine should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic medicines administered to the patient increase. However, tardive dyskinesia can develop, although much less commonly after relatively brief treatment periods at low doses.
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase (see Section 4.8 Adverse Effects (Undesirable Effects)). In such an event, quetiapine should be discontinued and appropriate medical treatment given.

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Neutropenia and agranulocytosis.

Severe neutropenia (< 0.5 x 109/L) without infection has been uncommonly reported in short term placebo controlled monotherapy clinical trials with quetiapine. There have been reports of agranulocytosis (severe neutropenia with infection) among all patients treated with quetiapine during clinical trials (rare) as well as post-marketing reports (including fatal cases). Most cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. There was no apparent dose relationship. Possible risk factors for neutropenia include pre-existing low white cell count (WBC), a history of drug induced neutropenia and concomitant use of other medicines that have been associated with neutropenia. There have been cases of agranulocytosis in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate. Quetiapine should be discontinued in patients with a neutrophil count < 1.0 x 109/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L) (see Section 4.8 Adverse Effects (Undesirable Effects)).

Withdrawal.

Acute withdrawal symptoms such as nausea, vomiting and insomnia have been described after abrupt cessation of antipsychotic medicines including quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable (see Section 4.8 Adverse Effects (Undesirable Effects)).

Dependence/tolerance.

There have been reports of quetiapine misuse, abuse, tolerance, and/or physical dependence. These cases include adult and adolescent patients using quetiapine alone or with other substances of abuse. Caution is needed when prescribing quetiapine to patients with a history of alcohol or drug abuse. Patients should be observed closely for signs of quetiapine misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior), particularly if they have a history of alcohol or drug abuse.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including quetiapine (see Section 4.8 Adverse Effects (Undesirable Effects)). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.
In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Lipids.

Increases in triglycerides and cholesterol and decreases in fasting HDL cholesterol have been observed in clinical trials with quetiapine (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitoring is recommended at baseline and periodically during treatment for all patients. Lipid changes should be managed as clinically appropriate.

Metabolic factors.

In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies. All patients taking antipsychotic medications such as quetiapine should be monitored for metabolic factors at the start of treatment and at intervals during treatment in accordance with current local guidelines. Changes in these parameters should be managed as clinically appropriate.

Pancreatitis.

Pancreatitis has been reported in clinical trials and during post-marketing experience. Among the post-marketing reports, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see Lipids section above; see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests), gallstones and alcohol consumption.

Use in hepatic impairment.

Hepatic failure, including fatalities, has been reported very rarely during the post-marketing period. There have been rare reports of hepatitis in clinical studies. Rare post-marketing reports of hepatitis (with or without jaundice), in patients with or without prior history, have been received. Very rare cases of hepatic steatosis, cholestatic or mixed liver injury have also been reported in the postmarketing period.
For patients who have known or suspected abnormal hepatic function prior to starting quetiapine, standard clinical assessment, including measurement of transaminase levels is recommended. Periodic clinical reassessment with transaminase levels is recommended for such patients, as well as for patients who develop any signs and symptoms suggestive of a new onset liver disorder during quetiapine therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Increased risk of mortality in elderly patients with dementia-related psychosis.

Elderly patients with dementia-related psychosis treated with atypical anti-psychotics are at an increased risk of death compared to placebo. A meta-analysis of seventeen placebo-controlled trials with dementia related behavioural disorders showed a risk of death in the drug-treated patients of approximately 1.6 to 1.7 times that seen in placebo-treated patients. The clinical trials included in the meta-analysis were undertaken with olanzapine, aripiprazole, risperidone and quetiapine. Over the course of these trials averaging about 10 weeks in duration, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Quetiapine is not approved for the treatment of elderly patients with dementia-related psychosis or behavioural disorders.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Quetiapine and other antipsychotic medicines should be used cautiously in patients at risk for aspiration pneumonia (e.g. elderly patients).

Constipation and intestinal obstruction.

Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine (see Section 4.8 Adverse Effects (Undesirable Effects)). This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and/or may not report symptoms of constipation.

Lactose monohydrate.

APX-Quetiapine XR tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Sleep apnoea.

In patients who have a history of or are at risk for sleep apnoea and are receiving concomitant central nervous system (CNS) depressants, quetiapine should be used with caution.

Anti-cholinergic (muscarinic) effects.

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to adverse drug reactions reflecting anti-cholinergic effects when quetiapine is used at recommended doses, when used concomitantly with other medications having anti-cholinergic effects, and in the setting of overdose. Quetiapine should be used with caution in patients receiving medications having anti-cholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma (see Section 5.1 Pharmacodynamic Properties, Mechanism of action; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

Use in the elderly.

See Section 4.2, Use in the elderly; Section 4.8; Section 5.1, Clinical trials; Section 5.2, Special populations, Use in elderly.

Paediatric use.

The safety and efficacy of quetiapine modified release tablets have not been established in patients under 18 years of age.
Paediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For paediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for paediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the potential benefits and risks associated with medication treatment. Medication treatment for both paediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.
Efficacy and safety of quetiapine have been demonstrated in adolescents aged from 13 years with schizophrenia and in children/adolescents aged from 10 years with bipolar I disorder experiencing acute mania in two clinical trials of 3 and 6 weeks duration, respectively. Safety data was provided for up to 26 weeks in a third open-label safety and tolerability trial [see Section 5.1 Pharmacodynamic Properties, Clinical trials, Children and adolescents (< 18 years of age)]. The safety and efficacy of quetiapine in children and adolescents have not been assessed beyond these time periods.
Although not all adverse reactions that have been identified in adult patients have been observed in clinical trials with quetiapine in children and adolescent patients, the same precautions that appear above for adults should be considered for children and adolescents. As seen in adults, increases in TSH, serum cholesterol, triglycerides, and weight have been observed (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests; Section 4.8 Adverse Effects (Undesirable Effects)).
The following events were reported more frequently in the short-term studies in children and adolescents than in studies in adults: EPS, increases in appetite and serum prolactin. Increased blood pressure has not been identified in the adult population but was seen in children and adolescents. Blood pressure should be monitored at the beginning of, and periodically during treatment in children and adolescents (see Section 4.8 Adverse Effects (Undesirable Effects)).
Long-term safety data including growth, maturation and behavioural development, beyond 26 weeks of treatment with quetiapine, are not available for children and adolescents (10 to 17 years of age).

Effects on laboratory tests.

Leukopenia and/or neutropenia.

As with other antipsychotics transient leukopenia and/or neutropenia have been observed in patients administered quetiapine. Possible risk factors for leukopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leukopenia and/or neutropenia. Occasionally, eosinophilia has been observed (see Section 4.8 Adverse Effects (Undesirable Effects)).

Serum transaminase.

Asymptomatic elevations in serum transaminase (ALT, AST) or γ-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Lipids.

Increases in triglyceride levels and total cholesterol (predominantly LDL cholesterol) have been observed during treatment with quetiapine. Decreases in fasting HDL cholesterol have also been observed (see Section 4.8 Adverse Effects (Undesirable Effects)).

Thyroid hormone levels.

Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. In short term placebo-controlled clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels were: total T4 - 3.4% for quetiapine versus 0.6% for placebo; free T4 - 0.7% for quetiapine versus 0.1% for placebo; total T3 - 0.54% for quetiapine versus 0.0% for placebo and free T3 - 0.2% for quetiapine versus 0.0% for placebo. The incidence of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. In short term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0.0% for both quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in T4 and TSH. As supported by the literature, these changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first 6 weeks of quetiapine treatment, with no further reduction during long-term treatment. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Methadone and tricyclic antidepressant enzyme immunoassays.

There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Antipsychotic and other centrally acting medicines.

Given the primary central nervous system effects of quetiapine, it should be used with caution in combination with other centrally acting medicines and alcohol.

Thioridazine.

Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.

Lorazepam.

The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times a day. Dosage adjustment is not required.

Levodopa and dopamine agonists.

As it exhibits in vitro dopamine antagonism, quetiapine may antagonise the effects of levodopa and dopamine agonists.
Potential interactions that have been excluded.

Antipsychotics.

The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antipsychotics risperidone (3 mg twice daily) or haloperidol (7.5 mg twice daily). The pharmacokinetics of lithium were not altered when co-administered with quetiapine (250 mg three times a day). The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered.

Imipramine and fluoxetine.

See CYP inhibitors below.

CYP inhibitors.

CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine (see Section 5.2 Pharmacokinetic Properties).

CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics and protease inhibitors).

During concomitant administration of medicines which are potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics and protease inhibitors), plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials (see Ketoconazole below). As a consequence of this lower doses of quetiapine should be used. Special consideration should be given in elderly or debilitated patients. The risk-benefit ratio needs to be considered on an individual basis.
It is also not recommended to take quetiapine together with grapefruit juice.

Ketoconazole.

In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co-administration of ketoconazole (200 mg once daily for 4 days) resulted in an increase in mean Cmax and AUC of quetiapine of 335% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean Tmax was unchanged.
Potential interactions that have been excluded.

Cimetidine.

The pharmacokinetics of quetiapine (150 mg three times a day) were not significantly altered (20% decrease in clearance) following co-administration with cimetidine (400 mg three times a day for 4 days) a known P450 enzyme inhibitor. Dosage adjustment for quetiapine is not required when it is given with cimetidine.

Imipramine and fluoxetine.

The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (75 mg twice daily; a known CYP2D6 inhibitor) or fluoxetine (60 mg once daily; a known CYP3A4 and CYP2D6 inhibitor).

Hepatic enzyme inducers (e.g. carbamazepine and phenytoin).

Quetiapine (administration of multiple daily doses up to 750 mg/day, on a three times a day dosing schedule) did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine or phenytoin may substantially decrease systemic exposure to quetiapine (see Carbamazepine and phenytoin). Depending on clinical response, increased doses of quetiapine may be required to maintain control of psychotic symptoms in patients co-administered quetiapine and hepatic enzyme inducers (e.g. carbamazepine, phenytoin, barbiturates, rifampicin, glucocorticoids). The safety of doses above 800 mg/day has not been established in the clinical trials. Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient.
The dose of quetiapine may need to be reduced if phenytoin, carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g. sodium valproate).

Carbamazepine and phenytoin.

In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, and hence, in each patient, consideration for a higher dose of quetiapine, depending on clinical response, should be considered.
Co-administration of quetiapine (250 mg three times a day) and phenytoin (100 mg three times a day; another microsomal enzyme inducer) also caused increases in clearance of quetiapine by 5-fold.

Cardiovascular medicines.

Caution should be used when quetiapine is used concomitantly with medicines known to cause electrolyte imbalance or to increase QTc interval (see Section 4.4 Special Warnings and Precautions for Use, QT interval).
Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain anti-hypertensive medicines.

Medications to manage attention deficit hyperactivity disorder (ADHD).

The data regarding safety and efficacy of quetiapine for the treatment of bipolar mania in children and adolescents receiving psychostimulants for co-morbid ADHD are limited. Therefore, concomitant use of ADHD medication and quetiapine is not recommended. If concomitant therapy is considered necessary, patients should be carefully monitored for the effect of the combination of treatments on the signs and symptoms of both ADHD and acute mania. Effects on blood pressure may be cumulative and blood pressure should be carefully monitored.

Anti-cholinergic (muscarinic) effects.

Caution should be exercised treating patients receiving other medications having anti-cholinergic (muscarinic) effects (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of dioestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
(Category C)1
The safety and efficacy of quetiapine during human pregnancy have not been established.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including quetiapine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.
These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required additional medical treatment or monitoring. Quetiapine should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
Teratogenic effects were not observed following administration of quetiapine at oral doses up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum recommended clinical dose based on AUC) and 100 mg/kg in rabbits (approximately twice the maximum clinical exposure based on BSA).
1 Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
 There have been published reports of quetiapine excretion into human breast milk, however the degree of excretion was not consistent. In a study in lactating rats the concentration of quetiapine and/or its metabolites was higher in milk than in plasma. Women who are breast-feeding should therefore be advised to avoid breast-feeding while taking quetiapine.

4.7 Effects on Ability to Drive and Use Machines

Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Patients likely to drive or operate other machines should therefore be cautioned appropriately.

4.8 Adverse Effects (Undesirable Effects)

Clinical study experience.

Schizophrenia (adults). The treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) of schizophrenia in at least 5% of patients treated with quetiapine modified release tablets in placebo-controlled trials are listed in Table 1 regardless of causality.
Bipolar disorder (adults). The treatment-emergent adverse events that occurred during acute therapy of bipolar disorder in at least 5% of patients treated with quetiapine modified release tablets in placebo-controlled trials are listed in Table 2 regardless of causality.
Major depressive disorder (adults). The treatment-emergent adverse events that occurred during short-term monotherapy of MDD in at least 5% of patients treated with quetiapine modified release tablets in placebo-controlled trials are listed in Table 3 regardless of causality.
The treatment-emergent adverse events that occurred during adjunct therapy (up to 6 weeks) of MDD in at least 5% of patients treated with quetiapine modified release tablets in placebo-controlled trials are listed in Table 4 regardless of causality.
The pattern of adverse events in the elderly population treated with quetiapine modified release tablets (short-term monotherapy) was similar to that seen in younger patients, with somnolence, headache, dry mouth and dizziness predominating.
The treatment-emergent adverse events that occurred during maintenance monotherapy of MDD in at least 5% of patients treated with quetiapine modified release tablets in placebo-controlled trials are listed in Table 5 regardless of causality.
Generalised anxiety disorder (adults). The safety results of five placebo-controlled clinical trials show that quetiapine modified release tablets is generally safe and well tolerated when used for treatment of GAD. The treatment-emergent adverse events that occurred in at least 5% of patients (regardless of causality) treated with quetiapine modified release tablets in non-elderly placebo-controlled trials are listed in Tables 6 (pooled non-elderly short term trials) and 7 (non-elderly maintenance trial). The pattern of adverse events in the elderly population treated with quetiapine modified release tablets (short-term monotherapy) was similar to that seen in younger patients, with somnolence, dry mouth, dizziness and headache predominating.
Other findings observed during clinical studies.

Somnolence.

Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine. Somnolence may lead to falls.

Weight gain (adults).

In schizophrenia trials the proportions of patients meeting a weight gain criterion of ≥ 7% of body weight from baseline were 10% for quetiapine modified release tablets compared to 5% for placebo. In quetiapine modified release tablet mania trials the proportions of patients meeting the same weight gain criterion were 5.1% compared to 0% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8.2% for quetiapine modified release tablets compared to 0.8% for placebo. In MDD monotherapy trials (8 weeks), the proportions of patients meeting the same weight gain criterion were 3.9% for quetiapine modified release tablets compared to 2.4% for placebo. In MDD adjunctive therapy trials (6 weeks), the proportions of patients meeting the same weight gain criterion were 5.1% for quetiapine modified release tablets compared to 1.7% for placebo.
In schizophrenia trials the proportions of patients meeting a weight gain criterion of ≥ 7% of body weight from baseline were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significantly greater incidence of weight gain for quetiapine (23%) compared to placebo (6%). In quetiapine mania monotherapy trials the proportions of patients meeting the same weight gain criterion were 21% compared to 7% for placebo and in mania adjunct therapy trials the proportion of patients meeting the same weight criterion were 13% for quetiapine compared to 4% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8% for quetiapine compared to 2% for placebo.

Withdrawal (discontinuation symptoms).

In acute placebo-controlled monotherapy clinical trials in adults which evaluated discontinuation symptoms, the aggregated incidence of discontinuation symptoms after abrupt cessation was 16.0% for quetiapine and 7.3% for placebo. The aggregated incidence of individual adverse events (e.g. insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability) did not exceed 6.7% in any treatment group and usually resolved after 1 week post-discontinuation (see Section 4.4 Special Warnings and Precautions for Use, Withdrawal).

Leukopenia/neutropenia.

Possible risk factors for leukopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leukopenia and/or neutropenia. Neutrophil count decreases have commonly been observed. In all short-term placebo controlled monotherapy clinical trials, among patients with a baseline neutrophil count ≥ 1.5 x 109/L, the incidence of at least one occurrence of neutrophil count < 1.5 x 109/L was 1.9% in patients treated with quetiapine, compared to 1.5% in placebo-treated patients. The incidence ≥ 0.5 - < 1.0 x 109/L (moderate neutropenia) was 0.2% (uncommon) in patients treated with quetiapine and 0.2% in placebo-treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment-emergent neutrophil count < 1.0 x 109/L, among patients with a baseline neutrophil count ≥ 1.5 x 109/L, the incidence of at least one occurrence of neutrophil count < 0.5 x 109/L (severe neutropenia) was 0.21% (uncommon) in patients treated with quetiapine and 0% in placebo treated patients (see Section 4.4 Special Warnings and Precautions for Use, Neutropenia and agranulocytosis).

Lipid changes (adults).

In schizophrenia trials, the proportions of patients with elevations to levels of cholesterol ≥ 6.2064 mmol/L and triglycerides ≥ 2.258 mmol/L were 9% and 18% for quetiapine modified release tablets treated patients respectively compared to 9% and 5% for placebo treated patients respectively. In bipolar mania trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 7% and 15% for quetiapine modified release tablets treated patients respectively, compared to 4% and 6% for placebo treated patients respectively. In bipolar depression trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 7% and 8% for quetiapine modified release tablets treated patients respectively, compared to 3% and 8% for placebo treated patients respectively. In MDD monotherapy trials (8 weeks), the proportion of patients with cholesterol and triglycerides elevations to these levels were 5% and 12% for quetiapine modified release tablets treated patients respectively, compared to 3% and 9% for placebo treated patients respectively. In MDD adjunctive therapy trials (6 weeks), the proportion of patients with cholesterol and triglycerides elevations to these levels were 17% and 16% for quetiapine modified release tablets treated patients respectively, compared to 6% and 5% for placebo treated patients respectively.
In schizophrenia trials, the proportions of patients with elevations to levels of cholesterol ≥ 6.2064 mmol/L and triglycerides ≥ 2.258 mmol/L were 16% and 23% for quetiapine treated patients respectively compared to 7% and 16% for placebo treated patients respectively. In bipolar depression trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 9% and 14% for quetiapine treated patients respectively, compared to 6% and 9% for placebo treated patients respectively.
In placebo controlled trials decreases in fasting HDL cholesterol have been observed. In short-term placebo-controlled clinical trials the incidence of patients who shifted from ≥ 1.025 mmol/L to < 1.025 mmol/L was slightly higher in the quetiapine group compared to placebo (9.8% and 8.1% respectively). In long-term trials the incidence of patients who shifted from ≥ 1.025 mmol/L to < 1.025 mmol/L was 18.3% in quetiapine and 10.9% in placebo.

Increases in blood glucose levels.

In placebo-controlled clinical trials in adults, the percentage of patients who had a shift to a high blood glucose level (fasting blood glucose ≥ 7 mmol/L or a non-fasting blood glucose ≥ 11.1 mmol/L on at least one occasion) was 5.1% in patients treated with quetiapine and 4.2% in placebo treated patients (see Section 4.4 Special Warnings and Precautions for Use, Hyperglycaemia and diabetes mellitus).

Decreases in haemoglobin levels.

Decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. In short-term placebo controlled trials, decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least one occasion in 8.3% of quetiapine patients compared to 6.2% of placebo patients.

Extrapyramidal symptoms (EPS) [adults].

The following clinical trials included treatment with quetiapine and quetiapine modified release tablets. In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregate incidence of EPS was similar to placebo (schizophrenia: quetiapine 7.8%, placebo 8.0%; bipolar mania quetiapine 11.2%, placebo 11.4%). In short-term, placebo-controlled clinical trials in bipolar depression the aggregate incidence of EPS from the combined data was 8.9% for quetiapine compared to 3.8% for placebo, though the incidence of the individual adverse events (e.g. akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. In short-term, placebo controlled monotherapy clinical trials in MDD the aggregated incidence of extrapyramidal symptoms was 5.4% for quetiapine modified release tablets and 3.2% for placebo. In a short-term placebo controlled monotherapy trial in elderly patients with MDD, the aggregated incidence of extrapyramidal symptoms was 9.0% for quetiapine modified release tablets and 2.3% for placebo. In two placebo-controlled short-term adjunct therapy clinical trials for the treatment of MDD utilising between 150 mg and 300 mg of quetiapine modified release tablets, the incidence of any adverse reactions potentially related to EPS was 5.1% quetiapine modified release tablets and 4.2% for the placebo group. In short-term, placebo-controlled monotherapy clinical trials in GAD, the aggregated incidence of EPS was 4.9% for quetiapine modified release tablets and 3.2% for placebo. In a short-term placebo controlled monotherapy trial in elderly patients with GAD, the aggregated incidence of EPS was 5.4% for quetiapine modified release tablets and 2.2% for placebo. In long-term studies of schizophrenia, bipolar disorder, MDD and GAD the aggregated exposure adjusted incidence of treatment emergent EPS was similar between quetiapine and placebo. Also see Section 4.4 Special Warnings and Precautions for Use, Extrapyramidal symptoms (EPS) and Table 8.

Irritability.

In acute placebo-controlled clinical trials in patients ≥ 18 years of age, the incidence of irritability was 2.3% for quetiapine and 1.7% for placebo.

Dysphagia.

An increase in the rate of dysphagia with quetiapine vs placebo was only observed in the adult clinical trials in bipolar depression.

Other adverse drug reactions.

In addition to the above, the following adverse drug reactions have also been observed in adult clinical trials (placebo-controlled trials, active-arm controlled trials and open-label uncontrolled trials) with quetiapine.
Children and adolescents. The same adverse drug reactions described for adults should be considered for children and adolescents. Table 9 summarises adverse drug reactions that occur in a higher frequency category in children and adolescents patients (10-17 years of age) than in the adult population, or adverse drug reactions that have not been identified in the adult population.

Weight gain (children and adolescents).

In one 6-week, placebo-controlled trial in adolescent patients (13-17 years of age) with schizophrenia, the mean increase in body weight, was 2.0 kg in the quetiapine group and -0.4 kg in the placebo group. 21% of quetiapine-treated patients and 7% of placebo-treated patients gained ≥ 7% of their body weight.
In one 3-week, placebo-controlled trial in children and adolescent patients (10-17 years of age) with bipolar mania, the mean increase in body weight was 1.7 kg in the quetiapine group and 0.4 kg in the placebo group. 12% of quetiapine-treated patients and 0% of placebo-treated patients gained ≥ 7% of their body weight.
In the open-label study that enrolled patients from the above two trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine. After 26 weeks of treatment, the mean increases in body weight and BMI were 4.4 kg and 1.1 kg/m2 respectively. 45% of the patients gained ≥ 7% of their body weight (not adjusted for normal growth). 18.3% of the patients had a clinically significant change in BMI (adjusted for growth).
In one 8-week, placebo-controlled trial in children and adolescent patients (10-17 years of age) with bipolar depression, in which efficacy was not established, the mean increase in body weight was 1.4 kg in the quetiapine modified release group and 0.6 kg in the placebo group. For children and adolescents who completed the 8 weeks of quetiapine therapy 13.7% of quetiapine XR-treated patients and 6.8% of placebo-treated patients gained ≥ 7% of their body weight.

Extrapyramidal symptoms (EPS) [children and adolescents].

In a short-term placebo-controlled monotherapy trial in adolescent patients (13-17 years of age) with schizophrenia, the aggregated incidence of EPS was 12.9% for quetiapine and 5.3% for placebo, though the incidence of the individual adverse events (e.g. akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) was generally low and did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar mania, the aggregated incidence of EPS was 3.6% for quetiapine and 1.1% for placebo.
In a short-term placebo-controlled monotherapy trial in children and adolescent patients (10-17 years of age) with bipolar depression in which efficacy was not established, the aggregated incidence of extrapyramidal symptoms was 1.1% for quetiapine extended release tablet and 0.0% for placebo.
Suicide/suicidal thoughts or clinical worsening (all ages). In short-term placebo-controlled clinical trials across all indications and ages, the incidence of suicide-related events was 0.8% for both quetiapine (76/9327) and placebo (37/4845).
In these trials of patients with schizophrenia the incidence of suicide related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18-24 years of age, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥ 25 years of age, and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients < 18 years of age. There has been one trial conducted in patients 10-17 years of age in which efficacy was not established. The incidence of suicide related events was 1.0% (1/92) for quetiapine and 0% (0/100) for placebo. In this study there were two additional events in two patients that occurred during an extended post-treatment follow-up phase of the study; one of these patients was on quetiapine at the time of the event (see Section 4.4, Clinical worsening and suicide risk associated with psychiatric disorders).
In these trials of patients with bipolar mania the incidence of suicide related events was 0% for both quetiapine (0/60) and placebo (0/58) in patients 18-24 years of age, 1.2% for both quetiapine (6/496) and placebo (6/503) in patients ≥ 25 years of age, and 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients < 18 years of age.
In these trials of patients with bipolar depression the incidence of suicide related events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients 18-24 and 1.8% for both quetiapine (19/1616) and placebo (11/622) in patients ≥ 25 years of age. There have been no trials conducted in patients < 18 years of age with bipolar depression.
In these trials of patients with MDD the incidence of suicide related events was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo in patients 18-24 and 0.6% (11/1798) for quetiapine and 0.7% for placebo (7/1054) in patients ≥ 25 years of age. There have been no trials conducted in patients < 18 years of age with MDD.
In these trials of patients with GAD the incidence of suicide related events was 0.5% for quetiapine (1/194) and 0.9% for placebo (1/109) in patients 18-24 years of age and 0.4% for quetiapine (7/1810) and 0.1% for placebo (1/983) in patients ≥ 25 years of age.
Cataracts/lens opacities. In a clinical trial to evaluate the cataractogenic potential of quetiapine (200 - 800 mg/day) versus risperidone (2 - 8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in quetiapine compared with risperidone for patients with at least 21 months of exposure.

Post-marketing experience.

In addition to the above, the following post-marketing adverse drug reactions have been observed with quetiapine. See Table 10.
Very rare cases of cataract have been reported in the post-marketing data, but no causal link between these reports and quetiapine has been established.
There have been rare post-marketing reports of pancreatitis. Among the post-marketing reports, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see Section 4.4 Special Warnings and Precautions for Use, Lipids and Effects on laboratory tests), gallstones and alcohol consumption.
Very rare cases of exacerbation of pre-existing diabetes have been reported.
Hepatic failure, including fatalities, has been reported very rarely during the post-marketing period. Rare post-marketing reports of hepatitis (with or without jaundice), in patients with or without prior history, have been received. Very rare cases of hepatic steatosis, cholestatic or mixed liver injury have also been reported in the post-marketing period (see Section 4.4 Special Warnings and Precautions for Use).
Other adverse events reported since market introduction, which were temporally related to quetiapine therapy, but not necessarily causally related, include: cardiomyopathy, myocarditis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatraemia, cerebrovascular accident and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN).

Reporting suspected adverse effects.

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

4.9 Overdose

In clinical trials, experience with quetiapine in overdosage is limited. Survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In post-marketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma.
In post-marketing experience there were cases reported of QT prolongation with overdose.
Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose (see Section 4.4 Special Warnings and Precautions for Use, Concomitant cardiovascular illness).
In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e. drowsiness and sedation, tachycardia, hypotension and anticholinergic effects.

Management of overdose.

There is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. Whilst the prevention of absorption in overdose has not been investigated, administration of activated charcoal together with a laxative should be considered.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (adrenaline and dopamine should be avoided, since β-stimulation may worsen hypotension in the setting of quetiapine-induced α-blockade).
Close medical supervision and monitoring should be continued until the patient recovers.
Quetiapine overdose may lead to gastric bezoar formation and an appropriate diagnostic imaging is recommended to further guide patient management. Routine gastric lavage may not be effective in the removal of the bezoar due to the gum like sticky consistency of the mass.
Endoscopic pharmacobezoar removal has been performed successfully in many cases.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Quetiapine is an atypical antipsychotic agent. Quetiapine and the human plasma metabolite, norquetiapine, interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1 and D2 receptors; this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2 receptors is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effects (EPS) liability of quetiapine compared to typical antipsychotics. Quetiapine has no affinity for the norepinephrine transporter (NET) and low affinity for the serotonin 5HT1A receptor, whereas norquetiapine has high affinity for both. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to quetiapine extended release tablet's therapeutic efficacy as an antidepressant. Quetiapine and norquetiapine have high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may explain anti-cholinergic (muscarinic) effects. The norquetiapine metabolite 7-hydroxy norquetiapine also has affinity for histaminergic H1 and 5HT2B and 2C receptors at clinically relevant concentrations.

Pharmacodynamics.

Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2 receptor blockade. The extent to which the metabolites norquetiapine and 7-hydroxy norquetiapine contribute to the pharmacological activity of quetiapine in humans is uncertain.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2 receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration.

Clinical trials.

Clinical pharmacology studies in patients with schizophrenia, schizo-affective disorder and bipolar disorder were conducted to assess the tolerability of a 300 mg starting dose. Key safety assessments included vital sign measurements, adverse events, ECG, clinical laboratory tests and physical examinations. A starting dose of 300 mg/day for quetiapine modified release tablets was well tolerated in terms of the key assessments and the safety profile was similar to that seen with the recommended starting dose for quetiapine immediate release tablets. The recommended quetiapine modified release tablet starting dose was further supported by the clinical efficacy studies in schizophrenia.
Bipolar disorder (adults). Efficacy of quetiapine modified release tablets in the treatment of bipolar disorder indications was established in part, on the basis of extrapolation from the established effectiveness of quetiapine immediate release tablets.

Maintenance treatment in combination with lithium or sodium valproate.

The efficacy of quetiapine immediate release tablets in the maintenance treatment of bipolar disorder was established in two similarly designed placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder. These trials included patients whose most recent mood episode was mania (approximately 36%), depression (approximately 30%) or mixed state (approximately 34%); and patients with or without psychotic features. Patients with rapid cycling (approximately 37%) were also included.
Both trials consisted of an open label phase followed by a randomised treatment phase. In the open label phase (n=3414), patients were required to be stabilised on quetiapine immediate release tablets (400-800 mg/day) in combination with a mood stabiliser (lithium or valproate) for at least 12 weeks prior to randomisation. In the randomisation phase, patients who were symptomatically stable for at least 12 weeks (n=1326) either continued treatment (at the same dose, then adjusted as clinically indicated) in combination with a mood stabiliser or received placebo in combination with a mood stabiliser for up to 104 weeks. Approximately 40% of patients received lithium and 60% received valproate.
The primary endpoint was time to recurrence of any mood event (mania, depression or mixed state). A mood event was defined as medication initiation, hospitalisation, Young Mania Rating Scale (YMRS) score ≥ 20 or Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 on two consecutive assessments or study discontinuation due to a mood event. Quetiapine immediate release tablets were superior to placebo in increasing the time to recurrence of a mood event in both studies. Patients treated with quetiapine had a 70% less risk of experiencing a recurrence of a mood event (see Figure 1 and Table 11) compared to patients on placebo. Patients treated with quetiapine had a lower risk of experiencing a mood event prior to week 28 and week 52 compared to patients on placebo (see Table 12).
Maintenance treatment with quetiapine immediate release tablets was superior to placebo in increasing the time to recurrence of a depressive or a manic event (see Table 11). Patients treated with quetiapine also had a lower risk of experiencing a depressive or a manic event prior to week 28 and week 52 compared to patients on placebo (see Table 12).
Efficacy was demonstrated to be independent of the nature of the most recent episode (manic, mixed or depressive), the mood stabiliser (lithium or valproate), rapid cycling course, gender, age or ethnicity.

Maintenance treatment as monotherapy.

The efficacy of quetiapine using immediate release tablets in the maintenance treatment of bipolar disorder as monotherapy was established in a placebo-controlled trial in 1172 patients who met DSM-IV criteria for bipolar I disorder. Approximately 50% of the 2438 patients initially treated with quetiapine for their index episode achieved stabilisation and were eligible for enrolment in the placebo-controlled randomised phase. The most recent mood episode of patients included was mania (approximately 54%), depression (approximately 28%) or mixed state (approximately 18%). Patients with rapid cycling were also included.
The trial consisted of an open label phase followed by a randomised treatment phase. In the open label phase, patients were required to be stabilised on quetiapine immediate release tablets (300-800 mg/day) for at least 4 weeks prior to randomisation to quetiapine, placebo or lithium. In the randomisation phase, the dose of quetiapine and lithium could be adjusted as clinically indicated. Randomised treatment was intended for up to 104 weeks however the study was stopped early following a positive interim analysis.
The primary endpoint was time to relapse/recurrence of any mood event (mania, depression or mixed state). A mood event was defined as medication initiation, hospitalisation, YMRS score ≥ 20 or MADRS score ≥ 20 on two consecutive assessments or study discontinuation due to a mood event. Quetiapine was superior to placebo in increasing the time to relapse/recurrence of a mood event. Patients treated with quetiapine had a 71% less risk of experiencing a relapse/recurrence of a mood event (see Figure 2 and Table 13) compared to patients on placebo. Quetiapine was also superior to placebo in increasing time to relapse/recurrence of manic events and depressive events (see Table 13). Efficacy was demonstrated to be independent of the nature of the most recent episode (manic, mixed or depressive), rapid cycling course, gender, age or ethnicity.
Bipolar depression. The safety and efficacy of quetiapine modified release tablets for treatment of bipolar depression was demonstrated in an 8 week placebo controlled study (n=270) at a dose of 300 mg/day. Patients met the DSM-IV criteria for bipolar I or II disorder, with or without rapid cycling courses.
Anti-depressant activity was assessed by the change from baseline for MADRS total score (primary endpoint), at 8 weeks (day 57). The anti-depressant effect of quetiapine modified release tablets was superior compared to placebo as early as day 8 (week 1) and was maintained through to week 8 (see Figure 3). The proportion of patients showing ≥ 50% reduction in MADRS total score (responders) was higher for quetiapine modified release tablets compared to placebo by week 2 and continued to end-of-treatment (p < 0.001). The proportion of patients showing a MADRS total score ≤ 12 (remission) was higher for quetiapine modified release tablets compared to placebo group by Week 1 and continued to end-of-treatment (p < 0.05). The Clinical Global Impression-Bipolar-Severity of Illness (CGI-BP-S) and CGI-BP-Improvement (CGI-BP-I), measures of the clinicians impression of the severity of the patients overall illness and improvement from baseline, were also assessed with quetiapine modified release tablets superior to placebo at week 8. Efficacy was demonstrated to be independent of bipolar I or II diagnosis, rapid cycling course, gender, age or ethnicity.
The safety and efficacy of quetiapine 300 mg and 600 mg once daily for the treatment of bipolar depression was established in 4 similarly designed placebo controlled clinical trials (n=2461) over 8 weeks with 2 of these studies assessing maintenance of effect for up to 52 weeks. In all 4 studies quetiapine doses of 300 mg/day and 600 mg/day demonstrated clinical and statistical superiority to placebo in the treatment of depression at 8 weeks. The magnitude of the anti-depressant effect was also supported by the secondary outcome variables. Alleviation of anxiety symptoms by quetiapine in all 4 studies was confirmed by a statistically superior Hamilton Rating Scale for Anxiety (HAM-A) total score change from baseline compared to placebo. Efficacy was demonstrated to be independent of bipolar I or II diagnosis, rapid cycling course, gender, age or ethnicity.
Maintenance of the quetiapine effect in bipolar depression was demonstrated during the continuation phase with patients treated with quetiapine experiencing a significantly longer time to recurrence of any mood event (depression, mixed state or mania; defined as a MADRS score ≥ 20 or a YMRS score ≥ 16; initiation of an antipsychotic, anti-depressant, mood stabilizer etc; hospitalization for symptoms of depression and/or mania/hypomania; discontinuation due to symptoms of depression and/or mania/hypomania), compared to placebo as shown in Figure 4. Quetiapine patients had a lower risk of experiencing a mood event at weeks 26 and 52 compared to patients on placebo. Patients on quetiapine had a 49% less risk of experiencing a mood event compared with patients treated with placebo [HR 0.51 (95% CI 0.38, 0.69; p < 0.001)]. The risk of a mood event for quetiapine versus placebo was reduced by 41% for the 300 mg dose and by 55% for the 600 mg dose.
Quetiapine patients also had a lower risk of experiencing a depressive event at weeks 26 and 52 compared to patients on placebo. The analysis of time to a depressive event mirrored the overall mood event results with patients on quetiapine having a 57% less risk of experiencing a depressive event compared with patients treated with placebo (HR 0.43, 95% CI 0.30, 0.62, p < 0.001). The risk of a depressive event for quetiapine versus placebo was reduced by 52% for the 300 mg dose and by 61% for the 600 mg dose.
No increased risk for a manic or hypomanic event was observed. Quetiapine treatment of a depressive episode was also not associated with a switch to mania or hypomania.
Time to all cause discontinuation, including the composite mood event, was also examined with the Kaplan-Meier estimate of time to 50% all cause discontinuation being 311 days for quetiapine treatment, compared to 156 days for placebo treatment.
The maintenance of effect observed in patients treated with quetiapine was demonstrated to be independent of bipolar diagnosis (i.e. I or II), gender or age.
There was no increased risk of suicidal behaviour or ideation associated with quetiapine treatment for bipolar depression in either the acute or continuation phase.
Acute mania. The safety and efficacy of quetiapine modified release tablets for treatment of bipolar mania was demonstrated in a 3 week placebo controlled study (n=308) at doses of 400-800 mg/day. Patients met the DSM-IV criteria for bipolar I disorder, with the most recent episode being either manic or mixed. Patients with or without rapid cycling courses were also included.
The primary outcome variable for this trial was change from baseline to day 22 in the YMRS total score. Quetiapine modified release tablets were demonstrated to be superior to placebo in reducing the level of manic symptoms as early as day 4 and for up to 3 weeks (day 22) of treatment (see Figure 5).
The proportion of patients showing ≥ 50% reduction in YMRS total score (responders) was statistically significantly higher for the quetiapine modified release tablets group compared to the placebo group at day 8 (week 1) and at the end of treatment. The proportion of patients showing a YMRS total score ≤ 12 (remission) was statistically significantly higher for the quetiapine modified release tablets group compared to the placebo group by day 8 (week 1) and at the end of treatment. The changes in CGI-BP-S and CGI-BP-I overall illness scores were statistically significant in favour of quetiapine modified release tablets at day 4 and at end of treatment.
The efficacy of quetiapine in the treatment of manic episodes was further established in three short-term placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder. The primary outcome variable for these trials was change from baseline to day 21 in the YMRS total score. In two 12-week trials (n=300, n=299) comparing quetiapine to placebo, quetiapine was superior to placebo in reducing manic symptoms. The majority of patients who responded at day 21 maintained responses to day 84. In a 3-week placebo controlled trial (n=170) comparing quetiapine to placebo in patients on a mood stabiliser (lithium or valproate), quetiapine was superior to placebo in reducing manic symptoms.
Schizophrenia (adults). The efficacy of quetiapine modified release tablets in the treatment of schizophrenia was demonstrated in the following clinical studies:
a 6-week placebo-controlled trial in patients who met DSM-IV criteria for schizophrenia;
an active-controlled quetiapine immediate release-to-quetiapine modified release switching study in clinically stable outpatients with schizophrenia;
a placebo-controlled relapse prevention study conducted in patients with stabilised schizophrenia.

Placebo-controlled efficacy and safety data.

The primary outcome variable in the placebo-controlled trial was change from baseline to final assessment in the Positive and Negative Symptom Scale (PANSS) total score. Quetiapine modified release tablets (once daily) was administered as 300 mg on (Day 1) and increased up to the required dose by Day 2 or 3. Quetiapine modified release tablets 400 mg/day, 600 mg/day and 800 mg/day were associated with statistically significant improvements in psychotic symptoms compared to placebo. The effect size of the 600 mg and 800 mg doses was greater than that of the 400 mg dose.
In three, 6-week clinical studies in patients with schizophrenia (N=951) the incidence of treatment emergent suicidal ideation or suicide attempt, as measured by the Columbia Analysis of Suicidal Behaviour, was low in quetiapine modified release treated patients (0.6%) and similar to placebo (0.9%).

Switching from quetiapine immediate release to quetiapine modified release.

In the 6-week active-controlled switching study the primary outcome variable was the proportion of patients who showed lack of efficacy, i.e. who discontinued study treatment due to lack of efficacy or whose PANSS total score increased 20% or more from randomization to any visit. In patients stabilised on quetiapine immediate release 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of quetiapine modified release given once daily. Switching patients from quetiapine immediate release to quetiapine modified release at equivalent total doses was safe and well tolerated in terms of adverse events, vital signs, ECG and laboratory parameters. The safety profile of quetiapine modified release was comparable to quetiapine immediate release.

Relapse prevention.

A long-term placebo-controlled relapse prevention study was conducted in patients with stabilised schizophrenia who had been maintained on quetiapine modified release tablets for 16 weeks. Randomised treatment was planned for 12 months (or until relapse), however the maximum duration was approximately 9 months due to early termination as a result of a positive interim analysis. This study concluded that quetiapine modified release tablets was significantly more effective than placebo in preventing relapse (hospitalisation due to worsening of schizophrenia, and increase in PANSS total score of 30% from baseline, score 6 or 7 on CGI-I scale or need for other antipsychotic medication to treat psychosis) with 11 (11.7%) with relapse in the quetiapine modified release tablets group and 50 (48.5%) in the placebo group (p < 0.0001). The estimated risks of relapse after 6 months treatments was 14.3% for the quetiapine modified release tablets treatment group compared to 68.2% for placebo (p < 0.0001). The mean dose of quetiapine modified release tablets was 669 mg. There were no additional safety findings associated with treatment with quetiapine modified release tablets for up to 12 months. In particular, reports of adverse events related to EPS and weight gain did not increase with longer-term treatment with quetiapine modified release tablets.
Major depressive disorder (adults). The efficacy of quetiapine modified release tablets in the treatment of major depressive disorder (MDD) was established in 4 placebo-controlled monotherapy clinical trials (including 1 study in elderly patients), 2 clinical trials as combination therapy with an antidepressant, and 1 monotherapy, placebo-controlled maintenance trial. All trials included patients who met DSM-IV criteria for MDD, single or recurrent episodes, with and without psychotic features. The majority of patients in all studies were diagnosed as having recurrent MDD.

Acute treatment of major depressive disorder.

The efficacy of quetiapine modified release tablets as monotherapy in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed dose trials, and one 8-week placebo-controlled, modified fixed dose trial [n=1445]. The majority of patients were dosed once daily with either 150 mg or 300 mg with one trial (Study 1) assessing a 50 mg dose. The primary endpoint in these trials was the change from baseline to week 6 or 8 in the MADRS total score.
Quetiapine modified release tablets at a dose of 50 mg, 150 mg, and 300 mg once daily was superior to placebo in reduction of depressive symptoms as measured by change in MADRS total score, with significant improvement observed within the first week and continuing throughout the study. Duloxetine included as an active comparator in one study (Study 2) did not demonstrate statistically significant superiority compared to placebo until day 15. See Table 14.
The efficacy of quetiapine modified release tablets in the treatment of MDD was further demonstrated in two 6-week placebo-controlled, fixed dose trials (n=936) as combination therapy with an antidepressant in patients who had previously shown an inadequate response to at least one antidepressant. Quetiapine modified release 300 mg once daily in combination with ongoing antidepressant therapy was superior to antidepressant therapy alone in reduction of MADRS total score in both trials while quetiapine modified release 150 mg was superior to antidepressant therapy alone in one study only. Improvement in depressive symptoms was seen at week 1 through end of study (week 6).

Use in elderly patients.

The safety and efficacy of quetiapine modified release tablets was evaluated in an 11-week, double blind, randomised, placebo-controlled study in non-demented elderly patients (aged 66-89 years) with MDD. The mean dose of quetiapine modified release was 160 mg/day. Quetiapine modified release tablets flexibly dosed in the range of 50 to 300 mg per day demonstrated superiority over placebo in reducing depressive symptoms as measured by improvement in MADRS total score, with significant improvement observed within the first week and continuing throughout the study (week 9).

Maintenance treatment in major depressive disorder.

The efficacy of quetiapine modified release tablets in the prevention of relapse in MDD was established in a long-term clinical trial consisting of an open label phase followed by a double-blind randomised treatment phase. Patients stabilised in the open label phase (n=771) were randomised to placebo or to continue on quetiapine modified release for up to 52 weeks. At the end of the open-label phase 21%, 46% and 32% of patients were prescribed quetiapine modified release 50 mg, 150 mg and 300 mg respectively. The dose of quetiapine modified release could be adjusted during the randomisation period based on clinical need with 91.7% of patients remaining on the same dose throughout the randomisation period. The primary endpoint was time to occurrence of a depressive event. Patients on quetiapine modified release tablets (mean dose 177 mg/day) experienced a statistically significant longer time to relapse than did patients on placebo with patients on quetiapine modified release having a 66% less risk of experiencing a depressive event compared to patients on placebo (HR [95% CI]=0.34[0.25,0.47], p < 0.0001). See Figure 6. Based on analysis of the dose at randomisation, the risk of experiencing a depressive event decreased with increasing dose (hazard ratios: 50 mg, 0.46 [95% CI 0.23, 0.91], p=0.025; 150 mg, 0.36 [95% CI 0.22, 0.57], p < 0.001; 300 mg, 0.26 [CI 0.15, 0.45], p < 0.001).
Generalised anxiety disorder (adults). The efficacy of quetiapine modified release tablets in the monotherapy treatment of generalised anxiety disorder (GAD) was established in 4 placebo-controlled clinical trials (including 1 study in elderly patients) and 1 placebo-controlled maintenance trial. All trials included patients who met DSM-IV criteria for GAD.

Acute treatment of generalised anxiety disorder.

The efficacy of once daily quetiapine modified release tablet monotherapy in the treatment of GAD was demonstrated in three 10-week placebo-controlled, fixed dose trials (n=2588 MITT population). Three quetiapine modified release tablet doses were assessed - 50, 150 and 300 mg/day. Two trials also included an active comparator (escitalopram 10 mg/day in one, and paroxetine 20 mg/day in another). Patients had a mean HAM-A total score of 26 at enrolment.
Quetiapine modified release tablets at a dose of 50, 150 and 300 mg once daily was superior to placebo in reduction of anxiety symptoms as measured by HAM-A total score. Efficacy was demonstrated as early as day 4 and the treatment effect continued throughout the trial (8 weeks - primary endpoint; see Table 15). No additional benefit was provided by the 300 mg/day dose compared with the 150 mg/day dose. Both active comparators (escitalopram and paroxetine) were statistically superior to placebo at week 8, however neither demonstrated superiority to placebo at day 4. The magnitude of the anti-anxiety effect of quetiapine modified release tablets was supported by various secondary outcome variables. Statistically significant improvements were also seen with quetiapine modified release tablets in depressive symptoms (as measured by MADRS total score; mean total score at enrolment was ≤ 16) and sleep symptoms (as measured with the Pittsburgh Sleep Quality Index [PSQI] global score).

Use in elderly patients.

The safety and efficacy of quetiapine modified release tablets was evaluated in an 11-week, double blind, randomised, placebo-controlled study in non-demented elderly patients (aged 66-86 years) with GAD. The proportion of randomised patients over 75 years of age was 13%. Quetiapine modified release tablets demonstrated superiority over placebo in reducing anxiety symptoms as measured by improvement in HAM-A total score, with significant improvement observed within the first week and continuing throughout the study (week 9 - primary endpoint; see Table 15). All assessed secondary variables (including health-related quality of life and sleep quality) also demonstrated superiority of quetiapine modified release tablets to placebo in elderly patients.

Maintenance treatment of anti-anxiety effects.

The efficacy of quetiapine modified release 50 mg, 150 mg, or 300 mg once daily in the maintenance treatment of the anti-anxiety effect was established in a long-term clinical trial consisting of an open label phase (4 to 8 week run-in phase and 12 to 18 week stabilisation phase) followed by a double-blind randomised treatment phase. Patients meeting randomisation criteria (i.e. patients who remained stable for at least 12 weeks; n=433) were randomised to placebo or to continue on quetiapine modified release tablets (at the same dose as the open label phase) for up to 52 weeks. Due to the efficacy of quetiapine modified release tablets, the mean randomised time of exposure was 56% greater in the quetiapine modified release tablet arm compared to placebo (106.9 vs 68.6 days), with 64 quetiapine modified release tablet patients on treatment for more than 28 weeks. The dose of quetiapine modified release tablets could be adjusted based on clinical need during both the open label and the randomisation phases. At the end of the open-label period 49% of patients received 150 mg/day, with 26% and 25% receiving 50 mg/day and 300 mg/day, respectively. 93% of patients remained on the same dose throughout the randomisation period.
Patients on quetiapine modified release tablets (mean dose 163 mg/day) experienced a statistically significant longer time to occurrence of an anxiety event (primary endpoint) than did patients on placebo, with patients on quetiapine modified release tablets having an 81% less risk of experiencing an anxiety event compared to patients on placebo (Hazard ratio [HR] 0.19; 95% CI 0.12, 0.31; p < 0.0001). See Figure 7. The efficacy of quetiapine modified release tablets in the maintenance treatment of patients with GAD was further supported by the secondary variables, including maintaining reduction of anxiety and depressive symptoms, and improved level of functioning, health related quality of life and sleep quality.
Children and adolescents (< 18 years of age). The safety and efficacy of quetiapine modified release tablets have not been evaluated in patients under 18 years of age, however three clinical trials have been conducted with quetiapine modified release in children and adolescents; two short-term randomised placebo-controlled trials - a 6 week trial in schizophrenia (patients aged 13-17 years) and a 3 week trial in bipolar mania (patients aged 10 to 17 years) - and an open-label 26 week safety and tolerability trial (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical study experience) which also assessed efficacy measures. The safety and efficacy of quetiapine modified release tablets in children and adolescents have not been assessed beyond these time periods.

5.2 Pharmacokinetic Properties

Absorption.

Quetiapine is well absorbed and extensively metabolised by the liver following oral administration. Steady state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosage range.
Peak plasma concentrations of quetiapine are achieved approximately 6 hours after administration (Tmax) of quetiapine modified release tablets. Dose-proportional pharmacokinetics are displayed for doses of quetiapine modified release tablets of up to 800 mg administered once daily. The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) for Quetiapine modified release tablets administered once daily are comparable to those achieved for the same total daily dose of immediate-release quetiapine fumarate administered twice daily. When quetiapine modified release tablets administered once daily are compared to the same total daily dose of quetiapine immediate release administered once daily, the AUC is comparable and the Cmax is 59% lower for the modified release tablets. The AUC and Cmax for the metabolite norquetiapine are 18% and 37% lower than for the immediately release tablets, respectively.
In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the Cmax (44%-52%) and AUC (20%-22%) for the modified release tablets. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. It is recommended that quetiapine modified release tablets are taken once daily without food.
There are no clinically relevant differences in the observed apparent oral clearance (CL/F) and exposure of quetiapine between subjects with schizophrenia and bipolar disorder.

Distribution.

Quetiapine is approximately 83% bound to plasma proteins.

Metabolism.

Quetiapine is extensively metabolised by the liver. In vitro investigations established that CYP3A4 is likely to be the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4. CYP2D6 and CYP2C9 are also involved in quetiapine metabolism.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak to modest inhibitors of human cytochrome P450 3A4, 2C19, 2D6, 1A2 and 2C9 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other medicines will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.

Excretion.

The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours respectively.
Following administration of radiolabelled quetiapine, less than 5% of unchanged drug related material is accounted for in the urine or faeces. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is < 5% excreted in the urine.

Special populations.

Gender.

The kinetics of quetiapine do not differ between men and women.

Use in renal impairment.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2), but the individual clearance values are within the range for normal subjects.

Use in hepatic impairment.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. Since quetiapine is extensively metabolised by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients (see Section 4.2 Dose and Method of Administration).

Use in elderly.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen. Quetiapine showed no evidence of genotoxicity in a series of assays for gene mutation (bacteria and Chinese hamster ovary cells) and chromosomal damage (human lymphocytes and the in vivo micronucleus test).

Carcinogenicity.

In the rat study (20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia. The incidence of carcinoma of the adrenal cortex was increased in male rats at the highest dose.
In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain lactose monohydrate, microcrystalline cellulose, light magnesium oxide, carrageenan, povidone, magnesium stearate, titanium dioxide, macrogol 400, iron oxide yellow (50 mg, 200 mg and 300 mg tablets only) and iron oxide red (50 mg tablets only).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

50 mg/ 150 mg/ 200 mg/ 300 mg/ 400 mg.

Blister packs (Alu/Alu or PVC/PVDC/Alu blister packs of 60 tablets).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Chemical name: Bis[2-(2-[4-(dibenzo[b,f][1,4]-thiazepin-11-yl) piperazin-1-yl] ethoxy) ethanol] fumarate.
Quetiapine fumarate has a molecular formula of C46H54N6O8S2 and a molecular weight of 883.
Quetiapine fumarate is a weak acid (pKa 3.3, 6.8) which exhibits moderate pH dependent solubility (94.3 mg/mL to 2.37 mg/mL at pH values from 1 to 9) and lipophilicity characteristics (Log P) which vary with pH (0.45 in water, 1.37 at pH 5, 2.65 at pH 7 and 2.59 at pH 9). Quetiapine fumarate has an aqueous solubility of 3.29 mg/mL at 25°C.

CAS number.

111974-72-2.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine - S4.

Summary Table of Changes