Kagitz 300 mg Depottablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

22-09-2020

Produktens egenskaper Produktens egenskaper (SPC)

16-04-2019

Aktiva substanser:
kvetiapinfumarat
Tillgänglig från:
Aristo Pharma GmbH
ATC-kod:
N05AH04
INN (International namn):
quetiapine fumarate
Dos:
300 mg
Läkemedelsform:
Depottablett
Sammansättning:
laktosmonohydrat Hjälpämne; kvetiapinfumarat 345,405 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 10 tabletter; Blister, 14 tabletter; Blister, 20 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 50 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 90 tabletter; Blister, 98 tabletter; Blister, 100 tabletter; Burk, 60 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
54263
Tillstånd datum:
2017-03-06

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

23-07-2021

Produktens egenskaper Produktens egenskaper - engelska

23-07-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

06-03-2017

Läs hela dokumentet

Package leaflet: Information for the user

Kagitz 50 mg prolonged-release tablets

Kagitz 300 mg prolonged-release tablets

Kagitz 400 mg prolonged-release tablets

quetiapine

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Kagitz is and what it is used for

What you need to know before you take Kagitz

How to take Kagitz

Possible side effects

How to store Kagitz

Contents of the pack and other information

1.

What Kagitz is and what it is used for

Kagitz contains a substance called quetiapine. This belongs to a group of medicines called anti-

psychotics. Kagitz can be used to treat several illnesses, such as:

Bipolar depression and major depressive episodes in major depressive disorder: where you feel

sad. You may find that you feel depressed, feel guilty, lack energy, lose your appetite or can’t

sleep.

Mania: where you may feel very excited, elated, agitated, enthusiastic or hyperactive or have poor

judgment including being aggressive or disruptive.

Schizophrenia: where you may hear or feel things that are not there, believe things that are not

true or feel unusually suspicious, anxious, confused, guilty, tense or depressed.

When Kagitz prolonged-release tablet is being taken to treat major depressive episodes in major

depressive disorder, it will be taken in addition to another medicine being used to treat this illness.

Your doctor may continue to prescribe Kagitz even when you are feeling better.

2.

What you need to know before you take Kagitz

Do not take Kagitz:

if you are allergic to quetiapine or any of the other ingredients of this medicine (listed in section

if you are taking any of the following medicines:

some medicines for HIV

azole medicines (for fungal infections)

erythromycin or clarithromycin (for infections)

nefazodone (for depression).

If you are not sure, talk to your doctor or pharmacist before taking this medicine.

Warnings and precautions

Talk to your doctor before taking Kagitz if:

You, or someone in your family, have or have had any heart problems, for example heart rhythm

problems, weakening of the heart muscle or inflammation of the heart.

You are taking any medicines that may have an impact on the way your heart beats.

You have low blood pressure.

You have had a stroke, especially if you are elderly.

You have problems with your liver.

You have ever had a fit (seizure).

You have diabetes or have a risk of getting diabetes. If you do, your doctor may check your blood

sugar levels while you are taking Kagitz.

You know that you have had low levels of white blood cells in the past (which may or may not

have been caused by other medicines).

You are an elderly person with dementia (loss of brain function). If you are, you should not take

Kagitz because the group of medicines that Kagitz belongs to may increase the risk of stroke, or

in some cases the risk of death, in elderly people with dementia.

You or someone else in your family has a history of blood clots, as medicines like these have

been associated with formation of blood clots.

You have or have had a condition where you stop breathing for short periods during your normal

nightly sleep (called “sleep apnoea”) and are taking medicines that slow down the normal activity

of the brain (“depressants”).

You have or have had a condition where you can’t completely empty your bladder (urinary

retention), have an enlarged prostate, a blockage in your intestines, or increased pressure inside

your eye. These conditions are sometimes caused by medicines (called “anti- cholinergics”) that

affect the way nerve cells function in order to treat certain medical conditions.

You have a history of alcohol or drug abuse.

Tell your doctor immediately if you experience any of the following after taking Kagitz:

A combination of fever, severe muscle stiffness, sweating or a lowered level of consciousness (a

disorder called “neuroleptic malignant syndrome”). You may need an immediate medical

treatment.

Uncontrollable movements, mainly of your face or tongue.

Dizziness or a severe sense of feeling sleepy. This could increase the risk of accidental injury

(fall) in elderly patients.

Fits (seizures).

A long-lasting and painful erection (priapism).

Have a fast and irregular heartbeat, even when you are at rest, palpitations, breathing problems,

chest pain or unexplained tiredness. Your doctor will need to check your heart and if necessary,

refer you to a cardiologist immediately.

These conditions can be caused by this type of medicine.

Tell your doctor as soon as possible if you have:

A fever, flu-like symptoms, sore throat, or any other infection, as this could be a result of a very

low white blood cell count, which may require you to stop taking Kagitz and/or receive treatment.

Constipation along with persistent abdominal pain or constipation which has not responded to

treatment, as this may lead to a more serious blockage of the bowel.

Thoughts of suicide and worsening of your depression

If you are depressed you may sometimes have thoughts of harming or killing yourself. These may be

increased when first starting treatment, since these medicines all take time to work, usually about two

weeks but sometimes longer. These thoughts may also be increased if you suddenly stop taking your

medication. You may be more likely to think like this if you are a young adult. Information from

clinical trials has shown an increased risk of suicidal thoughts and/or suicidal behaviour in young

adults aged less than 25 years with depression.

If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital

straight away. You may find it helpful to tell a relative or close friend that you are depressed, and ask

them to read this leaflet. You might ask them to tell you if they think your depression is getting worse,

or if they are worried about changes in your behaviour.

Weight gain

Weight gain has been seen in patients taking Kagitz. You and your doctor should check your weight

regularly.

Children and Adolescents

Kagitz is not for use in children and adolescents below 18 years of age.

Other medicines and Kagitz

Tell your doctor or pharmacists if you are taking, have recently taken or might take any other

medicines.

Do not take Kagitz if you are taking any of the following medicines:

Some medicines for HIV.

Azole medicines (for fungal infections).

Erythromycin or clarithromycin (for infections).

Nefazodone (for depression).

Tell your doctor if you are taking any of the following medicines:

Epilepsy medicines (like phenytoin or carbamazepine).

High blood pressure medicines.

Barbiturates (for difficulty sleeping).

Thioridazine or Lithium (other anti-psychotic medicines).

Medicines that have an impact on the way your heart beats, for example, medicines that can cause

an imbalance in electrolytes (low levels of potassium or magnesium) such as diuretics (water

pills) or certain antibiotics (medicines to treat infections).

Medicines that can cause constipation.

Medicines (called “anti-cholinergics”) that affect the way nerve cells function in order to treat

certain medical conditions.

Before you stop taking any of your medicines, please talk to your doctor first.

Kagitz with food, drink and alcohol

Kagitz prolonged-release tablet can be affected by food and you should therefore take your tablets

at least one hour before a meal or prior to bedtime.

Be careful how much alcohol you drink. This is because the combined effect of Kagitz and

alcohol can make you sleepy.

Do not drink grapefruit juice while you are taking this medicine. It can affect the way the

medicine works.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor for advice before taking this medicine.

Do not take Kagitz during pregnancy unless this has been discussed with your doctor. Do not take

Kagitz if you are breast-feeding.

The following symptoms which can represent withdrawal may occur in newborn babies of mothers

that have used Kagitz in the last trimester (last three months of their pregnancy): shaking, muscle

stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your

baby develops any of these symptoms you may need to contact your doctor.

Driving and using machines

Your Kagitz tablets may make you feel sleepy. Do not drive or use any tools or machines until you

know how the tablets affect you.

Kagitz contains lactose

Kagitz prolonged-release tablet contains lactose which is a type of sugar. If you have been told by

your doctor that you have an intolerance to some sugars, talk to your doctor before taking this

medicine.

Effect on Urine Drug Screens

If you are having a urine drug screen, taking Kagitz may cause positive results for methadone or

certain medicines for depression called tricyclic antidepressants (TCAs) when some test methods are

used, even though you may not be taking methadone or TCAs. If this happens, a more specific test can

be performed.

3.

How to take Kagitz

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure. Your doctor will decide on your starting dose. The maintenance dose (daily dose)

will depend on your illness and needs but usually between 150 mg and 800 mg.

You will take your tablets once a day.

Do not split, chew or crush the tablets.

Swallow your tablets whole with a glass of water.

Take your tablets without food (at least one hour before a meal or at bedtime, your doctor will tell

you when).

Do not drink grapefruit juice while you are taking Kagitz. It can affect the way the medicine

works.

Do not stop taking your tablets even if you feel better, unless your doctor tells you.

Liver problems

If you have liver problems your doctor may change your dose.

Elderly people

If you are elderly your doctor may change your dose.

Use in children and adolescents

Kagitz should not be used by children and adolescents aged under 18 years.

If you take more Kagitz than you should

If you take more Kagitz than prescribed by your doctor, you may feel sleepy, feel dizzy and

experience abnormal heart beats. Contact your doctor or nearest hospital straight away. Take the

tablets with you.

If you forget to take Kagitz

If you forget to take a dose, take it as soon as you remember. If it is almost time to take the next dose,

wait until then. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Kagitz

If you suddenly stop taking Kagitz, you may be unable to sleep (insomnia), or you may feel sick

(nausea), or you may experience headache, diarrhoea, being sick (vomiting), dizziness or irritability.

Your doctor may suggest you reduce the dose gradually before stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common: may affect more than 1 in 10 people

Dizziness (may lead to falls), headache, dry mouth.

Feeling sleepy, which may lead to falls (this may go away with time, as you keep taking Kagitz).

Discontinuation symptoms (symptoms which occur when you stop taking Kagitz) include not

being able to sleep (insomnia), feeling sick (nausea), headache, diarrhoea, being sick (vomiting),

dizziness and irritability. Gradual withdrawal over a period of at least 1 to 2 weeks is advisable.

Putting on weight.

Abnormal muscle movements. These include difficulty starting muscle movements, shaking,

feeling restless or muscle stiffness without pain.

Changes in the amount of certain fats (triglycerides and total cholesterol) in the blood.

Common: may affect up to 1 in 10 people

Rapid heartbeat.

Feeling like your heart is pounding, racing or has skipped beats.

Constipation, upset stomach (indigestion).

Feeling weak.

Swelling of arms or legs.

Low blood pressure when standing up. This may make you feel dizzy or faint (may lead to falls).

Increased levels of sugar in the blood.

Blurred vision.

Abnormal dreams and nightmares.

Feeling hungrier.

Feeling irritated.

Disturbance in speech and language.

Thoughts of suicide and worsening of your depression.

Shortness of breath.

Vomiting (mainly in the elderly).

Fever.

Changes in the amount of thyroid hormones in your blood.

Decreases in the number of certain types of blood cells.

Increases in the amount of liver enzymes measured in the blood.

Increases in the amount of the hormone prolactin in the blood. Increases in the hormone prolactin

could in rare cases lead to the following:

Men and women to have swelling of breasts and unexpectedly produce breast milk.

Women to have no monthly period or irregular periods.

Uncommon: may affect up to 1 in 100 people

Fits or seizures

Allergic reactions that may include raised lumps (weals), swelling of the skin and swelling around

the mouth.

Unpleasant sensation in the legs (also called restless legs syndrome).

Difficulty swallowing

Uncontrollable movements, mainly of your face or tongue.

Sexual dysfunction.

Diabetes.

Change in electrical activity of the heart seen on ECG (QT prolongation).

A slower than normal heart rate which may occur when starting treatment and which may be

associated with low blood pressure and fainting.

Difficulty in passing urine.

Fainting (may lead to falls).

Stuffy nose.

Decrease in the amount of red blood cells.

Decrease in the amount of sodium in the blood.

Worsening of pre-existing diabetes.

Rare: may affect up to 1 in 1,000 people

A combination of high temperature (fever), sweating, stiff muscles, feeling very drowsy or faint

(a disorder called “neuroleptic malignant syndrome”).

Yellowing of the skin and eyes (jaundice).

Inflammation of the liver (hepatitis).

A long-lasting and painful erection (priapism).

Swelling of breasts and unexpected production of breast milk (galactorrhoea).

Menstrual disorder.

Blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the

leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in

breathing. If you notice any of these symptoms seek medical advice immediately.

Walking, talking, eating or other activities while you are asleep.

Body temperature decreased (hypothermia).

Inflammation of the pancreas.

A condition (called “metabolic syndrome”) where you may have a combination of 3 or more of

the following: an increase in the fat around your abdomen, a decrease in “good cholesterol”

(HDL-C), an increase in a type of fat in your blood called trigylcerides, high blood pressure and

an increase in your blood sugar.

Combination of fever, flu-like symptoms, sore throat, or any other infection with very low white

blood cell count, a condition called agranulocytosis.

Bowel obstruction.

Increased blood creatine phosphokinase (a substance from muscles).

Very rare: may affect up to 1 in 10,000 people

Severe rash, blisters, or red patches on the skin.

A severe allergic reaction (called anaphylaxis) which may cause difficulty in breathing or shock.

Rapid swelling of the skin, usually around the eyes, lips and throat (angioedema).

A serious blistering condition of the skin, mouth, eyes and genitals (Stevens-Johnson syndrome).

Inappropriate secretion of a hormone that controls urine volume.

Breakdown of muscle fibers and pain in muscles (rhabdomyolysis).

Not known: frequency cannot be estimated from the available data

Skin rash with irregular red spots (erythema multiforme).

Serious, sudden allergic reaction with symptoms such as fever and blisters on the skin and peeling

of the skin (toxic epidermal necrolysis).

Symptoms of withdrawal may occur in newborn babies of mothers that were taking Kagitz during

their pregnancy.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Widespread rash, high body

temperature, liver enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes

and other body organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms

which is also known as DRESS or drug hypersensitivity syndrome). Stop using Kagitz if you

develop these symptoms and contact your doctor or seek medical attention immediately.

Disorder of the heart muscle (cardiomyopathy).

Inflammation of the heart muscle (myocarditis).

Inflammation of blood vessels (vasculitis), often with skin rash with small red or purple bumps.

The class of medicines to which Kagitz belongs can cause heart rhythm problems, which can be

serious and in severe cases fatal.

Some side effects are only seen when a blood test is taken. These include changes in the amount of

certain fats (triglycerides and total cholesterol) or sugar in the blood, changes in the amount of thyroid

hormones in your blood, increased liver enzymes, decreases in the number of certain types of blood

cells, decrease in the amount of red blood cells, increased blood creatine phosphokinase (a substance

in the muscles), decrease in the amount of sodium in the blood, and increases in the amount of the

hormone prolactin in the blood. Increases in the hormone prolactin could in rare cases lead to the

following:

Men and women to have swelling of breasts and unexpectedly produce breast milk.

Women to have no monthly period or irregular periods.

Your doctor may ask you to have blood tests from time to time.

Additional side effects in children and adolescents

The same side effects that may occur in adults may also occur in children and adolescents.

The following side effects have been seen more often in children and adolescents or have not been

seen in adults:

Very common: may affect more than 1 in 10 people

Increase in the amount of a hormone called prolactin, in the blood. Increases in the hormone

prolactin could in rare cases lead to the following:

boys and girls to have swelling of breasts and unexpectedly produce breast milk

girls to have no monthly period or irregular periods.

Increased appetite.

Vomiting.

Abnormal muscle movements. These include difficulty starting muscle movements, shaking,

feeling restless or muscle stiffness without pain.

Increase in blood pressure

Common: may affect up to 1 in 10 people

Feeling weak, fainting (may lead to falls).

Stuffy nose.

Feeling irritated.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via <To be completed nationally >.

By reporting side effects, you can help provide more information on the safety of this medicine.

5.

How to store Kagitz

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the container after EXP. The expiry

date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Kagitz contains

The active substance is quetiapine. Each tablet contain 50 mg, 300 mg or 400 mg of quetiapine

(as quetiapine fumarate).

The other ingredients are:

Tablet core: Microcrystalline cellulose, Lactose monohydrate, Sodium citrate, Hypromellose,

Magnesium Stearate

Tablet coating: Hypromellose, Macrogol 400, Titanium Dioxide (E171). The 50 mg, and 300 mg

tablets also contain Iron Oxide Yellow (E172) The 50 mg tablets contain Iron Oxide Red (E172).

What Kagitz looks like and contents of the pack

Kagitz 50 mg tablets are peach, bi-convex, capsule shaped, coated tablets, of dimension about 16.5

mm X 6.6 mm, debossed “AI001” on one side and plain on other side.

Kagitz 300 mg tablets are pale yellow, bi-convex, capsule shaped, coated tablets, of dimension about

19.1 mm X 8.1 mm, debossed “AI004” on one side and plain on other side.

Kagitz 400 mg tablets are white to off white, bi-convex, capsule shaped, of dimension about 20.5 mm

X 9.3 mm, coated tablets, debossed “AI005” on one side and plain on other side.

PVC-Aclar/Aluminium blisters in cartons of 10, 14, 20, 28, 30, 50, 56, 60, 90, 98 and 100 tablets.

White, plastic (HDPE) bottle with a child-resistant plastic (polypropylene) screw cap containing 60

tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

<To be completed nationally>

Manufacturer:

<To be completed nationally>

This medicinal product is authorised in the Member States of the EEA under the following

names:

< {Name of the Member State} > < {Name of the medicinal product} >

This leaflet was last revised in 201-07-22

<To be completed nationally>.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Kagitz 50 mg prolonged-release tablets

Kagitz 300 mg prolonged-release tablets

Kagitz 400 mg prolonged-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Kagitz 50 mg contains 50 mg quetiapine (as quetiapine fumarate)

Excipient: 119mg lactose monohydrate per tablet

Kagitz 300 mg contains 300 mg quetiapine (as quetiapine fumarate)

Excipient: 96 mg lactose monohydrate per tablet

Kagitz 400 mg contains 400 mg quetiapine (as quetiapine fumarate)

Excipient: 128 lactose monohydrate per tablet

For the full list of excipients, see Section 6.1.

3.

PHARMACEUTICAL FORM

Prolonged-release tablet

Kagitz 50 mg tablets are peach, bi-convex, capsule shaped, coated tablets, of dimension about

16.5 mm x 6.6 mm, debossed “AI001” on one side and plain on other side.

Kagitz 300 mg tablets are pale yellow, bi-convex, capsule shaped, coated tablets, of dimension about 19.1

mm x 8.1 mm, debossed “AI004” on one side and plain on other side.

Kagitz 400 mg tablets are white to off white, bi-convex, capsule shaped, coated tablets, of dimension about

20.5 mm x 9.3 mm, debossed “AI005” on one side and plain on other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Kagitz prolonged-release tablet is indicated for:

Treatment of schizophrenia

Treatment of bipolar disorder

For the treatment of moderate to severe manic episodes in bipolar disorder

For the treatment of major depressive episodes in bipolar disorder

For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder

who previously responded to quetiapine treatment.

Add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD)

who have had sub-optimal response to antidepressant monotherapy (see Section 5.1). Prior to initiating

treatment, clinicians should consider the safety profile of Kagitz (see Section 4.4).

4.2

Posology and method of administration

Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear

information on the appropriate dosage for their condition.

Posology

Adults:

For the treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder

Kagitz prolonged-release tablet should be administrated at least one hour before a meal. The daily dose at

the start of therapy is 300 mg on Day 1 and 600 mg on Day 2. The recommended daily dose is 600 mg,

however if clinically justified the dose may be increased to 800 mg daily. The dose should be adjusted within

the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of

the patient. For maintenance therapy in schizophrenia no dosage adjustment is necessary.

For the treatment of major depressive episodes in bipolar disorder

Kagitz prolonged-release tablet should be administered at bedtime. The total daily dose for the first four

days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended

daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the

300 mg group (see Section 5.1). Individual patients may benefit from a 600 mg dose. Doses greater than 300

mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the

event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could

be considered.

For preventing recurrence in bipolar disorder

For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have

responded to quetiapine for acute treatment of bipolar disorder should continue on Kagitz prolonged-release

tablet at the same dose administered at bedtime. Kagitz dose can be adjusted depending on clinical response

and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day. It is important that

the lowest effective dose is used for maintenance therapy.

For add-on treatment of major depressive episodes in MDD

Kagitz prolonged-release tablet should be administered prior to bedtime. The daily dose at the start of therapy

is 50 mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect was seen at 150 and 300

mg/day in short-term trials as add-on therapy (with amitriptyline, bupropion, citalopram, duloxetine,

escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine - see Section 5.1) and at 50 mg/day in short-

term monotherapy trials. There is an increased risk of adverse events at higher doses. Clinicians should

therefore ensure that the lowest effective dose, starting with 50 mg/day, is used for treatment. The need to

increase the dose from 150 to 300 mg/day should be based on individual patient evaluation.

Switching from quetiapine immediate-release tablets:

For more convenient dosing, patients who are currently being treated with divided doses of immediate-

release quetiapine tablets may be switched to Kagitz prolonged-release tablet at the equivalent total daily

dose taken once daily. Individual dosage adjustments may be necessary

Elderly:

As with other antipsychotics and antidepressants, quetiapine should be used with caution in the elderly,

especially during the initial dosing period. The rate of dose titration of quetiapine 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 patients when compared to 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 major depressive episodes in MDD, dosing should begin with 50 mg/day on Days 1-

3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. The lowest effective dose, starting from 50

mg/day should be used. Based on individual patient evaluation, if dose increase to 300 mg/day is required

this should not be prior to Day 22 of treatment.

Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in the

framework of bipolar disorder.

Paediatric Population:

Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of

data to support use in this age group. The available evidence from placebo- controlled clinical trials is

presented in Sections 4.4, 4.8, 5.1 and 5.2.

Renal impairment:

Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment:

Quetiapine is extensively metabolised by the liver. Therefore, quetiapine 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.

Method of administration:

Kagitz prolonged-release tablet should be administered once daily, without food. The tablets should be

swallowed whole and not split, chewed or crushed.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-

antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. (see Section 4.5).

4.4

Special warnings and precautions for use

As quetiapine has several indications, the safety profile should be considered with respect to the individual

patient's diagnosis and the dose being administered.

Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however

long-term efficacy and safety has been evaluated in adult patients as monotherapy (see Section 5.1).

Paediatric population:

Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of

data to support use in this age group. Clinical trials with quetiapine have shown that in addition to the known

safety profile identified in adults (see Section 4.8), certain adverse events occurred at a higher frequency in

children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting,

rhinitis and syncope), or may have different implications for children and adolescents (extrapyramidal

symptoms and irritability) and one was identified that has not been previously seen in adult studies (increases

in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.

Furthermore, the long-term safety implications of treatment with quetiapine on growth and maturation have

not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are

not known.

In placebo-controlled clinical trials with children and adolescent patients, quetiapine was associated with an

increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for

schizophrenia, bipolar mania and bipolar depression (see Section 4.8).

Suicide/suicidal thoughts or clinical worsening:

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related

events). This risk persists until significant remission occurs. As improvement may not occur during the first

few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is

general clinical experience that the risk of suicide may increase in the early stages of recovery.

In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of

quetiapine treatment, due to the known risk factors for the disease being treated.

Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk

of suicide related events. In addition, these conditions may be co-morbid with major depressive episodes.

The same precautions observed when treating patients with major depressive episodes should therefore be

observed when treating patients with other psychiatric disorders.

Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation

prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts,

and should receive careful monitoring during treatment. A meta analysis of placebo controlled clinical trials

of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal

behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially

in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about

the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in

behaviour and to seek medical advice immediately if these symptoms present.

In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar

disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25

years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%,

respectively). In clinical studies of patients with MDD the incidence of suicide-related events observed in

young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for

placebo.

Metabolic Risk:

Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose

(see hyperglycemia) and lipids, which was seen in clinical studies, patient's metabolic parameters should be

assessed at the time of treatment initiation and changes in these parameters should be regularly controlled

for during the course of treatment. Worsening in these parameters should be managed as clinically

appropriate (see also Section 4.8).

Extrapyramidal symptoms:

In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence

of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in

bipolar disorder and major depressive disorder (see Sections 4.8 and 5.1).

The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively

unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand

still. This is most likely to occur within the first few weeks of treatment. In patients who develop these

symptoms, increasing the dose may be detrimental.

Tardive Dyskinesia:

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).

Somnolence and dizziness:

Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see

Section 4.8). In clinical trials for treatment of patients with bipolar depression and major depressive disorder,

onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity.

Patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of

2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to

be considered.

Orthostatic Hypotension:

Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see Section

4.8) which, like somnolence has onset usually during the initial dose-titration period. This could increase the

occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be

advised to exercise caution until they are familiar with the potential effects of the medication.

Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular

disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be

considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Sleep apnoea syndrome:

Sleep apnoea syndrome has been reported in patients using quetiapine. In patients receiving concomitant

central nervous system depressants and who have a history of or are at risk for sleep apnoea, such as those

who are overweight/obese or are male, quetiapine should be used with caution.

Seizures:

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with

quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure

disorder. As with other antipsychotics, caution is recommended when treating patients with a history of

seizures (see Section 4.8).

Neuroleptic Malignant Syndrome:

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see

Section

4.8).

Clinical

manifestations

include

hyperthermia,

altered

mental

status,

muscular

rigidity,

autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be

discontinued and appropriate medical treatment given.

Severe Neutropenia and agranulocytosis:

Severe neutropenia (neutrophil count <0.5 X 10

/L) has been reported in quetiapine clinical trials. Most

cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine.

There was no apparent dose relationship. During post-marketing experience, some cases were fatal. Possible

risk factors for neutropenia include pre-existing low white blood cell count (WBC) and history of drug

induced neutropenia. However, some cases occurred in patients without pre-existing risk factors. Quetiapine

should be discontinued in patients with a neutrophil count <1.0 X 10

/L. Patients should be observed for

signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 10

/L) (see Section

5.1).

Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence

of obvious predisposing factor(s), and should be managed as clinically appropriate.

Patients should be advised to immediately report the appearance of signs/symptoms consistent with

agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during quetiapine

therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed

promptly, especially in the absence of predisposing factors.

Anti-cholinergic (muscarinic) effects:

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic

receptor subtypes. This contributes to ADRs 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 Sections

4.5, 4.8, 5.1, and 4.9.)

Interactions:

See also Section 4.5.

Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin

substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine

therapy. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur

if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme

inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer

(e.g. sodium valproate).

Weight:

Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored

and managed as clinically appropriate as in accordance with utilised antipsychotic guidelines (see Sections

4.8 and 5.1).

Hyperglycaemia:

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis

or coma has been reported rarely, including some fatal cases (see Section 4.8). In some cases, a prior increase

in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is

advisable in accordance with utilized antipsychotic guidelines. Patients treated with any antipsychotic agent

including quetiapine, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia,

polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes

mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored

regularly.

Lipids:

Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed

in clinical trials with quetiapine (see Section 4.8). Lipid changes should be managed as clinically appropriate.

QT Prolongation:

In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase

in absolute QT intervals. In post-marketing, QT prolongation was reported with quetiapine at the therapeutic

doses (see Section 4.8) and in overdose (see Section 4.9). As with other antipsychotics, caution should be

exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT

prolongation. Also caution should be exercised when quetiapine is prescribed either with medicines known

to increase QT interval, or with concomitant neuroleptics, especially in the elderly, in patients with

congenital

long

syndrome,

congestive

heart

failure,

heart

hypertrophy,

hypokalaemia

hypomagnesaemia (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). In patients with suspected cardiomyopathy or myocarditis discontinuation of

quetiapine should be considered.

Withdrawal:

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and

irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at

least one to two weeks is advisable. (See Section 4.8.)

Elderly patients with dementia-related psychosis:

Quetiapine is not approved for the treatment of dementia-related psychosis.

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised

placebo controlled trials in the dementia population with some atypical antipsychotics. The mechanism for

this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other

patient populations. Quetiapine should be used with caution in patients with risk factors for stroke.

In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with dementia-related

psychosis are at an increased risk of death compared to placebo. In two 10- week placebo controlled

quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the

incidence of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo group. The patients

in these trials died from a variety of causes that were consistent with expectations for this population.

Dysphagia:

Dysphagia (see Section 4.8) has been reported with quetiapine. Quetiapine should be used with caution in

patients at risk for aspiration pneumonia.

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 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. Patients with

intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Venous thromboembolism (VTE):

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 risk factors for VTE

should be identified before and during treatment with quetiapine and preventive measures undertaken.

Pancreatitis:

Pancreatitis has been reported in clinical trials and during post marketing experience. Among post marketing

reports, while not all cases were confounded by risk factors, many patients had factors which are known to

be associated with pancreatitis such as increased triglycerides (see Section 4.4), gallstones and alcohol

consumption.

Additional information:

Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is

limited; however, combination therapy was well tolerated (see Section 4.8 and 5.1). The data showed an

additive effect at week 3.

Lactose:

Kagitz prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Misuse and Abuse:

Cases of misuse and abuse have been reported. Caution may be needed when prescribing quetiapine to

patients with a history of alcohol or drug abuse.

4.5

Interaction with other medicinal products and other forms of interaction

Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in

combination with other centrally acting medicinal products and alcohol.

Caution should be exercised treating patients receiving other medications having anti- cholinergic

(muscarinic) effects (see Section 4.4).

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated

metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of

quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the

AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is

contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.

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, which could affect the efficacy of quetiapine therapy. Co-administration of

quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of

quetiapine by approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine

treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of

removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if

required, replaced with a non-inducer (e.g. sodium valproate) (see Section 4.4).

pharmacokinetics

quetiapine

were

significantly

altered

co-administration

antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6

inhibitor).

The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics

risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of

quetiapine with approx. 70%.

The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine.

The pharmacokinetics of lithium were not altered when co-administered with quetiapine.

In a 6-week, randomised, study of lithium and quetiapine fumarate versus placebo and quetiapine fumarate

in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particular tremor),

somnolence, and weight gain were observed in the lithium add-on group compared to the placebo add-on

group (see Section 5.1).

The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent

when co-administered. A retrospective study of children and adolescents who received valproate, quetiapine,

or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the

monotherapy groups.

Formal interaction studies with commonly used cardiovascular medicinal products have not been performed.

Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause

electrolyte imbalance or to increase QT interval.

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.

4.6

Fertility, pregnancy and lactation Pregnancy

First trimester

The moderate amount of published data from exposed pregnancies (i.e. between 300-1000 pregnancy

outcomes), including individual reports and some observational studies do not suggest an increased risk of

malformations due to treatment. However, based on all available data, a definite conclusion cannot be drawn.

Animal studies have shown reproductive toxicity (see Section 5.3). Therefore, quetiapine should only be

used during pregnancy if the benefits justify the potential risks.

Third trimester

Neonates exposed to antipsychotics (including quetiapine) during the third trimester of pregnancy are at risk

of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and

duration

following

delivery.

There

have

been

reports

agitation,

hypertonia,

hypotonia,

tremor,

somnolence, respiratory distress or feeding disorder. Consequently, newborns should be monitored

carefully.

Breast-feeding

Based on very limited data from published reports on quetiapine excretion into human breast milk, excretion

of quetiapine at therapeutic doses appears to be inconsistent. Due to lack of robust data, a decision must be

made whether to discontinue breast-feeding or to discontinue quetiapine therapy taking into account the

benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

The effects of quetiapine on human fertility have not been assessed. Effects related to elevated prolactin

levels were seen in rats, although these are not directly relevant to humans (see Section 5.3 preclinical data).

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. Therefore, patients should be advised not to drive or operate machinery, until individual

susceptibility to this is known.

4.8

Undesirable effects

The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine (≥10%) are somnolence,

dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride

levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight

gain, decreased haemoglobin and extrapyramidal symptoms.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal

necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in

association with quetiapine treatment.

The incidences of ADRs associated with quetiapine therapy, are tabulated below (Table 1) according to the

format recommended by the Council for International Organizations of Medical Sciences (CIOMS III

Working Group 1995).

Table 1 ADRs associated with quetiapine therapy

The frequencies of adverse events are ranked according to the following: Very common (≥1/10), common

(≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not

known (cannot be estimated from the available data).

SOC

Very Common Common

Uncommon

Rare

Very Rare

Not known

Blood and

lymphatic

system

disorders

Decreased

haemoglobin

Leucopenia

1,28

decreased

neutrophil

count,

eosinophils

increased

Neutropenia

Thrombocytopenia

Anaemia, platelet

count decreased

Agranulocytosis

Immune

system

disorders

Hypersensitivity

(including allergic

skin reactions)

Anaphylactic

reaction

Endocrine

disorders

Hyperprolactinae

, decreases

in total T

decreases in

free T

decreases in

total T

increases in

Decreases in free

Hypothyroidism

Inappropriate

antidiuretic

hormone

secretion

Metabolism

nutritional

disorders

Elevations in

serum

triglyceride

levels

10,30

Elevations in

total

cholesterol

(predominantly

cholesterol)

11,30

Decreases in

cholesterol

17,30

Weight gain

8,30

Increased

appetite, blood

glucose

increased to

hyperglycaemic

levels

Hyponatraemia

Diabetes

Mellitus

Exacerbation of

pre-existing

diabetes

Metabolic

syndrome

Psychiatric

disorders

Abnormal

dreams and

nightmares,

Suicidal

ideation and

suicidal

behaviour

Somnambulism

and related

reactions such as

sleep talking and

sleep related

eating disorder

Nervous

system

disorders

Dizziness

4,16

somnolence

2,16

headache,

Extrapyramidal

symptoms

Dysarthria

Seizure

, Restless

legs syndrome,

Tardive

dyskinesia

Syncope

4,16

Cardiac

Tachycardia

Cardiomyopathy,

disorders

Palpitations

prolongation

1,12,

Bradycardia

Myocarditis

Eye-disorders

Vision blurred

Vascular

disorders

Orthostatic

hypotension

4,16

Venous

thromboembolism

Respiratory,

thoracic and

mediastinal

disorder

Dyspnoea

Rhinitis

Gastrointestin

al disorders

Dry mouth

Constipation,

dyspepsia,

vomiting

Dysphagia

Pancreatitis

Intestinal

obstruction/

Ileus

Hepato-

biliary

disorders

Elevations in

serum alanine

aminotransferase

(ALT)

Elevations in

gamma-GT

levels

Elevations in

serum aspartate

aminotransferase

(AST)

Jaundice

Hepatitis

Skin and

subcutaneous

tissue

disorders

Angioedema

,Stevens-

Johnson

syndrome

Toxic Epidermal

Necrolysis,

Erythema

Multiforme,

Drug Reaction

with

Eosinophilia and

Systemic

Symptoms

(DRESS),

Cutaneous

vasculitis

Musculoskelet

al and

connective

tissue

disorders

Rhabdomyol

ysis

Renal and

urinary

disorders

Urinary retention

Pregnancy,

puerperium

and perinatal

conditions

Drug

withdrawal

syndrome

neonatal

Reproductive

system and

breast

disorders

Sexual

dysfunction

Priapism,

galactorrhoea,

breast swelling,

menstrual disorder

General

disorders and

administration

site

conditions

Withdrawal

(discontinuation

symptoms

Mild asthenia,

peripheral

oedema,

irritability,

pyrexia

Neuroleptic

malignant

syndrome

hypothermia

Investigations

Elevations in

blood creatine

phosphokinase

See Section 4.4.

Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the

continued administration of quetiapine.

Asymptomatic elevations (shift from normal to ≥3 X ULN at any time) in serum transaminase (ALT,

AST) or gamma-GT levels have been observed in some patients administered quetiapine. These elevations

were usually reversible on continued quetiapine treatment.

As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly

induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope,

especially during the initial dose-titration period. (see Section 4.4).

Calculation of Frequency for these ADR's have only been taken from postmarketing data with the

immediate release formulation of quetiapine.

Fasting blood glucose ≥126mg/dL (≥ 7.0 mmol/L) or a non fasting blood glucose ≥200mg/dL (≥ 11.1

mmol/L) on at least one occasion.

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

in bipolar depression.

Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of

treatment in adults.

The following withdrawal symptoms have been observed most frequently in acute placebo- controlled,

monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache,

diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly

after 1 week post-discontinuation.

(10) Triglycerides ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150 mg/dL (≥1.694

mmol/L) (patients <18 years of age) on at least one occasion.

(11) Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL (≥5.172

mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥30 mg/dL

(≥0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase

was 41.7 mg/dL (≥1.07 mmol/L).

(12) See text below.

(13) Platelets ≤100 x 109/L on at least one occasion.

(14) Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated

with neuroleptic malignant syndrome.

(15) Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34

pmol/L) females at any time.

(16) May lead to falls.

(17) HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L) females at any time.

(18) Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In

placebo controlled trials with quetiapine the mean change and the incidence of patients who have a shift to

a clinically significant level is similar between quetiapine and placebo.

(19) Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.

(20) Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early

after treatment discontinuation (see Sections 4.4 and 5.1).

(21) See Section 5.1.

(22) Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least

one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these

patients, the mean maximum decrease in haemoglobin at any time was -1.50 g/dL.

(23) These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or

underlying cardiac/respiratory disease.

(24) Based on shifts from normal baseline to potentially clinically important value at any time post-baseline

in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 X LLN (pmol/L) and shift in

TSH is >5 mIU/L at any time.

(25) Based upon the increased rate of vomiting in elderly patients (≥65 years of age).

(26) Based on shift in neutrophils from > = 1.5 x 109/L at baseline to <0.5 x 109/L at any time during

treatment and based on patients with severe neutropenia (<0.5 x 109/L) and infection during all quetiapine

clinical trials (see Section 4.4).

(27) Based on shifts from normal baseline to potentially clinically important value at any time post-baseline

in all trials. Shifts in eosinophils are defined as ≥1 x 109 cells/L at any time.

(28) Based on shifts from normal baseline to potentially clinically important value at any time post-baseline

in all trials. Shifts in WBCs are defined as ≤3 x 109 cells/L at any time.

(29) Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.

(30) In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and

lipids was observed in clinical studies (see Section 4.4)

(31) See Section 4.6.

(32) May occur at or near initiation of treatment and be associated with hypotension and/or syncope.

Frequency based on adverse event reports of bradycardia and related events in all clinical trials with

quetiapine.

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de

pointes have been reported with the use of neuroleptics and are considered class effects.

Paediatric population

The same ADRs described above for adults should be considered for children and adolescents. The following

table summarises ADRs that occur in a higher frequency category in children and adolescents patients (10-

17 years of age) than in the adult population or ADRs that have not been identified in the adult population.

Table 2 ADRs in children and adolescents associated with quetiapine therapy that occur in a higher

frequency than adults, or not identified in the adult population

The frequencies of adverse events are ranked according to the following: Very common (>1/10), common

(>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000).

SOC

Very Common

Common

Endocrine disorders

Elevations in prolactin

Metabolism and nutritional disorders

Increased appetite

Nervous system disorders

Extrapyramidal symptoms

Syncope

Vascular disorders

Increases in blood pressure

Respiratory, thoracic and mediastinal disorders

Rhinitis

Gastrointestinal disorders

Vomiting

General disorders and administration site conditions

Irritability

Prolactin levels (patients < 18 years of age): >20 μg/L (>869.56 pmol/L) males; >26 μg/L (>1130.428

pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 μg/L.

Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health

criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two

acute (3-6 weeks) placebo-controlled trials in children and adolescents.

Note: The frequency is consistent to that observed in adults, but might be associated with different

clinical implications in children and adolescents as compared to adults.

See Section 5.1.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via <To be completed Nationally>.

4.9

Overdose

Symptoms

In general, reported signs and symptoms were those resulting from an exaggeration of the active substance's

known pharmacological effects, i.e., drowsiness and sedation, tachycardia, hypotension and anti-cholinergic

effects.

Overdose

could

lead

QT-prolongation,

seizures,

status

epilepticus,

rhabdomyolysis,

respiratory

depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with pre-

existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (see Section

4.4, Orthostatic Hypotension).

In case of overdose with extended-release quetiapine there is a delayed peak sedation and peak pulse and

prolonged recovery compared with IR Quetiapine overdose.

In case of a quetiapine extended-release overdose gastric bezoar formation has been reported and

appropriate diagnostic imaging is recommended to further guide patient management.

Endoscopic pharmacobezoar removal has been performed successfully in some cases.

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.

Based on public literature, patients with delerium and agitation and a clear anti-cholinergic syndrome may

be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as

standard

treatment,

because

potential

negative

effect

physostigmine

cardiac

conductance.

Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of

dysrhythmias, any degree of heart block or QRS-widening.

Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in

severe poisonings and if possible to perform within one hour of ingestion. The administration of activated

charcoal should be considered.

In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as

intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta

stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade.

Close medical supervision and monitoring should be continued until the patient recovers.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines

ATC code: N05A H04

Mechanism of action:

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite,

norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit

affinity for brain serotonin (5HT

) and dopamine D

- and D

- receptors. It is this combination of receptor

antagonism with a higher selectivity for 5HT

relative to D

-receptors, which is believed to contribute to the

clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine compared

to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine

receptors but high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at

adrenergic alpha2 receptors Quetiapine also has low affinity for muscarinic receptors, while norquetiapine

moderate

high

affinity

several

muscarinic

receptors,

which

explain

anti-cholinergic

(muscarinic) effects. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may

contribute to quetiapine fumarate’s therapeutic efficacy as an antidepressant.

Pharmacodynamic effects:

Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the

action

dopamine

agonists,

measured

either

behaviourally

electrophysiologically,

elevates

dopamine metabolite concentrations, a neurochemical index of D

-receptor blockade.

In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile.

Quetiapine does not produce dopamine D

-receptor supersensitivity after chronic administration. Quetiapine

produces only weak catalepsy at effective dopamine D

- 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

haloperidol-sensitised

drug-naïve

Cebus

monkeys

after

acute

chronic

administration. (See Section 4.8.)

Clinical efficacy and Safety:

Schizophrenia

The efficacy of quetiapine prolonged-release in the treatment of schizophrenia was demonstrated in one 6-

week placebo-controlled trial in patients who met DSM-IV criteria for schizophrenia, and one active-

controlled quetiapine immediate release-to-quetiapine prolonged- release switching study in clinically stable

outpatients with schizophrenia.

The primary outcome variable in the placebo-controlled trial was change from baseline to final assessment

in the PANSS total score. Quetiapine prolonged-release 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 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 randomisation 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 prolonged-release given once daily.

In a long-term study in stable schizophrenic patients who had been maintained on quetiapine prolonged-

release for 16 weeks, quetiapine prolonged-release was more effective than placebo in preventing relapse.

The estimated risks of relapse after 6 months treatments was 14.3% for the quetiapine prolonged-release

treatment group compared to 68.2% for placebo. The average dose was 669 mg. There were no additional

safety findings associated with treatment with quetiapine prolonged-release for up to 9 months (median 7

months). In particular, reports of adverse events related to EPS and weight gain did not increase with longer-

term treatment with quetiapine prolonged-release.

Bipolar Disorder

In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo

in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. The efficacy of quetiapine

prolonged-release was further demonstrated with significance versus placebo in an additional 3 week study.

Quetiapine prolonged-release was dosed in the range of 400 to 800 mg/day and the mean dose was

approximately 600 mg/day. Quetiapine data in combination with divalproex or lithium in acute moderate to

severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The

data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300 mg/day

quetiapine prolonged-release showed superior efficacy to placebo in reduction of MADRS total score.

In 4 additional clinical trials with quetiapine, with a duration of 8 weeks in patients with moderate to severe

depressive episodes in bipolar I or bipolar II disorder, quetiapine immediate release 300 mg and 600 mg was

significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on

the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline.

There was no difference in magnitude of effect between the patients who received 300 mg quetiapine

immediate release and those who received 600 mg dose.

In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients

who responded on quetiapine immediate release 300 or 600 mg, was efficacious compared to placebo

treatment with respect to depressive symptoms, but not with regard to manic symptoms.

In two recurrence prevention studies evaluating quetiapine in combination with mood stabilizers, in patients

with manic, depressed or mixed mood episodes, the combination with quetiapine was superior to mood

stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed).

Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium

or valproate.

In a 6-week, randomised, study of lithium and quetiapine prolonged-release versus placebo and quetiapine

prolonged-release in adult patients with acute mania, the difference in YMRS mean improvement between

the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders

(defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs.

68% in the placebo add-on group).

In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic,

depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence

of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients

with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%)

in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing

continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium

treatment does not appear to be associated with an increased time to recurrence of a mood event.

Major depressive episodes in MDD

Two short-term (6 week) studies enrolled patients who had shown an inadequate response to at least one

antidepressant. Quetiapine 150 mg and 300 mg/day, given as add-on treatment to ongoing antidepressant

therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or

venlafaxine) demonstrated superiority over antidepressant therapy alone in reducing depressive symptoms

as measured by improvement in MADRS total score (LS mean change vs. placebo of 2-3.3 points).

Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however

long-term efficacy and safety has been evaluated in adult patients as monotherapy (see below).

The following studies were conducted with quetiapine prolonged-release as monotherapy treatment,

however quetiapine prolonged-release is only indicated for use as add-on therapy:

In three out of four short term (up to 8 weeks) monotherapy studies, in patients with major depressive

disorder, quetiapine prolonged-release 50 mg, 150 mg and 300 mg/day demonstrated superior efficacy to

placebo in reducing depressive symptoms as measured by improvement in the Montgomery-Åsberg

Depression Rating Scale (MADRS) total score (LS mean change vs. placebo of 2-4 points).

In a monotherapy relapse prevention study, patients with depressive episodes stabilised on open label

quetiapine prolonged-release treatment for at least 12 weeks were randomised to either quetiapine

prolonged-release once daily or placebo for up to 52 weeks. The mean dose of quetiapine prolonged-release

during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for quetiapine prolonged-

release treated patients and 34.4% for placebo- treated patients.

In a short-term (9 week) study non-demented elderly patients (aged 66 to 89 years) with major depressive

disorder, quetiapine prolonged-release dosed flexibly in the range of 50 mg to 300 mg/day demonstrated

superior efficacy to placebo in reducing depressive symptoms as measured by improvement in MADRS total

score (LS mean change vs placebo -7.54). In this study patients randomised to quetiapine prolonged-release

received 50 mg/day on Days 1-3, the dose could be increased to 100 mg/day on Day 4, 150 mg/day on Day

8 and up to 300 mg/day depending on clinical response and tolerability. The mean dose of quetiapine

prolonged-release was 160 mg/day. Other than the incidence of extrapyramidal symptoms (see Section 4.8

and 'Clinical Safety' below) the tolerability of quetiapine prolonged-release once daily in elderly patients

was comparable to that seen in adults (aged 18-65 years). The proportion of randomised patients over 75

years of age was 19%.

Clinical safety

In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence

of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for

placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal

symptoms were seen in quetiapine treated patients compared to those treated with placebo in short-term,

placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar

depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared

to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive

disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for quetiapine prolonged-release

and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major

depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for quetiapine

prolonged-release and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual

adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle

contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment

group.

In short term, fixed dose (50 mg/d to 800 mg/d), placebo-controlled studies (ranging from 3 to 8 weeks), the

mean weight gain for quetiapine-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for

the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated

patients. The percentage of quetiapine treated patients who gained ≥7% of body weight ranged from 5.3%

for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily

doses), compared to 3.7% for placebo treated patients.

A 6-week, randomised, study of lithium and quetiapine prolonged-release versus placebo and quetiapine

prolonged-release in adult patients with acute mania indicated that the combination of quetiapine prolonged-

release with lithium leads to more adverse events (63% versus 48% in quetiapine prolonged-release in

combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms

reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority

of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the

placebo add-on group. The incidence of somnolence was higher in the quetiapine prolonged-release with

lithium add-on group (12.7%) compared to the Quetiapine with the placebo add-on group (5.5%). In

addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%)

at the end of treatment compared to patients in the placebo add-on group (4.7%).

Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which

patients were treated with quetiapine, followed by a randomised withdrawal period during which patients

were randomised to quetiapine or placebo. For patients who were randomised to quetiapine, the mean weight

gain during the open label period was 2.56 kg, and by week 48 of the randomised period, the mean weight

gain was 3.22 kg, compared to open label baseline. For patients who were randomised to placebo, the mean

weight gain during the open label period was 2.39 kg, and by week 48 of the randomised period the mean

weight gain was 0.89 kg, compared to open label baseline.

placebo-controlled

studies

elderly

patients

with

dementia-related

psychosis,

incidence

cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in

placebo-treated patients.

In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count ≥1.5 X

/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 10

/L, was 1.9% in

patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5

- <1.0 X 10

/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients. In

all clinical trials (placebo-controlled, open- label, active comparator) in patients with a baseline neutrophil

count ≥1.5 X 10

/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 10

/L was

2.9% and to <0.5 X 10

/L was 0.21% in patients treated with quetiapine.

Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. The incidence

of shifts in TSH was 3.2 % for quetiapine versus 2.7 % for placebo. The incidences of reciprocal, potentially

clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in

thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in

total and free T

was maximal within the first six weeks of quetiapine treatment, with no further reduction

during long-term treatment. For about 2/3 of all cases, cessation of quetiapine treatment was associated with

a reversal of the effects on total and free T

, irrespective of the duration of treatment.

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 (4%) compared with risperidone (10%), for patients

with at least 21 months of exposure.

Paediatric population

Clinical efficacy

The efficacy and safety of quetiapine was studied in a 3-week placebo controlled study for the treatment of

mania (n=284 patients from the US, aged 10-17). About 45% of the patient population had an additional

diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n=

222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to quetiapine

were excluded. Treatment with quetiapine was initiated at 50 mg/day and on day 2 increased to 100 mg/day;

subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day)

using increments of 100 mg/day given two or three times daily.

In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus

placebo) was –5.21 for quetiapine 400 mg/day and –6.56 for quetiapine 600 mg/day. Responder rates

(YMRS improvement ≥50%) were 64% for quetiapine 400 mg/day, 58% for 600 mg/day and 37% in the

placebo arm.

In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active

minus placebo) was –8.16 for quetiapine 400 mg/day and –9.29 for quetiapine 800 mg/day. Neither low dose

(400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the

percentage of patients achieving response, defined as ≥30% reduction from baseline in PANSS total score.

Both in mania and schizophrenia higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy trial with quetiapine prolonged-release in children and

adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.

No data are available on maintenance of effect or recurrence prevention in this age group.

Clinical safety

In the short-term paediatric trials with quetiapine described above, the rates of EPS in the active arm vs.

placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs. 1.1% in the bipolar mania trial, and 1.1%

vs. 0% in the bipolar depression trial. The rates of weight gain ≥ 7% of baseline body weight in the active

arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7 % vs. 6.8% in

the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs.

1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar

depression trial. During an extended post-treatment follow-up phase of the bipolar depression trial, there

were two additional suicide related events in two patients; one of these patients was on quetiapine at the time

of the event.

Long-term safety

A 26-week open-label extension to the acute trials (n=380 patients), with quetiapine flexibly dosed at 400-

800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and

adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were

reported with higher frequency in children and adolescents than in adult patients (see Sections 4.4 and 4.8).

With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least

0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically

significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this

criterion.

5.2

Pharmacokinetic properties Absorption

Quetiapine is well absorbed following oral administration. Quetiapine prolonged-release tablet achieves

peak quetiapine and norquetiapine plasma concentrations at approximately 6 hours after 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 and dose-proportional for doses up to 800

mg administered once daily. When quetiapine prolonged-release tablet administered once daily is compared

to the same total daily dose of immediate-release quetiapine fumarate (quetiapine immediate release)

administered twice daily, the area under the plasma concentration-time curve (AUC) is equivalent, but the

maximum plasma concentration (C

) is 13% lower at steady state. When quetiapine prolonged-release

tablet is compared to quetiapine immediate release, the norquetiapine metabolite AUC is 18% lower.

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 quetiapine C

and AUC of approximately 50% and 20%

respectively. It cannot be excluded that the effect of a high fat meal on the formulation may be larger. In

comparison, a light meal had no significant effect on the C

or AUC of quetiapine. It is recommended

that quetiapine prolonged-release tablet is taken once daily without food.

Distribution:

Quetiapine is approximately 83% bound to plasma proteins.

Biotransformation:

Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of

unchanged drug-related material in the urine or faeces, following the administration of radiolabelled

quetiapine.

In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450

mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.

Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of

human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 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 drugs 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.

Elimination:

The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.

Approximately 73% of a radiolabelled drug was excreted in the urine and 21% in the faeces with less than

5% of the total radioactivity representing unchanged drug-related material. 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 pharmacokinetics of quetiapine does not differ between men and women

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.

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.

Hepatic impairment

The mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic

impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma

levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these

patients (see Section 4.2).

Paediatric population

Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on

steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose- normalised plasma

levels of the parent compound, quetiapine, in children and adolescents (10- 17 years of age) were in general

similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC

and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children

(10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.

No information is available for quetiapine prolonged-release in children and adolescents.

5.3

Preclinical safety data

There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory

animals at a clinically relevant exposure level the following deviations were seen, which as yet have not

been confirmed in long-term clinical research:

In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular

cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of

red and white blood cell count have been observed; and in dogs lens opacity and cataracts (for cataracts/lens

opacities, see Section 5.1).

In an embryo foetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This

effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects

were apparent at maternal exposure levels similar or slightly above those in humans at the maximal

therapeutic dose. The relevance of this finding for humans is unknown.

In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of

diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to

elevated prolactin levels and not directly relevant to humans because of species differences in hormonal

control of reproduction.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Cellulose, Microcrystalline

Lactose monohydrate

Sodium citrate

Hypromellose

Magnesium Stearate

Film coat:

Hypromellose

Macrogol 400

Titanium Dioxide (E171)

Iron Oxide Yellow (E172) (50 mg, and 300 mg tablets)

Iron Oxide Red (E172) (50 mg tablets)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

PVC-Aclar/Aluminium blisters in cartons of 10, 14, 20, 28, 30, 50, 56, 60, 90, 98 and 100 tablets.

White, HDPE bottle with a child-resistant polypropylene screw cap containing 60 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements for disposal

7.

MARKETING AUTHORISATION HOLDER

<To be completed nationally>

8.

MARKETING AUTHORISATION NUMBERS

<To be completed nationally>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<To be completed nationally>

10.

DATE OF REVISION OF THE TEXT

201-07-22

<To be completed nationally>

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