Brancico XL 200mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Quetiapine fumarate
Available from:
Zentiva Pharma UK Ltd
ATC code:
N05AH04
INN (International Name):
Quetiapine fumarate
Dosage:
200mg
Pharmaceutical form:
Modified-release tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04020100; GTIN: 5000283658283
Authorization number:
PL 17780/0762

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Package leaflet: Information for the user

Brancico XL 200 mg, 300 mg or 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

1. What Brancico XL is and what it is used for

2. What you need to know before you take

Brancico XL

3. How to take Brancico XL

4. Possible side effects

5. How to store Brancico XL

6. Contents of the pack and other information

1. What Brancico XL is and what it is used for

Brancico XL contains a substance called quetiapine.

This belongs to a group of medicines called

antipsychotics. Brancico XL 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 Brancico XL 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 Brancico XL

even when you feel better.

2. What you need to know before you take

Brancico XL

Do not take Brancico XL

If you are allergic to quetiapine or any of the

other ingredients of this medicine (listed in

section 6)

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)

Do not take Brancico XL if the above applies to

you. If you are not sure, talk to your doctor or

pharmacist before taking Brancico XL.

Warnings and precautions

Talk to your doctor or pharmacist before taking

Brancico XL 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 or if 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

Brancico XL.

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, Brancico XL should

not be taken because the group of medicines

that Brancico XL 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 apnea”) 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 Brancico XL:

A combination of fever, severe muscle stiffness,

sweating or a lowered level of consciousness

(a disorder called “neuroleptic malignant

syndrome”). Immediate medical treatment may

be needed.

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).

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 Brancico XL to be stopped and/or

treatment to be given.

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

Brancico XL. You and your doctor should check

your weight regularly.

Children and Adolescents

Brancico XL is not for use in children and

adolescents below 18 years of age.

Other medicines and Brancico XL

Tell your doctor or pharmacist if you are taking,

have recently taken or might take any other

medicines.

Do not take Brancico XL 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.

Brancico XL with food, drink and alcohol

Brancico XL 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 Brancico XL and

alcohol can make you sleepy.

Do not drink grapefruit juice while you are

taking Brancico XL. 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 or pharmacist for advice before

taking this medicine.

You should not take Brancico XL during pregnancy

unless this has been discussed with your doctor.

Brancico XL should not be taken if you are

breast-feeding.

The following symptoms which can represent

withdrawal may occur in newborn babies, of

mothers that have used Brancico XL 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 tablets may make you feel sleepy. Do not

drive or use any tools or machines until you know

how the tablets affect you.

Effect on Urine Drug Screens

If you are having a urine drug screen, taking

Brancico XL may cause positive results for

methadone or certain drugs 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.

Brancico XL contains lactose

If you have been told by your doctor that you have

an intolerance to some sugars, contact your doctor

before taking this medicinal product.

3. How to take Brancico XL

Always take this medicine exactly as your doctor or

pharmacist 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 will usually be 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 drink 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

Brancico XL. It can affect the way the medicine

works.

Do not stop taking your tablets even if you feel

better, unless your doctor tells you to.

Patients with liver problems

If you have liver problems your doctor may change

your dose.

Elderly

If you are elderly your doctor may change your

dose.

Use in children and adolescents under

18 years

Brancico XL should not be used by children and

adolescents aged under 18 years.

If you take more Brancico XL than you should

If you take more Brancico XL than prescribed by

your doctor, you may feel sleepy, feel dizzy and

experience abnormal heart beats. Contact your

doctor or nearest hospital straight away. Keep the

Brancico XL tablets with you.

If you forget to take a dose of Brancico XL

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 dose.

If you stop taking Brancico XL

If you suddenly stop taking Brancico XL, 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.

2818790

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 or dry

mouth;

Feeling sleepy - this may go away with time, as

you keep taking Brancico XL (may lead to falls);

Discontinuation symptoms (symptoms which

occur when you stop taking Brancico XL)

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).

Common (may affect up to 1 in 10 people):

Rapid heartbeat;

Feeling like your heart is pounding, racing or

has skipped beats;

Constipation or 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 more hungry;

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 sensations 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 fat around

your abdomen, a decrease in “good

cholesterol” (HDL-C), an increase in a type of

fat in your blood called triglycerides, 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 the 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 have used quetiapine

during their pregnancy.

The class of medicines to which Brancico XL

belongs can cause heart rhythm problems, which

can be serious and in severe cases may be 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.

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 the Yellow Card Scheme:

www.mhra.gov.uk/yellowcard. By reporting side

effects you can help provide more information on

the safety of this medicine.

5. How to store Brancico XL

Keep this medicine out of the sight and reach of

children.

Do not use Brancico XL after the expiry date

which is stated on the container after EXP. The

expiry date refers to the last day of that month.

Brancico XL 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 protect the environment

6. Contents of the pack and further

information

What Brancico XL contains

The active substance is quetiapine. Brancico XL

tablets contain 200 mg, 300 mg or 400 mg of

quetiapine (as quetiapine fumarate).

The other ingredients are:

Tablet core: lactose anhydrous, Methacrylic acid –

ethyl acrylate copolymer (1:1), type A, maltose,

magnesium stearate and talc.

Tablet coating: Methacrylic acid – ethyl acrylate

copolymer (1:1), type A, triethyl citrate.

What Brancico XL looks like and contents of

the pack

The 200 mg prolonged-release tablets are white

to off white, oblong biconvex and engraved with

‘200’ on one side, 15.2 mm in length, 7.7 mm in

width and 4.8 mm in thickness.

The 300 mg prolonged-release tablets are white

to off white, oblong biconvex and engraved with

‘300’ on one side and 18.2 mm in length, 8.2 mm

in width and 5.4 mm in thickness.

The 400 mg prolonged-release tablets are white

to off white, oval biconvex and engraved with

‘400’ on one side and 20.7 mm in length, 10.2 mm

in width and 6.3 mm in thickness.

Brancico XL prolonged-release tablets are

available as PVC/PCTFE- Aluminium foil blisters

packed in a cardboard box.

The pack sizes are: 10, 30, 50, 60, 100, and

180 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and

Manufacturer

Marketing Authorisation Holder:

Zentiva, One Onslow Street, Guildford, Surrey,

GU1 4YS, UK

Manufacturer:

Pharmathen International S.A, Sapes Industrial

Park Block 5, Rodopi, 69300, Greece or

Pharmathen S.A, 6, Dervenakion str., Pallini,

Attiki, 153 51, Greece

This leaflet was last revised in April 2016

’Zentiva’ is a register

d trademark © 2016 Zentiva

Read the complete document

Object 1

Brancico XL 200 mg prolonged-release tablets

Summary of Product Characteristics Updated 27-Sep-2016 | Zentiva

1. Name of the medicinal product

Brancico XL 200 mg prolonged-release tablets

2. Qualitative and quantitative composition

Brancico XL 200 mg contains 200 mg quetiapine (as quetiapine fumarate)

Excipient with known effect: 56 mg lactose (anhydrous) per tablet

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged-release tablet

200 mg: a white to off white, oblong biconvex tablet, 15.2 mm in length, 7.7 mm in width and 4.8 mm in

thickness, engraved with “200“ on one side.

4. Clinical particulars

4.1 Therapeutic indications

Brancico XL 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 quetiapine (see section 4.4).

4.2 Posology and method of administration

Posology

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

clear information on the appropriate dosage for their condition.

Adults

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

Brancico XL should be administered 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

Brancico XL 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 Brancico XL for acute treatment of bipolar disorder should continue on Brancico XL at the

same dose administered at bedtime. Brancico XL 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

Brancico XL 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 Brancico XL at the equivalent total daily dose taken once

daily.

Individual dosage adjustments may be necessary.

Elderly

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

especially during the initial dosing period. The rate of dose titration of Brancico XL 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

Brancico Xl 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 metabolized by the liver. Therefore, Brancico XL 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

Brancico XL 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 Brancico XL 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 adults 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 x10

/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 x10

/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, 4.9 and 5.1).

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 utilized 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 utilised 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 QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or

hypomagnesaemia (see section 4.5).

Cardiomyopathy and myocarditis

Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing

experience, however, a causal relationship to quetiapine has not been established. Treatment with

quetiapine should be reassessed in patients with suspected cardiomyopathy or myocarditis.

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 randomized

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). 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 sections 4.8 and 5.1). The data showed an

additive effect at week 3.

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.

Lactose

Brancico XL 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.

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).

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

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 versus placebo and quetiapine 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 of agitation, hypertonia, hypotonia, tremor,

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

carefully.

Breastfeeding

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 breast feeding 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).

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,

headache, dizziness, 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.

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

Blood and

lymphatic

system

disorders

Decreased

haemoglobin

Leucopenia

1,28

decreased neutrophil

count, eosinophils

increased

Neutropenia

Thrombocytope

nia, Anaemia,

platelet count

decreased

Agranulocytosis

Immune system

disorders

Hypersensitivity

(including

allergic skin

reactions)

Anaphylactic

reaction

Endocrine

disorders

Hyperprolactinaemia

, decreases in total

, decreases in free

, decreases in total

Decreases in

free T

24

Hypothyroidism

Inappropriate

antidiuretic

hormone

secretion

, increases in TSH

Metabolism

and nutritional

disorders

Elevations in

serum

triglyceride

levels

10,30

Elevations in

total cholesterol

(predominantly

cholesterol)

11,30

Decreases in

HDL cholesterol

17, 30

, Weight

gain

8,30

Increased appetite,

blood glucose

increased to

hyperglycaemic

levels

6,30

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

, headache,

Extrapyramidal

symptoms

1, 21

Dysarthria

Seizure

Restless legs

syndrome,

Tardive

dyskinesia

1, 5

Syncope

4, 16

Cardiac

disorders

Tachycardia

Palpitations

QT prolongation

1, 12,18

Bradycardia

Eye Disorders

Vision blurred

Vascular

disorders

Orthostatic

hypotension

4, 16

Venous

thromboembolism

Respiratory,

thoracic and

mediastinal

disorder

Dyspnoea

Rhinitis

Gastrointestina

l disorders

Dry mouth

Constipation,

dyspepsia, vomiting

Dysphagia

Pancreatitis

Intestinal

obstruction/Ileus

Hepatobiliary

disorders

Elevations in serum

alanine

aminotransferase

(ALT)

Elevations in gamma-

GT levels

Elevations in

serum aspartate

aminotransferas

e (AST)

Jaundice

Hepatitis

Skin and

subcutaneous

tissue disorders

Angioedema

Stevens-

Johnson

syndrome

Musculoskeleta

l and

connective

tissue disorders

Rhabdomyolysi

Renal and

urinary

disorders

Urinary

retention

Pregnancy,

puerperium

and perinatal

conditions

Reproductive

system and

breast

disorders

Sexual

dysfunction

Priapism,

galactorrhoea,

breast swelling,

menstrual disorder

General

disorders and

administration

site conditions

Withdrawal

(discontinuation)

symptoms

1, 9

Mild asthenia,

peripheral oedema,

irritability, pyrexia

Neuroleptic

malignant

syndrome

hypothermia

Investigations

Elevations in

blood creatine

phosphokinase

1. See Section 4.4.

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

continued administration of quetiapine.

3. Asymptomatic elevations (shift from normal to > 3x 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.

4. 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).

5. Calculation of Frequency for these ADR's have only been taken from post-marketing data with the

immediate release formulation of quetiapine.

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

mmol/L) on at least one occasion.

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

in bipolar depression.

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

treatment in adults.

9. 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 10

/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 hemoglobin 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 anytime 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 10

/L at baseline to <0.5 x 10

/L at any time during

treatment and based on patients with severe neutropenia (<0.5 x 10

/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 anytime post-baseline

in all trials. Shifts in eosinophils are defined as >1x 10

cells/L at any time.

28. Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline

in all trials. Shifts in WBCs are defined as ≤ 3x10

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

3, 4

Syncope

Vascular disorders

Increases in blood pressure

Respiratory, thoracic and

mediastinal disorders

Rhinitis

Gastrointestinal disorders

Vomiting

General disorders and

administration site conditions

Irritability

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

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

2. 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.

3. 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.

4. 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 the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard

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 to 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).

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 anticholinergic syndrome may

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

standard treatment, because of potential negative effect of physostigmine on 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, thiazepines and oxepines.

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 (5HT2) and dopamine D1- and D2- receptors. It is this combination of

receptor antagonism with a higher selectivity for 5HT2 relative to D2- 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 α

- receptors and moderate

affinity at adrenergic α

receptors. Quetiapine also has low or no affinity for muscarinic receptors, while

norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-

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

norquetiapine may contribute to quetiapine'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 of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates

dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.

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

profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration.

Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine

demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic

but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine

exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and

chronic administration. (See Section 4.8)

Clinical efficacy

Schizophrenia

The efficacy of quetiapine 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

immediate release-to- prolonged-release quetiapine 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. Prolonged-release quetiapine 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, ie, who discontinued study treatment due to lack of efficacy or whose

PANSS total score increased 20% or more from randomization to any visit. In patients stabilised on

immediate release quetiapine 400 mg to 800 mg, efficacy was maintained when patients were switched to

an equivalent daily dose of prolonged-release quetiapine given once daily.

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

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

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

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

additional safety findings associated with treatment with prolonged-release quetiapine 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 prolonged-release quetiapine.

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

prolonged-release quetiapine was further demonstrated with significance versus placebo in an additional 3

week study. Prolonged-release quetiapine 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

prolonged-release quetiapine 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, immediate-release quetiapine 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 immediate-release quetiapine 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 immediate-release quetiapine 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 versus placebo and quetiapine 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. Prolonged-release 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 prolonged-release quetiapine as monotherapy treatment,

however prolonged-release quetiapine 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, prolonged-release quetiapine 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

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

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

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

quetiapine 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, prolonged-release quetiapine 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 prolonged-release

quetiapine 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

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

section 4.8 and 'Clinical Safety' below) the tolerability of prolonged-release quetiapine once daily in

elderly patients was comparable to that seen in adults (aged 18-65 years). The proportion of randomized

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 prolonged-

release quetiapine 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 prolonged-release quetiapine 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 (50mg/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 versus placebo and quetiapine in adult patients

with acute mania indicated that the combination of quetiapine with lithium leads to more adverse events

(63% versus 48% in quetiapine 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 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 randomized withdrawal period during which patients

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

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

mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomized to

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

randomized period the mean weight gain was 0.89 kg, compared to open label baseline.

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of

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

incidences of shifts in TSH was 3.2 % for quetiapine versus 2.7 % for placebo. The incidence 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 T4 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 T4, 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 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 pediatric 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. Prolonged-release quetiapine achieves peak

quetiapine and norquetiapine plasma concentrations at approximately 6 hours after administration (T

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 prolonged-release quetiapine administered once daily is compared

to the same total daily dose of immediate-release quetiapine fumarate administered twice daily, the area

under the plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration

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

quetiapine, 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 prolonged-release 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 prolonged-release quetiapine 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-normalized 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 prolonged-release quetiapine 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 embryofoetal 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

Core

Methacrylic acid “ ethyl acrylate copolymer (1:1), type A

Lactose anhydrous

Magnesium stearate

Maltose

Talc

Coating

Methacrylic acid “ ethyl acrylate copolymer (1:1), type A

Triethyl Citrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

A cardboard box containing the appropriate number of white opaque PVC/PCTFE-Aluminium foil

blisters and an instruction leaflet.

The pack sizes are:

Brancico XL 200 mg: 10, 30, 50, 60, 100, and 180 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as:

Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8. Marketing authorisation number(s)

PL 17780/0762

9. Date of first authorisation/renewal of the authorisation

25/05/16

10. Date of revision of the text

25/05/16

Company Contact Details

Zentiva

Address

One Onslow Street, Guildford, Surrey, GU1 4YS

+44 (0) 1483 554831

Medical Information e-mail

[email

protected]

Telephone

+44 (0)1483 505 515

Medical Information Direct Line

+44 (0)845 372 7101

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