SEROQUEL XR 400 MG

Israel - English - Ministry of Health

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Active ingredient:
QUETIAPINE FUMARATE
Available from:
ASTRA ZENECA (ISRAEL) LTD
ATC code:
N05AH04
Pharmaceutical form:
TABLETS EXTENDED RELEASE
Composition:
QUETIAPINE FUMARATE 400 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
ASTRA ZENECA UK LIMITED
Therapeutic group:
QUETIAPINE
Therapeutic area:
QUETIAPINE
Therapeutic indications:
Seroquel XR is indicated for the treatment of Schizophrenia .Seroquel XR is effective in preventing relapse in stable schizophrenic patients who have been maintained on Seroquel XR. Seroquel XR is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorder.Treatment of acute mania associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate.Seroquel XR is indicated for the treatment of major depressive episodes in bipolar disorder. Seroquel XR is indicated for preventing recurrence in bipolar disorder in patients whose manic, mixed or depressive episode has responded to quetiapine treatment as monotherapy or in combination with lithium or sodium valproate. Seroquel XR is indicated for add-on treatment of major depressive episods in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy (see section 5.1 Pharmacodynamic properties). Prior to initiating treatment, clinicians sho
Authorization number:
141 92 31976 00
Authorization date:
2014-10-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

18-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

06-08-2019

Patient Package Leaflet in Accordance With

the Pharmacists’ Regulations (Preparations) – 1986

The medicine is dispensed with a doctor’s prescription only

SEROQUEL XR

SEROQUEL XR

SEROQUEL XR

50 mg

150 mg

200 mg

Extended-release Extended-release Extended-release

tablets

tablets

tablets

Composition:

Each tablet contains:

Each tablet contains:

Each tablet contains:

Quetiapine 50 mg

Quetiapine 150 mg

Quetiapine 200 mg

(as fumarate)

(as fumarate)

(as fumarate)

SEROQUEL XR

SEROQUEL XR

300 mg

400 mg

Extended-release

Extended-release

tablets

tablets

Composition:

Each tablet contains:

Each tablet contains:

Quetiapine 300 mg

Quetiapine 400 mg

(as fumarate)

(as fumarate)

For inactive ingredients please refer to Section 6: "Further Information ".

Read this leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine. If you have further

questions, refer to the doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment. Do not pass

it on to others. It may harm them, even if it seems to you that their ailment is

similar.

The medicine is not intended for children and adolescents below the age of 18

years.

This medicine is not intended for elderly people who suffer from dementia.

Antidepressants and antianxiety medicines increase the risk of suicidal

behavior and thoughts among children, adolescents and young adults up

to 25 years of age. When beginning treatment with this medicine, patients

of all ages and their relatives, must monitor behavioral changes such as:

worsening of depression, suicidal thoughts, aggressiveness etc. If

changes such as these occur, refer immediately to the doctor.

Elderly patients who suffer from dementia-related psychosis, and are been

treated with antipsychotics, have an increased risk of death.

1.

WHAT IS THE MEDICINE INTENDED FOR?

to treat schizophrenia.

to treat manic episodes associated with bipolar disorders.

to treat depression associated with bipolar disorders.

to treat depression together with an additional antidepressant.

Therapeutic group:

Antipsychotics.

2.

BEFORE USING THE MEDICINE

X Do not use Seroquel XR if:

you are sensitive (allergic) to the active ingredient or to any of the other

ingredients contained in the medicine (please see section 6 – “Further

Information”).

you are taking the following medicines:

medicines for treating acquired immune deficiency syndrome (HIV)

medicines from the azole family (for fungal infections)

erythromycin or clarithromycin (to treat infections)

nefazodone (for depression)

If you are not sure, refer to the doctor before taking Seroquel XL.

Special warnings regarding use of Seroquel XR

! Before treatment with Seroquel XR, tell the doctor if:

you have low blood-pressure.

you have liver problems.

you have ever had seizures.

you have had a stroke, particularly if you are elderly.

you have had a low white blood cell count in the past (which may or may

not have been caused by other medicines).

you or a family member have or have had heart problems such as heart

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

heart, or if you are taking medicines that affect heart rate.

you or a family member have a medical history of blood clots, as

medicines of this type are involved in creating blood clots.

you have diabetes, or if you are at risk of developing diabetes. In such a

case, the doctor may test your blood sugar levels while you are being

treated with Seroquel XR.

Do not take Seroquel XR if you are elderly and have dementia, because

Seroquel XR may increase the risk of stroke, or in some cases it may

increase the risk of death in elderly people with dementia.

you are an elderly person with Parkinson’s disease/parkinsonism.

you have or have had: a condition where you stop breathing for short

periods during your nightly sleep (called “sleep apnea”) and are taking

medicines that slow down the normal activity of the brain.

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 “anticholinergics”) that affect the

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

you have a history of alcohol or drug abuse.

Inform the doctor immediately if you feel any of the following after taking

Seroquel XR:

A combination of fever, acute muscle stiffness, sweating, or reduced

consciousness (this is a phenomenon called “neuroleptic malignant

syndrome”). You may need urgent medical treatment.

Involuntary movements, mainly of the face and tongue.

Dizziness, if you feel sleepy, which can increase the risk of accidental falls

in elderly people.

Fits (seizures).

Long-lasting and painful erection.

Inform the doctor as soon as possible if you feel any of the following after taking

Seroquel XR:

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

Seroquel XR 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.

Suicidal thoughts and exacerbated depression

Depression is known to be the risk factors for suicidal thoughts. Increased

suicidal thoughts can occur when first starting treatment with Seroquel, since

it takes time for the medicine to work, usually about two weeks but sometimes

longer. These thoughts are more likely in young adults. 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 suicidal thoughts 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.

DRESS - Drug Rash with Eosinophilia and Systemic Symptoms

Widespread rash, high body temperature, liver enzyme elevations,

eosinophilia, enlarged lymph nodes and other body organs involvement. Stop

using Seroquel XR if you develop these symptoms and contact your doctor or

seek medical attention immediately.

Weight gain

Weight gain has been seen in patients taking Seroquel XL. You and your

doctor should check your weight regularly.

Children and adolescents

The medicine is not intended for children and adolescents below 18 years of age!

If you are taking other medicines

If you are taking, or have recently taken, other medicines including non-

prescription medicines and nutritional supplements, tell the doctor or

pharmacist.

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

medicines for treating acquired immune deficiency syndrome (AIDS).

Azole medicines (for fungal infections).

Erythromycin or clarithromycin (for infections).

Nefazodone (for depression).

Tell your doctor or the pharmacist if you are taking:

medicines for epilepsy (such as phenytoin or carbamazepine)

medicines for lowering blood pressure

barbiturates (for insomnia)

thioridazine or lithium (other antipsychotics)

medicines that affect the heart beats, for instance, medicines that can cause

an electrolyte imbalance (low levels of potassium and magnesium), such as

diuretics or certain antibiotics (medicines for infections)

medicines that can cause constipation

medicines (called anticholinergic), 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.

! Use of the medicine and food

Do not drink grapefruit juice during treatment with this medicine. Grapefruit

juice can affect the way the medicine works.

Seroquel XL can be affected by food. Thereof take this medicine at least one

hour before eating or prior to bedtime.

! Use of the medicine and alcohol consumption

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

Seroquel XL and alcohol can make you sleepy.

! Pregnancy and breastfeeding

If you are pregnant, planning to become pregnant, or are breastfeeding, consult

with a doctor before using this medicine. Do not take Seroquel XR during

pregnancy unless you have discussed this with your doctor. Do not take

Seroquel XR while you are breastfeeding.

The following symptoms may occur in newborns of mothers who took Seroquel

XR during the last trimester of pregnancy: tremor, muscle stiffness and/or

weakness, sleepiness, agitation, breathing problems, and difficulty eating. If your

baby develops any of these signs, consult the attending doctor.

! Driving and operating machinery

Using this medicine may make you feel sleepy. Do not drive or use any

dangerous machinery until you know how the medicine affects you.

! Important information about some of the ingredients of the medicine

The tablets contain lactose, which is a type of sugar. If you have been told by the

doctor that you are unable to digest certain sugars, consult the doctor before

taking this medicine.

Seroquel XR 50 mg tablets - each tablet contains 125.72 mg lactose

monohydrate.

Seroquel XR 150 mg tablets - each tablet contains 74.65 mg lactose

monohydrate.

Seroquel XR 200 mg tablets - each tablet contains 52.87 mg lactose

monohydrate.

Seroquel XR 300 mg tablets - each tablet contains 49.31 mg lactose

monohydrate.

Seroquel XR 400 mg tablets - each tablet contains 15.50 mg lactose

monohydrate.

Effect on Urine Drug Screens

Seroquel can cause a positive result in urine tests for medicines that you are

not taking, such as: methadone or tricyclic antidepressants. These results

must be confirmed using further specific tests.

3.

HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the doctor or

pharmacist if you are uncertain. The dosage and course of treatment will be

determined by the doctor only. The doctor will adjust the daily dose of the

medicine to range between 50 mg and 800 mg, depending on your disease and

individual needs.

Do not exceed the recommended dose.

You will take your tablets once a day.

The dosage will be reduced gradually before stopping treatment.

Do not stop treatment with the medicine even if you feel better, unless your

doctor tells you.

Take the medicine at least one hour before eating or before going to sleep.

Method of use:

Do not chew, do not crush, and do not halve the tablets! Since the tablets

are extended-release tablets.

Swallow the tablets whole with water.

Do not drink grapefruit juice while you are taking Seroquel XL. It can affect the

way the medicine works.

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

This medicine is not intended for children and adolescents under the age of 18.

If you accidentally take a higher dosage

If you accidentally have taken an overdose, or if a child has accidentally

swallowed the medicine, refer immediately to a doctor or proceed to a hospital

emergency room, and bring the package of the medicine with you. You may feel

sleepiness, dizziness, and abnormal heart-beats.

If you forget to take the medicine

If you forgot to take the medicine at the scheduled time, take the dose as soon as

you remember. Do not take a double dose under any circumstances. Adhere to

the treatment recommended by your doctor.

If you stop taking the medicine

If you stop taking the medicine abruptly, you may experience the following

symptoms: inability to sleep, nausea, headache, diarrhea, vomiting, dizziness,

and nervousness. Your doctor can recommend you to gradually reduce the

dosage.

Do not take medicines in the dark! Check the label and the dose each time you

take a medicine. Wear glasses if you need them.

If you have further questions regarding use of this medicine, consult a doctor or

pharmacist.

4.

SIDE EFFECTS

As with any medicine, use of Seroquel XR may cause side effects in some users.

Do not be alarmed by reading the list of side effects. You may not suffer from any

of them.

Very common side effects (occur in more than 1 in 10 people):

Dizziness (may cause falls), headache, dry mouth

Sleepiness (may disappear with continued use of the medicine, may

cause falls)

Weight gain

Discontinuation Symptoms (symptoms which occur when you stop taking

Seroquel XR) include: vomiting, dizziness, nausea, headache, diarrhea,

insomnia and agitation. Gradual withdrawal over a period of 1 to 2 weeks

is advisable.

Abnormal muscle movements (these include difficulty starting muscle

movements, shaking, restlessness, or muscle stiffness without pain)

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

Common side effects (occur in less than 1 in 10 people):

Rapid heart rate

Feeling that your heart is pounding, racing, or has skipped beats

Constipation, indigestion

Weakness

Swelling of the arms or legs

Low blood pressure in standing position which can result in being dizzy or

feeling faint (may cause falls)

Increase in blood sugar levels

Blurred vision

Unusual dreams, nightmares

Feeling more hungry

Nervousness

Disturbances in speech and language

Suicidal thoughts and exacerbated depression

Shortness of breath

Vomiting (mainly in the elderly)

Fever

Changes in the amount of thyroid hormones in your blood

Decreases in the amount 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 breasts and unexpectedly

produce breast milk.

Women to have no monthly periods or irregular periods.

Uncommon side effects (occur in less than 1 in 100 people):

Fits or seizures

Allergic reactions that may include difficulty breathing or shock, raised

lumps on the skin, swelling of the skin and swelling around the mouth

Restless-legs syndrome (unpleasant sensation in the legs)

Difficulty swallowing

Involuntary movements, mainly of the face or tongue

Difficulties in sexual function

Change in the electric activity of the heart that is detectable in an ECG

(prolongation of the QT interval)

A slower than normal heart rate, which can occur upon starting

treatment, and may be associated with low blood pressure and fainting

Development of diabetes or exacerbation of existing diabetes

Difficulty urinating

Nasal congestion

Fainting (may cause falls)

Decrease in the amount of red blood cells

Decrease in the amount of sodium in the blood

Rare side effects (occur in the less than 1 in 1,000 people):

Combination of fever, sweating, muscle stiffness, acute tiredness or

fainting, marked increase in blood pressure or heartbeats (neuroleptic

malignant syndrome)

Yellowing of the skin and eyes (jaundice)

Inflammation of the liver (hepatitis)

Prolonged and painful erection

Swelling of breasts and unexpected production of breast milk

Blood clots in the veins, particularly in the legs (manifested by swelling,

pain, and redness of the leg), which may travel in the blood stream to the

lungs causing chest pain and difficulty in breathing. If you notice any of

these symptoms seek medical advice immediately.

Disruption of the menstrual cycle in women

Walking, talking, eating, and other activities, while asleep

Decrease in body temperature (hypothermia)

Inflammation of the pancreas

A condition combining three or more of the following symptoms: increase

in abdominal fat, decrease in ‘good cholesterol’ (HDL-C), increase in

blood triglycerides, high blood pressure, and an increase in blood sugar

level (metabolic syndrome)

Combination of fever, flu-like symptoms, sore throat, mouth ulcers or any

other infection together with a very low white blood cell count; a condition

called agranulocytosis

Bowel obstruction

Increased blood creatine phosphokinase levels

Very rare side effects (occur in less than 1 in 10,000 people):

Severe allergic reaction (called anaphylactic shock) that may include

difficulty breathing and shock

Rapid swelling of the skin, usually around the eyes, lips, and throat

(angioedema)

Severe blistering of the skin, mouth, eyes, and genitals (Stevens-Johnson

syndrome)

Acute rash, blisters, or red patches on the skin

Abnormal secretion of the hormone that controls the volume of the urine

Breakdown of muscle fibers and muscle pain (rhabdomyolysis)

Side effects of unknown frequency:

Rash with irregular red spots

Sudden acute allergic reaction with symptoms such as fever and blisters on

the skin, and skin peeling

Symptoms of withdrawal may occur in newborn babies of mothers that have

used Seroquel during their pregnancy

Stroke

The group of medicines Seroquel XR is part of can cause disturbances in heart

rate, which can be severe, and in most severe cases cause death

The following side effects have been observed in blood tests:

Change in levels of fats in the blood (triglycerides and cholesterol)

Rise in blood sugar level (glucose)

Changes in levels of thyroid hormones

Decrease in the number of certain types of blood cells

Decrease in the number of red blood cells; these cells transport oxygen

in the body

Increase in the amount of liver enzyme

Decrease in blood sodium levels

Increase in creatinine phosphokinase levels, a muscle component.

Increase in the levels of the hormone prolactin in the blood. Rarely, this

may lead to:

swelling of the breasts in men and women, and production of breast-

milk

in women, menstrual cycle stops or becomes irregular.

If a side effect occurs, or if one of the side effects worsens, or if you suffer from a

side effect not mentioned in the leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health by clicking on the link

“Report Side Effects of Drug Treatment” found on the Ministry of Health

homepage www.health.gov.il that directs you to the online form for reporting side

effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=Advers

EffectMedic@moh.gov.il

5.

HOW SHOULD THE MEDICINE BE STORED?

Do not store this medicine at a temperature exceeding 30°C.

Do not use the medicine after the expiry date (exp. date) appearing on the

package. The expiry date refers to the last day of that month. In case of doubt,

consult the pharmacist who dispensed the medicine to you.

Do not store different medicines in the same package.

Avoid poisoning!

This medicine, and any other medicine, should be kept in a safe place out of the

reach of children and/or infants in order to avoid poisoning. Do not induce

vomiting unless explicitly instructed to do so by the doctor!

Even if kept in their original package and stored as recommended, medicines

may be kept for a limited period only. Please note the expiry date of the

medicine!

6.

FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Cellulose microcrystalline; Sodium citrate; Lactose monohydrate; Magnesium

stearate; Hypromellose; Macrogol; Titanium dioxide (E171); Iron oxide, yellow

(E172) (50, 200 and 300 mg tablets); Iron oxide, red (E172) (50 mg tablets).

What does the medicine look like?

Seroquel XR 50 mg tablets are capsule-shaped, bi-convex, peach-colored, with

XR50 engraved on one side.

Seroquel XR 150 mg tablets are capsule-shaped, bi-convex, white in color, with

XR150 engraved on one side.

Seroquel XR 200 mg tablets are capsule-shaped, bi-convex, yellow in color,

with XR200 engraved on one side.

Seroquel XR 300 mg tablets are capsule-shaped, bi-convex, pale yellow in

color, with XR300 engraved on one side.

Seroquel XR 400 mg tablets are capsule-shaped, bi-convex, white in color, with

XR400 engraved on one side.

Registration number of the medicine in the National Drug Registry of the

Ministry of Health:

Seroquel XR 50 mg tablets:

1418931973

Seroquel XR 150 mg tablets:

1469733472

Seroquel XR 200 mg tablets:

1419031974

Seroquel XR 300 mg tablets:

1419131975

Seroquel XR 400 mg tablets:

1419231976

Manufacturer:

AstraZeneca UK Ltd., Macclesfield, UK.

License holder and importer:

AstraZeneca (Israel) Ltd., P.O.B 1455, Hod-Hasharon 4524075.

This leaflet was checked and approved by the Ministry of Health in: April 2017

and was updated according to Ministry of Health guidelines in May 2019.

The content of this leaflet was approved by the Ministry of Health in Apr 2017 and updaccording to

the guidelines of the Ministry of Health in May 2019

1.

NAME OF THE MEDICINAL PRODUCT

Seroquel XR 50 mg prolonged-release tablets

Seroquel XR 150 mg prolonged-release tablets

Seroquel XR 200 mg prolonged-release tablets

Seroquel XR 300 mg prolonged-release tablets

Seroquel XR 400 mg prolonged-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Seroquel XR 50 mg contains 50 mg quetiapine (as quetiapine fumarate)

Excipient : 125.72 mg lactose monohydrate per tablet

Seroquel XR 150 mg contains 150 mg quetiapine (as quetiapine fumarate)

Excipient : 74.65 mg lactose monohydrate

per tablet

Seroquel XR 200 mg contains 200 mg quetiapine (as quetiapine fumarate)

Excipient : 52.87 mg lactose monohydrate per tablet

Seroquel XR 300 mg contains 300 mg quetiapine (as quetiapine fumarate)

Excipient : 49.31 mg lactose monohydrate

per tablet

Seroquel XR 400 mg contains 400 mg quetiapine (as quetiapine fumarate)

Excipient : 15.50 mg lactose monohydrate

per tablet

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Prolonged-release tablet

Seroquel XR 50 mg tablets are peach-coloured and engraved with “XR 50” on one side

Seroquel XR 150 mg: White, bi-convex, capsule shaped tablets, marked with XR150.

Seroquel XR 200 mg tablets are yellow and engraved with “XR 200” on one side

Seroquel XR 300 mg tablets are pale yellow and engraved with “XR 300” on one side

Seroquel XR 400 mg tablets are white and engraved with “XR 400” on one side

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED

PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. SEROQUEL XR is not approved for the treatment of patients with

dementia-related psychosis.

Suicidal Thoughts and Behavior

Antidepressants increased the risk of suicidal thoughts and behavior in children,

adolescents, and young adults in short-term studies. These studies did not show an

increase in the risk of suicidal thoughts and behavior with antidepressant use in patients

over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and

older.

In patients of all ages who are started on antidepressant therapy, monitor closely for

worsening, and for emergence of suicidal thoughts and behaviors. Advise families and

caregivers of the need for close observation and communication with the prescriber.

SEROQUEL XR is not approved for use in pediatric patients under 18 years of age.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Seroquel XR is indicated for the treatment of Schizophrenia.

Seroquel XR is effective in preventing relapse in stable schizophrenic patients who have been

maintained on Seroquel XR.

Seroquel XR is indicated for the treatment of moderate to severe manic episodes associated with

bipolar disorder.

Seroquel XR is indicated for the treatment of major depressive episodes in bipolar disorder.

Treatment of acute mania associated with bipolar I disorder as monotherapy or in combination with

lithium or sodium valproate.

Seroquel XR is indicated for preventing recurrence in bipolar disorder in patients whose manic,

mixed or depressive episode has responded to quetiapine treatment, as monotherapy or in

combination with lithium or sodium valproate.

Seroquel XR is indicated for add-on treatment of major depressive episods in patients with Major

Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy

(see section 5.1 Pharmacodynamic properties). Prior to initiating treatment, clinicians should

consider the safety profile of Seroquel XR (see section 4.4 Special warnings and precautions for

use).

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.

Seroquel XR should be administered once daily, without food (Seroquel XR should be

administrated at least one hour before a meal). The tablets should be swallowed whole and not

split, chewed or crushed.

Adults:

For the treatment of schizophrenia and manic episodes associated with bipolar disorder

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 depressive episodes associated with bipolar disorder

Seroquel XR should be administered at evening. The 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. Depending on the patient’s response Seroquel XR maybe titrated up to 600 mg

daily. Antidepressant efficacy was demonstrated at 300 mg and 600 mg/day; however, no

additional benefit was seen in the 600 mg group above 300 mg daily during short-term treatment

(see section 5.1).

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. When treating depressive episodes in

bipolar disorder, treatment should be prescribed by physicians experienced in treating bipolar

disorder.

For preventing recurrence in bipolar disorder

For prevention of recurrence of manic, depressive or mixed episodes in bipolar disorder, patients

who have responded to Seroquel XR for acute treatment of bipolar disorder should continue on

Seroquel XR at the same dose. The dose may 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:

Seroquel XR should be administered once daily in the evening. 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 Pharmacodynamic properties) 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 Seroquel immediate-release tablets:

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

immediate release Seroquel tablets may be switched to Seroquel XR at the equivalent total daily

dose taken once daily. Individual dosage adjustments may be necessary.

Elderly:

As with other antipsychotics and antidepressant, Seroquel XR should be used with caution in the

elderly, especially during the initial dosing period. The rate of dose titration of Seroquel XR 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 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:

The safety and efficacy of Seroquel XR have not been evaluated in children and adolescents.

Renal impairment:

Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment:

Quetiapine is extensively metabolized by the liver. Therefore, Seroquel XR should be used with

caution in patients with known hepatic impairment, especially during the initial dosing period.

Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in

increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of

the individual patient.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients of this product.

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 Seroquel XR 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 treated with 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. A population-based retrospective study of

quetiapine for the treatment of patients with major depressive disorder showed an increased risk of

self-harm and suicide in patients aged 25 to 64 years without a history of self-harm during use of

quetiapine with other antidepressants.

Metabolic risk

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

glucose (see hyperglycaemia) 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 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

Seroquel 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 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 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

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.

Elderly patients with Parkinson's disease (PD)/parkinsonism

A population-based retrospective study of quetiapine for the treatment of patients with MDD,

showed an increased risk of death during use of quetiapine in patients aged >65 years. This

association was not present when patients with PD were removed from the analysis. Caution

should be exercised if quetiapine is prescribed to elderly patients with PD.

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 Section 4.8 and 5.1).

The data showed an additive effect at week 3.

Lactose:

Seroquel XR 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).

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 SEROQUEL XR versus placebo and SEROQUEL

XR 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.

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 Seroquel XL

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, 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.

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).

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

Thrombocytope

nia, Anaemia,

platelet count

decreased

Agranulocyto

Immune

system

disorders

Hypersensitivity

(including

allergic skin

reactions)

Anaphylactic

reaction

Endocrine

disorders

Hyperprolactinaemi

, decreases in

total T

decreases in free

, decreases in

total T

increases in TSH

Decreases in

free T

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

Increased appetite,

blood glucose

increased to

hyperglycaemic

levels

6, 30

Hyponatraemia

, Diabetes

Mellitus

Exacerbation of

pre-existing

diabetes

Metabolic

syndrome

cholesterol

17,30

, Weight

gain

8,30

Psychiatric

disorders

Abnormal dreams

and nightmares,

Suicidal ideation

and suicidal

behaviour

Somnambuli

sm and

related

reactions

such as

sleep talking

and sleep

related

eating

disorder

Nervous

system

disorders

Dizziness

somnolence

headache,

Extrapyramidal

symptoms

1, 21

Dysarthria

Seizure

Restless legs

syndrome,

Tardive

dyskinesia

1, 5,

Syncope

4,16

Cardiac

disorders

Tachycardia

Palpitations

prolongation

1,12,

Bradycardia

disorders

Vision blurred

Vascular

disorders

Orthostatic

hypotension

4,16

Venous

thromboemb

olism

Stroke

Respiratory

, thoracic

mediastinal

disorder

Dyspnoea

Rhinitis

Gastrointes

tinal

disorders

Dry mouth

Constipation,

dyspepsia,

vomiting

Dysphagia

Pancreatitis

Intestinal

obstruction/Il

Hepato-

biliary

disorders

Elevations in serum

alanine

aminotransferase

(ALT)

Elevations in

gamma-GT levels

Elevations in

serum aspartate

aminotransferas

e (AST)

Jaundice

Hepatitis

Skin and

subcutaneo

us tissue

disorders

Angioedema

Stevens-

Johnson

syndrome

Toxic

Epidermal

Necrolysis,

Erythema

Multiforme

Drug Rash

with

Eosinophili

Systemic

Symptoms

(DRESS)

Musculoske

letal and

connective

tissue

disorders

Rhabdomyolys

Renal and

urinary

disorders

Urinary retention

Pregnancy,

puerperium

perinatal

conditions

Drug

withdrawal

syndrome

neonatal

Reproducti

ve system

and breast

disorders

Sexual

dysfunction

Priapism,

galactorrhoe

a, breast

swelling,

menstrual

disorder

General

disorders

administrati

on site

conditions

Withdrawal

(discontinuatio

symptoms

Mild asthenia,

peripheral oedema,

irritability, pyrexia

Neuroleptic

malignant

syndrome

hypothermia

Investigatio

Elevations in

blood

creatine

phosphokina

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 post marketing 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

(8) 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

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 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 T

, free T

, total T

and free T

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 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 10

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 10

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.

(33)

Based on one retrospective non-randomised epidemiological study.

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.

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.

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 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.

(2) Based on shifts above clinically significant thresholds (adapted from the National Institute of

Health criteria) or increases >20mmHg 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 to the Ministry of Health

according to the National Regulation by an online form:

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh

.gov.il)

4.9

Overdose

Symptoms

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

substance’s known pharmacological effects, ie, drowsiness and sedation, tachycardia, hypotension

and anticholinergic 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.

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.

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 Seroquel 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 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 Seroquel XR'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 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 in haloperidol-

sensitised or drug-naive Cebus monkeys after acute and chronic administration.

Clinical efficacy:

Schizophrenia

The efficacy of Seroquel XR 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 Seroquel IR-to-Seroquel XR 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. Seroquel XR 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 Seroquel immediate release 400 mg to 800 mg, efficacy was maintained when

patients were switched to an equivalent daily dose of Seroquel XR given once daily.

In a long-term study in stable schizophrenic patients who had been maintained on Seroquel XR for

16 weeks, Seroquel XR was more effective than placebo in preventing relapse. The estimated

risks of relapse after 6 months treatments was 14.3% for the Seroquel XR treatment group

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

findings associated with treatment with Seroquel XR 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 Seroquel XR.

Bipolar Disorder

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

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

efficacy of Seroquel XR was further demonstrated with significance versus placebo in an additional

3-week study. Seroquel XR was dosed in the range of 400 to 800 mg/day and the mean dose was

approximately 600 mg/day. Seroquel 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

Seroquel XR 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, Seroquel IR 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 Seroquel IR 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 Seroquel IR 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 Seroquel XL versus placebo and Seroquel XL 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. Seroquel XR 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 Seroquel XR as monotherapy treatment, however

Seroquel XR 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, Seroquel XR 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 Seroquel XR treatment for at least 12 weeks were randomised to either Seroquel XR once

daily or placebo for up to 52 weeks. The mean dose of Seroquel XR during the randomised phase

was 177 mg/day. The incidence of relapse was 14.2% for Seroquel XR 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, Seroquel XR 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 Seroquel XR 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 Seroquel XR was 160 mg/day. Other than the incidence of

extrapyramidal symptoms (see section 4.8 Undesirable effects and 'Clinical Safety' below) the

tolerability of Seroquel XR 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 Seroquel XR 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 Seroquel XR and 2.3% for

placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (e.g.

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 SEROQUEL XR versus placebo and SEROQUEL XR

in adult patients with acute mania indicated that the combination of SEROQUEL XR with lithium

leads to more adverse events (63% versus 48% in SEROQUEL XR 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 SEROQUEL XR with lithium add-on group (12.7%)

compared to the SEROQUEL XR with the placebo add-on group (5.5%). In addition, a higher

percentage of patients treated in the lithium addon 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.

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 10

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

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 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 T4, irrespective of the duration of treatment.

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of Seroquel (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 Seroquel (4%) compared with

risperidone (10%), for patients with at least 21 months of exposure.

Paediatric population

Clinical efficacy

The efficacy and safety of Seroquel 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 Seroquel were excluded. Treatment with Seroquel 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 Seroquel 400 mg/day and –6.56 for Seroquel 600 mg/day.

Responder rates (YMRS improvement

50%) were 64% for Seroquel 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 Seroquel 400 mg/day and –9.29 for Seroquel 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 Seroquel XL 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.

Long-term safety

A 26-week open-label extension to the acute trials (n= 380 patients), with Seroquel 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 section 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. Seroquel XR 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 Seroquel XR administered once daily is compared to

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

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

but the maximum plasma concentration (Cmax) is 13% lower at steady state. When Seroquel XR

is compared to Seroquel 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 Seroquel XR Cmax 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 Cmax

or AUC of quetiapine. It is recommended that Seroquel XR 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. norquetiapineis 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 m

), 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 (Seroquel) 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 Seroquel XL 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 T

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

Cellulose, microcrystalline

Sodium citrate

Lactose monohydrate

Magnesium stearate

Hypromellose 2208

Coating

Hypromellose 2910

Polyethylene glycol

Titanium dioxide (E171)

Iron oxide, yellow (E172) (50 mg, 200 mg and 300 mg tablets)

Iron oxide, red (E172) (50 mg tablets)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product indicated on the package materials.

6.4

Special precautions for storage

Store below 30°C.

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Polychlorotrifluoroethylene and polyvinylchloride with aluminium blister

Tablet Strength

Carton (pack)

contents

Blisters

50 mg,150 mg, 200 mg, 300 mg

and 400 mg tablets

10 tablets

1 blister of 10 tablets

30 tablets

3 blisters of 10

tablets

50 tablets

10 blisters of 5

tablets

60 tablets

6 blisters of 10

tablets

100 tablets

10 blisters of 10

tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements.

7.

MANUFACTURER:

Astra Zeneca UK Limited

8.

LICENSE HOLDER:

AstraZeneca (Israel) Ltd.,

P.O.B 1455, Hod-Hasharon 4524075

ינוי

2019

אפור

/

ה

דבכנ

/

ה

חקור

/

ת

דבכנ

/

םולש ה

בר

,

: רישכתה ןולעב ןוכדע םוסרפ

mg

50/150/200/300/400

Seroquel XR

release tablets

-

prolonged

:בכרה

Seroquel XR 50 mg contains 50 mg quetiapine (as quetiapine fumarate)

Excipient : 125.72 mg lactose monohydrate per tablet

Seroquel XR 150 mg contains 150 mg quetiapine (as quetiapine fumarate)

Excipient : 74.65 mg lactose monohydrate per tablet

Seroquel XR 200 mg contains 200 mg quetiapine (as quetiapine fumarate)

Excipient : 52.87 mg lactose monohydrate per tablet

Seroquel XR 300 mg contains 300 mg quetiapine (as quetiapine fumarate)

Excipient : 49.31 mg lactose monohydrate per tablet

Seroquel XR 400 mg contains 400 mg quetiapine (as quetiapine fumarate)

Excipient : 15.50 mg lactose monohydrate per tablet

:היוותה

Seroquel XR is indicated for the treatment of Schizophrenia.

Seroquel XR is effective in preventing relapse in stable schizophrenic patients who have

been maintained on Seroquel XR.

Seroquel XR is indicated for the treatment of moderate to severe manic episodes associated

with bipolar disorder.

Seroquel XR is indicated for the treatment of major depressive episodes in bipolar disorder.

Treatment of acute mania associated with bipolar I disorder as monotherapy or in

combination with lithium or sodium valproate.

Seroquel XR is indicated for preventing recurrence in bipolar disorder in patients whose

manic, mixed or depressive episode has responded to quetiapine treatment, as monotherapy

or in combination with lithium or sodium valproate.

Seroquel XR is indicated for add-on treatment of major depressive episods in patients with

Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant

monotherapy. Prior to initiating treatment, clinicians should consider the safety profile of

Seroquel XR.

ךיראתב תואירבה דרשמ תוארוהל םאתהב ןולע ןוכדע לע עידוהל תשקבמ לארשי הקינזהרטסא תרבח

לירפא

2019

.

:אוה אפורל ןולעב ירקיעה ןוכדעה

4.4

Special warnings and precautions for use

Paediatric population:

Suicide/suicidal thoughts or clinical worsening:

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. A population-

based retrospective study of quetiapine for the treatment of patients with major depressive

disorder showed an increased risk of self-harm and suicide in patients aged 25 to 64 years

without a history of self-harm during use of quetiapine with other antidepressants.

Elderly patients with Parkinson's disease (PD)/parkinsonism

A population-based retrospective study of quetiapine for the treatment of patients with MDD,

showed an increased risk of death during use of quetiapine in patients aged >65 years. This

association was not present when patients with PD were removed from the analysis. Caution

should be exercised if quetiapine is prescribed to elderly patients with PD.

4.8

Undesirable effects

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

Thrombocytope

nia, Anaemia,

platelet count

decreased

Agranulocyto

Immune

system

disorders

Hypersensitivity

(including

allergic skin

reactions)

Anaphyla

ctic

reaction

Endocrine

disorders

Hyperprolactinaemi

, decreases in

total T

decreases in free

, decreases in

total T

increases in TSH

Decreases in

free T

Hypothyroidism

Inappropri

antidiureti

hormone

secretion

Metabolism

Elevations in

Increased appetite,

Hyponatraemia

Metabolic

nutritional

disorders

serum

triglyceride

levels

10,30

Elevations in

total

cholesterol

(predominantly

cholesterol)

11,30

Decreases in

cholesterol

17,30

, Weight

gain

8,30

blood glucose

increased to

hyperglycaemic

levels

6, 30

, Diabetes

Mellitus

Exacerbation of

pre-existing

diabetes

syndrome

Psychiatric

disorders

Abnormal dreams

and nightmares,

Suicidal ideation

and suicidal

behaviour

Somnambuli

sm and

related

reactions

such as

sleep talking

and sleep

related

eating

disorder

Nervous

system

disorders

Dizziness

somnolence

headache,

Extrapyramidal

symptoms

1, 21

Dysarthria

Seizure

Restless legs

syndrome,

Tardive

dyskinesia

1, 5,

Syncope

4,16

Cardiac

disorders

Tachycardia

Palpitations

prolongation

1,12,

Bradycardia

disorders

Vision blurred

Vascular

disorders

Orthostatic

hypotension

4,16

Venous

thromboemb

olism

Stroke

Respiratory

, thoracic

mediastinal

disorder

Dyspnoea

Rhinitis

Gastrointes

tinal

disorders

Dry mouth

Constipation,

dyspepsia,

vomiting

Dysphagia

Pancreatitis

Intestinal

obstruction/Il

Hepato-

biliary

disorders

Elevations in serum

alanine

aminotransferase

(ALT)

Elevations in

serum aspartate

aminotransferas

e (AST)

Jaundice

Hepatitis

Elevations in

gamma-GT levels

Skin and

subcutaneo

us tissue

disorders

Angioede

Stevens-

Johnson

syndrome

Toxic Epidermal

Necrolysis,

Erythema

Multiforme

Drug Rash

with

Eosinophilia

Systemic

Symptoms

(DRESS)

Musculoske

letal and

connective

tissue

disorders

Rhabdom

yolysis

Renal and

urinary

disorders

Urinary retention

Pregnancy,

puerperium

perinatal

conditions

Drug withdrawal

syndrome

neonatal

Reproducti

ve system

and breast

disorders

Sexual

dysfunction

Priapism,

galactorrhoe

a, breast

swelling,

menstrual

disorder

General

disorders

administrati

on site

conditions

Withdrawal

(discontinuatio

symptoms

Mild asthenia,

peripheral oedema,

irritability, pyrexia

Neuroleptic

malignant

syndrome

hypothermia

Investigatio

Elevations in

blood

creatine

phosphokina

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.

4.9

Overdose

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.

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Clinical safety:

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 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

Seroquel XR 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 Seroquel XR and 2.3% for placebo. In both bipolar depression and

MDD, the incidence of the individual adverse events (e.g. akathisia, extrapyramidal disorder,

tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor

hyperactivity and muscle rigidity did not exceed 4% in any treatment group.

:אוה ןכרצל ןולעב ירקיעה ןוכדעה

2

.

הפורתב שומישה ינפל

לאוקורסב שומישל תועגונה תודחוימ תורהזא

XR

!

לאוקורסב לופיטה ינפל

XR

:םא אפורל רפס

שי

ךל ץחל

םד

ךומנ

ךניה לבוס תויעבמ

דבכב

יה

ךל

םעפ יא םיסוכרפ

.)ןויפכ(

,ץבש ךל היה רקיעב

םא

ךנה

שישק

ךל התייה

תריפס רבעב

יאת

םד

םינבל

םרגיהל אל הלכי וא םרגיהל הלכי רשא( הכומנ .)תורחא תופורתב שומישמ האצותכ

לבוס ךתחפשמ ינבמ והשימ וא התא ןוגכ ,בלב תויעבמ רבעב לבס וא

ב תוערפה בל בצק

.בלה בצק לע תועיפשמה תופורת לטונ ךנה םא וא בלה רירש לש תקלד וא תושלחה

תוברועמ הז גוסמ תופורתש ןויכ ,םד ישירק לש תיאופר הירוטסיה ךתחפשמ ןבל וא ךל שי .םד ישירק תריציב

ךנה

לבוס

תרכוסמ

וא

םא

ךנה

תצובקב

ןוכיס

תולחל

תרכוסב

הרקמב

הזכ

ןכת

אפורהו

קודבי

תא

תומר

רכוסה

ךמדב

ןמזב

התאש

לפוטמ

לאוקורסב

ןיא

לוטיל

לאוקורס

ןויטיש םע שישק ךנה םא

נמד

הי

לאוקורסש ןוויכ ,

הלולע לצא תוומל ןוכיסה תא ריבגהל הלולע םימיוסמ םירקמב וא ,ץבשל ןוכיסה תא ריבגהל נמד םע םישישק

.הי

ךנה םזינוסניקרפ/ןוסניקרפ תלחממ לבוסה שישק

ךל היה וא ךל שי

המישנ םוד ארקנ( הלילה תניש תעב תורצק המישנ תוקספה לש בצמ

נפא

)הא

חומה לש הליגרה תוליעפה תא תוטאמ רשא תופורת לטונ התאו

ךל היה וא ךל ש

ןתשה תיחופלש תא ירמגל ןקורל תלוכי רסוח לש בצמ

)ןתש תריצא(

ילע וא יעמ תמיסח ,תלדגומ הטטסורפ

לע םיתיעל םימרגנה םיבצמ ולא .יניע ךותה ץחלב ה

( תופורת ידי

לוכיטנא תוארקנ

)תויגרנ

הרטמב דקפתמ בצע את וב ןפואה לע תועיפשמה והשלכ יאופר בצמב לפטל

.תופורתל וא לוהוכלאל תורכמתה לש הירוטסיה ךל שי

םא ירשפאה םדקהב אפורה תא עדי לאוקורס תליטנ רחאל םיאבהמ דחאב שח ךנה

לש האצות תויהל לוכי רבדהש ןוויכ ,תרחא תקלד לכ וא ןורג באכ ,תעפש לש םינמיס ,םוח לאוקורסב לופיט תקספה שורדיו ןכתייש רבד ,תונבל םד תוירודכ תריפסב דואמ הכומנ המר

.לופיט ןתמ וא/ו

לש תוריצע וא ,ךשמתמ ןטב באכ םע תוריצע ליבוהל לוכי רבדה ,יתפורת לופיטל הביגה א .יעמה תמיסח לש רתוי רומח בצמל

תובשחמ

תוינדבוא

הרמחהו

לש

ןואכיד

ןואכיד

עודי

רוגכ

ןוכיסה

תוינדבוא תובשחמל

שחרתהל הלוכי תוינדבוא תובשחמב היילע דע ןמז חקולש ןוויכ ,לאוקורס םע לופיטה תליחתב

םייעובשכ ,לועפל הליחתמ הפורתהש .ךכמ רתוי םיתיעלו

ןוכיסב הילע הארמ םיינילק םירקחממ עדימ .םיריעצ םירגובמ ברקב תוצופנ רתוי הלא תובשחמ ליגל תחתמ םיריעצ םירגובמ ברקב תינדבוא תוגהנתה וא/ו תוינדבוא תובשחמל

םינש .ןואכדמ םילבוסה

שי ,תוינדבוא תובשחמ ךל שיו הדימב

תשוחת ףותיש .םילוח תיבל וא אפורל תידיימ תונפל שקבל לכות .הז ןולע אורקל םתונפהל שיו ,עייסל לוכי בורק רבח וא החפשמ בורק םע ןואכדה ךלש תוגהנתהב םייונישמ םיגאדומ םהש וא רימחמ ןואכדה יכ םישח םהו הדימב ךל רמול םהמ

תנומסת

DRESS

זואא םע תיתפורתה תושיגרה תנומסת פוני

םייתכרעמ םינימסתו היל

תולדגומ הפמיל תוטולב ,היליפוניזואא ,דבכ ימיזנא תמרב היילע ,הובג םוח ,תטשופמ החירפ לוטל דימ קיספהל שי הלא םינימסתמ לבוס ךנהו הדימב .םיפסונ םירביא לש תוברועמו לאווקרס

.יאופר לופיטל תונפל וא אפורל חוודלו

היילע לקשמב

4

.

תועפות

וול יא

תועפות

יאוול

אל

תוחיכש

תועיפומ

תוחפב

םדאמ

ךותמ

םישנא

תותיווע וא םיסוכרפ

תובוגת

תויגרלא

תולוכיש

לולכל

םישוג

םימרומ

לע

רועה

תוחיפנ

רועב

תוחיפנו

ביבסמ

הפל

תנומסת

םיילגרה

תוינבצעה

השוחת

אל

המיענ

םיילגרב

םיישק

העילבב

תועונת

אל

תוטלשנ

רקיעב

לש

םינפ

ןושלהו

םיישק

דוקפתב

ינימ

יוניש

תוליעפה

תילמשחה

לש

בלה

תיארנש

תקידבב

תכראה

עטקמ

בצק

בל

יטיא

ליגרהמ

רבד

לוכיש

תורקל

תליחתב

לופיטה

לוכיו

תויהל

רושק

ץחלל

םד

ךומנ

תויופלעתהלו

תוחתפתה

תרכ

וא

הרמחה

תרכוסב

תמייק

םיישק

ןתמב

ןתש

ףאב שדוג

( תופלעתה )תוליפנל םורגל לולע

הדירי

תומכב

לש

יאת

םד

םימודא

םדב ןרתנ לש תומכב הדירי

תועפות

יאוול

תורידנ

תועיפומ

תוחפב

םדאמ

ךותמ

1000

םישנא

בוליש

לש

םוח

העזה

תושקונ

םירירש

תופייע

הפירח

וא

ןופליע

לע

הי

הלודג

ץחלב

םדה

וא

תוקיפדב

בלה

neuroleptic malignant syndrome

הבהצה

לש

רועה

םייניעהו

תבהצ

)תבהצ( דבכב תקלד

הפקז

תבאוכו הכורא

תוחיפנ

דשב

רוציו

בלח

יתלב

יופצ

ישירק

םד

םידירו

דחוימב

םיילגרב

אטבתמ

תוחיפנב

באכ

תוימומדאו

לש

לגרה

םילולעה

עיגהל

םע

םרז

םדה

תואירל

םורגלו

יבאכ

הזח

יישקו

המישנ

םא

התא

ןיחבמ

דחאב

םינימסתהמ

הלאה

שי

תונפל

תידיימ

תלבקל

עויס

יאופר

םישנב ישדוחה רוזחמה תעפוהב שוביש

הכילה

רוביד

הליכא

תויוליעפו

תורחא

תעב

הניש

הדירי

תרוטרפמטב

ףוגה

)הימרתופיה(

תקלד

,בלבלה

בצ

וב

שי

בוליש

לש

השולש

וא

רתוי

םינימסתהמ

םיאבה

ילע

ןמושב

ינטבה

הדירי

תמרב

"

וכה לורטסל

בוטה

( "

(HDL-C

ילע

תומרב

םידירצילגירט

םדב

ץחל

םד

הובג

ילעו

רכוסב

םדב

קילובטמ

םורדניס

בוליש

לש

םוח

םינימסת

ייומד

תעפש

באכ

ןורג

םיביכ

הפב

וא

לכ

םוהיז

רחא

דחי

םע

הריפס

דואמ

הכומנ

לש

יאת

םד

םינבל

בצמ

ארקנה

סיזוטיצולונרגא

תמיסח

יעמ

תומרב היילע

םדב זאניקופסופ ןיניטארק

תועפות

יאוול

ןתוחיכשש

הניא

העודי

:

החירפ

רועב

םע

תודוקנ

תומודא

אל

תורידס

הבוגת

תיגרלא

הפירח

תימואתפ

םע

םינימסת

ןוגכ

םוח

תויחופלשו

לע

רועה

ףוליקו

רועה

ינימסת

הלימג

םילולע

שחרתהל

םידוליב

לש

תוהמא

ולטנש

לאוקורס

הב

ןויר

ץבש

ולעה םינ

תואירבה דרשמ רתאבש תופורתה רגאמב םימסרופמ

לעבל הינפ ידי לע םיספדומ םלבקל ןתינו .םושירה

,בר דובכב

ןוסבוד לבנק ןיראק

הנוממ תחקור

מ"עב )לארשי( הקינזהרטסא

)לארשי( הקינזהרטסא

עב

"

ת

.

ד

1455

,

ןורשה דוה

4524075

ןופלט

09-7406528

סקפ

09-7406527

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