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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Phreno® XR contains a substance called quetiapine. This belongs to a group of medicines called anti-psychotics. Phreno® XR can be used to treat several illnesses, such as:

Bipolar depression and major depressive episodes in major depressive disorder: where you feel sad. You may find that you feel depressed, feel guilty, lack energy, lose your appetite or can’t sleep.

Mania: where you may feel very excited, elated, agitated, enthusiastic or hyperactive or have poor judgment including being aggressive or disruptive.

Schizophrenia: where you may hear or feel things that are not there, believe things that are not true or feel unusually suspicious, anxious, confused, guilty, tense or depressed.

When Phreno® XR is being taken to treat major depressive episodes in major depressive disorder, it will be taken in addition to another drug being used to treat this illness.

Your doctor may continue to prescribe Phreno® XR even when you feel better.


Do not take Phreno® XR:

If you are allergic to quetiapine or any of the other ingredients of this medicine.

If you are taking any of the following medicines:

Some medicines for HIV.

Azole medicines (for fungal infections).

Erythromycin or clarithromycin (for infections).

Nefazodone (for depression).

If you are not sure, talk to your doctor or pharmacist before taking Phreno® XR.

Warnings and precautions

Talk to your doctor before using Phreno® XR.

If you, or someone in your family, have or have had any heart problems, for example heart rhythm problems, weakening of the heart muscle or inflammation of the heart or if you are taking any medicines that may have an impact on the way your heart beats.

If you have low blood pressure.

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

If you have problems with your liver.

If you have ever had a fit (seizure).

If you have diabetes or have a risk of getting diabetes. If you do, your doctor may check your blood sugar levels while you are taking Phreno® XR.

If you know that you have had low levels of white blood cells in the past (which may or may not have been caused by other medicines).

If you are an elderly person with dementia (loss of brain function). If you are, Phreno® XR should not be taken because the group of medicines that Phreno® XR belongs to may increase the risk of stroke, or in some cases the risk of death, in elderly people with dementia.

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

If you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots.

If you have or have had a condition where you stop breathing for short periods during your normal nightly sleep (called “sleep apnoea”) and are taking medicines that slow down the normal activity of the brain (“depressants”).

If you have or have had a condition where you can’t completely empty your bladder (urinary retention), have an enlarged prostate, a blockage in your intestines, or increased pressure inside your eye. These conditions are sometimes caused by medicines (called “anti-cholinergics”) that affect the way nerve cells function in order to treat certain medical conditions.

If you have a history of alcohol or drug abuse.

Tell your doctor immediately if you experience any of the following after taking Phreno® XR:

A combination of fever, severe muscle stiffness, sweating or a lowered level of consciousness (a disorder called “neuroleptic malignant syndrome”). Immediate medical treatment may be needed.

Uncontrollable movements, mainly of your face or tongue.

Dizziness or a severe sense of feeling sleepy. This could increase the risk of accidental injury (fall) in elderly patients.

Fits (seizures).

A long-lasting and painful erection (Priapism).

These conditions can be caused by this type of medicine.

Tell your doctor as soon as possible if you have:

A fever, flu-like symptoms, sore throat, or any other infection, as this could be a result of a very low white blood cell count, which may require Phreno® 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.

Thoughts of suicide and worsening of your depression: If you are depressed you may sometimes have thoughts of harming or killing yourself. These may be increased when first starting treatment, since these medicines all take time to work, usually about two weeks but sometimes longer. These thoughts may also be increased if you suddenly stop taking your medication. You may be more likely to think like this if you are a young adult. Information from clinical trials has shown an increased risk of suicidal thoughts and/or suicidal behaviour in young adults aged less than 25 years with depression. If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away. You may find it helpful to tell a relative or close friend that you are depressed, and ask them to read this leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are worried about changes in your behaviour.

Weight gain

Weight gain has been seen in patients taking Phreno® XR. You and your doctor should check your weight regularly.

Children and adolescents

Phreno® XR is not for use in children and adolescents below 18 years of age.

Other medicines and Phreno® XR

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Do not take Phreno® XR if you are taking any of the following medicines:

Some medicines for HIV.

Azole medicines (for fungal infections).

Erythromycin or clarithromycin (for infections).

Nefazodone (for depression).

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

Epilepsy medicines (like phenytoin or carbamazepine).

High blood pressure medicines.

Barbiturates (for difficulty sleeping).

Thioridazine or Lithium (other anti-psychotic medicines).

Medicines that have an impact on the way your heart beats, for example, drugs that can cause an imbalance in electrolytes (low levels of potassium or magnesium) such as diuretics (water pills) or certain antibiotics (drugs to treat infections).

Medicines that can cause constipation.

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

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

Phreno® XR with food, drink and alcohol

Phreno® XR can be affected by food and you should therefore take your tablets at least one hour before a meal or prior to bedtime.

Be careful how much alcohol you drink. This is because the combined effect of Phreno® XR and alcohol can make you sleepy.

Do not drink grapefruit juice while you are taking Phreno® XR. It can affect the way the medicine works.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or planning to have a baby ask your doctor for advice before taking this medicine. You should not take Phreno® XR during pregnancy unless this has been discussed with your doctor.

Phreno® XR should not be taken if you are breast-feeding.

The following symptoms which can represent withdrawal may occur in newborn babies of mothers that have used Phreno® XR in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor.

Driving and using machines

Your tablets may make you feel sleepy. Do not drive or use any tools or machines until you know how the tablets affect you.

Phreno® XR contains lactose

This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Effect on Urine Drug Screens

If you are having a urine drug screen, taking Phreno® XR may cause positive results for methadone or certain drugs for depression called tricyclic antidepressants (TCAs) when some test methods are used, even though you may not be taking methadone or TCAs. If this happens, a more specific test can be performed.


Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Your doctor will decide on your starting dose. The maintenance dose (daily dose) will depend on your illness and needs but usually between 150 mg and 800 mg.

You will take your tablets once a day.

Do not split, chew or crush the tablets.

Swallow your tablets whole with a drink of water.

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

Do not drink grapefruit juice while you are taking Phreno® XR. It can affect the way the medicine works.

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

Liver problems

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

Elderly people

If you are elderly your doctor may change your dose.

Use in children and adolescents

Phreno® XR should not be used by children and adolescents aged under 18 years.

If you take more Phreno® XR than you should

If you take more Phreno® XR than prescribed by your doctor, you may feel sleepy, feel dizzy and experience abnormal heart beats.

Contact your doctor or nearest hospital straight away. Take the Phreno® XR tablets with you.

If you forget to take Phreno® XR

If you forget to take a dose, take it as soon as you remember. If it is almost time to take the next dose, wait until then. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Phreno® XR

If you suddenly stop taking Phreno® XR, you may be unable to sleep (insomnia), or you may feel sick (nausea), or you may experience headache, diarrhea, being sick (vomiting), dizziness or irritability. Your doctor may suggest you reduce the dose gradually before stopping treatment.

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


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

Very common (may affect more than 1 in 10 people)

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

Feeling sleepy (this may go away with time, as you keep taking Phreno® XR) (may lead to falls).

Discontinuation symptoms (symptoms which occur when you stop taking Phreno® XR) include not being able to sleep (insomnia), feeling sick (nausea), headache, diarrhea, being sick (vomiting), dizziness and irritability. Gradual withdrawal over a period of at least 1 to 2 weeks is advisable.

Putting on weight.

Abnormal muscle movements. These include difficulty starting muscle movements, shaking, feeling restless or muscle stiffness without pain.

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

Common (may affect up to 1 in 10 people)

Rapid heartbeat.

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

Constipation, upset stomach (indigestion).

Feeling weak.

Swelling of arms or legs.

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

Increased levels of sugar in the blood.

Blurred vision.

Abnormal dreams and nightmares.

Feeling more hungry.

Feeling irritated.

Disturbance in speech and language.

Thoughts of suicide and worsening of your depression.

Shortness of breath.

Vomiting (mainly in the elderly).

Fever.

Changes in the amount of thyroid hormones in your blood.

Decreases in the number of certain types of blood cells.

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

Increases in the amount of the hormone prolactin in the blood. Increases in the hormone prolactin could in rare cases lead to the following:

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

Women to have no monthly period or irregular periods.

Uncommon (may affect up to 1 in 100 people)

Fits or seizures

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

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

Difficulty swallowing

Uncontrollable movements, mainly of your face or tongue.

Sexual dysfunction.

Diabetes.

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

A slower than normal heart rate which may occur when starting treatment and which may be associated with low blood pressure and fainting.

Difficulty in passing urine.

Fainting (may lead to falls).

Stuffy nose.

Decrease in the amount of red blood cells.

Decrease in the amount of sodium in the blood.

Worsening of pre-existing diabetes.

Rare (may affect up to 1 in 1,000 people)

A combination of high temperature (fever), sweating, stiff muscles, feeling very drowsy or faint (a disorder called “neuroleptic malignant syndrome”).

Yellowing of the skin and eyes (jaundice).

Inflammation of the liver (hepatitis).

A long-lasting and painful erection (priapism).

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

Menstrual disorder.

Blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately.

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

Body temperature decreased (hypothermia).

Inflammation of the pancreas.

A condition (called “metabolic syndrome”) where you may have a combination of 3 or more of the following: an increase in fat around your abdomen, a decrease in “good cholesterol” (HDL-C), an increase in a type of fat in your blood called triglycerides, high blood pressure and an increase in your blood sugar.

Combination of fever, flu-like symptoms, sore throat, or any other infection with very low white blood cell count, a condition called agranulocytosis.

Bowel obstruction.

Increased blood creatine phosphokinase (a substance from muscles).

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

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

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

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

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

Inappropriate secretion of a hormone that controls urine volume.

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

Not known (frequency cannot be estimated from the available data)

Skin rash with irregular red spots (erythema multiforme).

Serious, sudden allergic reaction with symptoms such as fever and blisters on the skin and peeling of the skin (toxic epidermal necrolysis).

Symptoms of withdrawal may occur in newborn babies of mothers that have used Phreno® XR during their pregnancy.

Stroke.

The class of medicines to which Phreno® XR belongs can cause heart rhythm problems, which can be serious and in severe cases may be fatal.

Some side effects are only seen when a blood test is taken.

These include changes in the amount of certain fats (triglycerides and total cholesterol) or sugar in the blood, changes in the amount of thyroid hormones in your blood, increased liver enzymes, decreases in the number of certain types of blood cells, decrease in the amount of red blood cells, increased blood creatine phosphokinase (a substance in the muscles), decrease in the amount of sodium in the blood, and increases in the amount of the hormone prolactin in the blood. Increases in the hormone prolactin could in rare cases lead to the following:

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

Women to have no monthly period or irregular periods.

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

Additional side effects in children and adolescents

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

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

Very common (may affect more than 1 in 10 people)

Increase in the amount of a hormone called prolactin, in the blood. Increases in the hormone prolactin could in rare cases lead to the following:

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

Girls to have no monthly period or irregular periods.

Increased appetite.

Vomiting.

Abnormal muscle movements. These include difficulty starting muscle movements, shaking, feeling restless or muscle stiffness without pain.

Increase in blood pressure.

Common (may affect up to 1 in 10 people)

Feeling weak, fainting (may lead to falls).

Stuffy nose.

Feeling irritated.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.


Keep out of the reach and sight of children.

Do not use Phreno® XR extended release tablets after the expiry date (EXP) which is stated on the blister and the carton.

The expiry date refers to the last day of that month.

Phreno® XR extended release tablets: Store below 30°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.


The active substance is Quetiapine (Fumarate).

The other ingredients are Methacrylic acid-ethyl acrylate copolymer, lactose anhydrous, crystalline maltose, purified water, talc, magnesium stearate, triethyl citrate, ethanol.

 


Phreno® XR 50 mg extended release tablets are white to off white, round biconvex tablets, engraved with “50” on one side, presented in PVC/PCTFE-Aluminum foil blisters, intended for oral use. Pack size: 30 and 60 tablets. Phreno® XR 200 mg extended release are white to off white, oblong biconvex tablets, engraved with “200” on one side, presented in PVC/PCTFE-Aluminum foil blisters, intended for oral use. Pack size: 30 and 60 tablets. Phreno® XR 300 mg extended release: white to off white, oblong biconvex tablets, engraved with “300” on one side, presented in PVC/PCTFE-Aluminum foil blisters, intended for oral use. Pack size: 30 and 60 tablets. Phreno® XR 400 mg: white to off white, oval biconvex tablets, engraved with “400” on one side, presented in PVC/PCTFE-Aluminum foil blisters, intended for oral use. Pack size: 30 and 60 tablets.

Med City Pharma-KSA.

1st Industrial city, Phase 5, Jeddah –KSA.

Tel: 00966920003288

Mobile: 00966555786968

P.O .Box: 4072 - Jeddah 22429

E-mail: info@medcitypharma.com

Manufactured by: Pharmathen International S.A-Greece


11/2023
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

يحتوي فرينو® طويل المفعول على مادة تسمى كويتيابين. والتي تنتمي إلى مجموعة من الأدوية تعرف بمضادات الذهان، من الممكن استعمال فرينو® طويل المفعول لعلاج العديد من الأمراض مثل:

الاكتئاب ثنائي القطب و نوبات الاكتئاب الشديدة في حالة الاضطراب الاكتئابي الرئيسي: حيث تشعر بالحزن. قد تجد نفسك تشعر بالاكتئاب، تشعر بالذنب، نقص الطاقة، فقدان الشهية أو عدم القدرة على النوم.

الهوس: حيث قد تشعر بالحماس الشديد، الابتهاج، الهياج، الحماس أو فرط الحركة أو سوء الحكم على الأمور و هذ يتضمن بأن تكون عدواني أو مخرب.

الفصام: حيث قد تسمع أو تشعر بأشياء غير موجودة في الواقع، الاعتقاد بأشياء غير صحيحة أو تشعر على غير عادة بالشك، القلق، الارتباك، الشعور بالذنب، التوتر أو الاكتئاب.

عندما يتم تناول فرينو® طويل المفعول لعلاج نوبات الاكتئاب الشديدة في حالة الاضطراب الاكتئابي الرئيسي، سيتم تناوله بالإضافة إلى دواء آخر يستعمل لعلاج هذا المرض.

قد يستمر طبيبك بوصف فرينو® طويل المفعول حتى لو شعرت بتحسن.

يجب عدم تناول فرينو® طويل المفعول في الحالات التالية:

إذا كنت تعاني من تحسس لكويتيابين أو لأي مكونات أخرى في هذا الدواء.

إذا كنت تتناول أي من الأدوية التالية:

بعض الأدوية لعلاج ڤيروس نقص المناعة المكتسبة.

الأدوية التي تنتمي إلى مجموعة أزول (للالتهابات الفطرية).

إريثرومايسين أو كلاريثرومايسين (للالتهابات).

نيفازودون (للاكتئاب).

إذا لم تكن متأكدا، تحدث إلى طبيبك أو الصيدلي قبل تناول فرينو® طويل المفعول.

 

الاحتياطات و المحاذير

تحدث مع طبيبك قبل تناول فرينو® طويل المفعول.

إذا كنت تعاني أو عانيت سابقا، أنت أو أي من أفراد عائلتك من أي مشاكل في القلب، مثل مشاكل في نظمية القلب، ضعف في عضلة القلب أو التهاب في القلب أو إذا كنت تتناول أي أدوية قد يكون لها تأثير على طريقة نبض القلب.

إذا كنت تعاني من انخفاض ضغط الدم.

إذا عانيت سابقا من سكتة دماغية، خاصة إذا كنت من كبار السن.

إذا كنت تعاني من مشاكل في الكبد.

إذا عانيت سابقا من نوبات ظهور أعراض مفاجئة (نوبات صرع).

إذا كنت تعاني من داء السكري أو تعاني من خطر التعرض لداء السكري. إذا حدث لك ذلك، قد يقوم طبيبك بالتأكد من مستوى السكر في الدم خلال تناولك فرينو® طويل المفعول.

إذا كنت تعلم أنك عانيت سابقا من انخفاض في مستوى خلايا الدم البيضاء (و الذي قد يكون أو قد لا يكون حدث بسبب أدوية أخرى).

إذا كنت من كبار السن الذين يعانون من الخرف (فقدان وظائف الدماغ)، إذا كنت كذلك، يجب عليك عدم تناول فرينو® طويل المفعول، لأن مجموعة الأدوية التي ينتمي إليها فرينو® طويل المفعول قد تزيد من خطر لتعرض للسكتة الدماغية، أو في بعض الحالات من خطر الوفاة، لدى كبار السن الذين يعانون من الخرف.

إذا كنت من كبار السن الذين يعانون من مرض باركنسون.

إذا عانيت سابقا أنت أو أي من أفراد عائلتك من تجلطات الدم، حيث أن أدوية كهذه ارتبطت بتكون الجلطات الدموية.

إذا كنت تعاني أو عانيت سابقا من حالة حيث تتوقف فيها عن التنفس لفترات قصيرة خلال نومك الطبيعي في الليل (و التي تسمى انقطاع النفس المؤقت خلال النوم)، و كنت تتناول أدوية تثبط الوظائف الطبيعية للدماغ (مثبطات).

إذا كنت تعاني أو عانيت سابقا من حالة حيث لا تستطيع تفريغ المثانة بشكل كامل (احتباس البول)، تضخم البروستات، انسداد في الأمعاء، أو ارتفاع الضغط داخل العين، تنتج هذه الحالات أحيانا بسبب الأدوية (تسمى مضادات الكولين) و التي تؤثر على الطريقة التي تقوم فيها الخلايا العصبية بوظيفتها من أجل علاج بعض الحالات المرضية.

إذا عانيت سابقا من إدمان الكحول أو المخدرات.

أخبر طبيبك فورا إذا عانيت من أي من الحالات التالية بعد تناول فرينو® طويل المفعول:

ظهور أعراض بشكل متزامن والتي تتضمن حمى، تصلب العضلات الحاد، التعرق، أو انخفاض مستوى الوعي (اضطراب يسمى متلازمة مضادات الذهان الخبيثة)، في هذه الحالة قد تحتاج إلى العلاج الطبي الفوري.

حركات غير مسيطر عليها، بشكل رئيسي في الوجه و اللسان.

الشعور بالدوار أو شعور حاد بالنعاس. هذا قد يزيد من خطر الإصابات العرضية (السقوط) عند المرضى كبار السن.

نوبات ظهور أعراض مفاجئة (نوبات الصرع).

انتصاب مؤلم و مطوَل (القساح).

هذه الحالات قد تحدث بسبب هذا النوع من الأدوية.

أخبر طبيبك في أقرب وقت ممكن إذا كنت تعاني من:

حمى، أعراض مشابهة للإنفلونزا، التهاب الحلق، أو أي التهاب آخر، حيث قد يكون هذا نتيجة لانخفاض كبير في عدد خلايا الدم البيضاء، و الذي قد يحتاج التوقف عن تناول فرينو® طويل المفعول و/أو إعطاء العلاج المناسب.

إمساك يصاحبه ألم مستمر في البطن، أو الإمساك الذي لا يستجيب للعلاج، حيث قد يؤدي ذلك إلى انسداد أكثر خطورة في الأمعاء.

أفكار انتحارية و ازدياد حالة الاكتئاب سوءا: إذا كنت تعاني من الاكتئاب قد تصبح لديك أحيانا أفكار لإيذاء أو قتل نفسك، قد تزداد هذه الأفكار سوءا في بداية العلاج، حيث أن جميع هذه الأدوية تحتاج إلى وقت لبدء عملها، عادة ما يقارب الأسبوعين لكن أحيانا يحتاج وقت أطول. قد تزداد هذه الأفكار أيضا إذا توقفت عن تناول دوائك بشكل مفاجئ. من المرجح أكثر أن تفكر بهذه الطريقة إذا كنت شاب بالغ. أظهرت معلومات من التجارب السريرية ازدياد خطر الأفكار الانتحارية و/أو السلوك الانتحاري لدى الشباب البالغين المصابين بالاكتئاب و الذين تقل أعمارهم عن 25 عام. إذا كانت لديك أفكار لإيذاء أو قتل نفسك في أي وقت، اتصل مع طبيبك أو اذهب إلى المستشفى في أقرب وقت. قد تجد أنه من المفيد بأن تخبر أحد الأقارب أو الأصدقاء بأنك تعاني الاكتئاب، و اطلب منهم قراءة هذه النشرة الداخلية. قد تطلب منهم إخبارك إذا كانوا يعتقدون بأن حالة الاكتئاب لديك تزداد سوءا، أو إذا كانوا يشعرون بالقلق اتجاه التغيرات في سلوكك.

 

زيادة الوزن

لقد تم ملاحظة حدوث زيادة في الوزن عند المرضى الذين يتناولون فرينو® طويل المفعول، يجب عليك أنت و طبيبك مراقبة وزنك بشكل منتظم.

الأطفال و المراهقون

إن فرينو® طويل المفعول غير معد للاستعمال للأطفال و المراهقين الذين تقل أعمارهم عن 18 عام.

أدوية أخرى مع فرينو® طويل المفعول

أخبر طبيبك أو الصيدلي إذا كنت تستعمل، أو استعملت مؤخرا أو من الممكن أن تستعمل أي أدوية أخرى.

 

لا تتناول فرينو® طويل المفعول إذا كنت تتناول أي من الأدوية التالية:

بعض الأدوية لعلاج ڤيروس نقص المناعة المكتسبة.

الأدوية التي تنتمي إلى مجموعة أزول (للالتهابات الفطرية).

إريثرومايسين أو كلاريثرومايسين (للالتهابات).

نيفازودون (للاكتئاب).

أخبر طبيبك إذا كنت تتناول أي من الأدوية التالية:

أدوية الصرع (مثل فينيتوين أو كاربامازيبين).

أدوية لعلاج ارتفاع ضغط الدم.

باربيتيوريتس (لصعوبات النوم).

ثيورايدازين أو ليثيوم (أدوية أخرى مضادة للذهان).

الأدوية التي لها تأثير على طريقة نبض القلب، على سبيل المثال، الأدوية التي قد تسبب عدم توازن في المواد الكهرلية (او العناصر الكهرلية) (انخفاض مستويات البوتاسيوم أو المغنيسيوم) مثل مدرات البول (أقراص الماء) أو بعض أنواع المضادات الحيوية (أدوية لعلاج الالتهابات).

الأدوية التي قد تسبب الإمساك.

الأدوية (تسمى مضادات الكولين) التي تؤثر على الطريقة التي تقوم فيها الخلايا العصبية بوظيفتها من أجل علاج بعض الحالات المرضية.

الرجاء التحدث مع طبيبك أولا قبل التوقف عن تناول أي من أدويتك.

تناول فرينو® طويل المفعول مع الطعام، الشراب و الكحول

من الممكن أن يتأثر فرينو® طويل المفعول بتناول الطعام، لذلك يجب عليك تناول الأقراص قبل ساعة على الأقل من تناول وجبة الطعام أو قبل النوم.

كن حذرا من كمية الكحول التي تقوم بشربها. و ذلك لأن المفعول المزدوج لفرينو® طويل المفعول مع الكحول قد يجعلك تشعر بالنعاس.

تجنب شرب عصير الجريب فروت خلال تناولك فرينو® طويل المفعول، حيث قد يؤثر هذا على طريقة عمل الدواء.

الحمل و الرضاعة الطبيعية

إذا كنت حامل أو مرضعة، تعتقدين بأنك حامل أو تخططين للحمل استشيري طبيبك قبل تناول هذا الدواء. يجب عدم تناول فرينو® طويل المفعول خلال فترة الحمل إلا إذا تم مناقشة ذلك مع طبيبك.

يجب عدم تناول فرينو® طويل المفعول إذا كنت مرضعة.

الأعراض التالية و التي قد تمثل أعراض التوقف عن تناول الدواء، قد تحدث عند الأطفال حديثي الولادة لأمهات تناولن فرينو® طويل المفعول في الثلث الأخير من الحمل (الشهور الثلاثة الأخيرة من الحمل): رجفان، تصلب العضلات و/أو الشعور بالضعف، النعاس، الهياج، مشاكل في التنفس، و مشاكل في التغذية. إذا حصل أي من هذه الأعراض عند طفلك قد تحتاج إلى الاتصال مع طبيبك.

القيادة واستخدام الآلات

قد يجعلك الدواء تشعر بالنعاس. تجنب القيادة أو استخدام أي من الأدوات أو الآلات إلى أن تعلم كيفية تأثير الأقراص عليك.

يحتوي فرينو® طويل المفعول على اللاكتوز

يحتوي هذا الدواء على اللاكتوز (نوع من السكر). إذا أخبرك طبيبك بأنك غير قادر على تحمل بعض أنواع السكريات، اتصل مع طبيبك قبل تناول هذا المستحضر الطبي.

التأثير على فحص وجود الدواء في البول

إذا كنت ستخضع لفحص وجود الدواء في البول، إن تناول فرينو® طويل المفعول قد يسبب ظهور نتائج إيجابية عند فحص وجود ميثادون أو أدوية معينة لعلاج الاكتئاب والتي تسمى مضادات الاكتئاب ثلاثية الحلقة، حتى ولو لم تكن تتناول ميثادون أو مضادات الاكتئاب ثلاثية الحلقة، إذا حصل هذا، من الممكن القيام بفحوصات أكثر دقة.

https://localhost:44358/Dashboard

دائما تناول هذا الدواء تماماً كما أخبرك طبيبك. تأكد من طبيبك أو الصيدلي إذا لم تكن متأكدا. سيقرر طبيبك جرعتك الابتدائية. ستعتمد الجرعة المحافظة (الجرعة اليومية) على حالتك المرضية و احتياجاتك لكنها تتراوح عادة بين 150 ملغم و 800 ملغم.

ستتناول الأقراص مرة واحدة في يوم.

لا تقوم بتقسيم الأقراص، مضغها أو طحنها.

تناول الأقراص كاملة مع شرب الماء.

تناول الأقراص بدون تناول الطعام (على الأقل قبل ساعة من تناول وجبة الطعام أو وقت النوم، سيخبرك طبيبك موعد تناولها).

تجنب شرب عصير الجريب فروت خلال تناولك فرينو® طويل المفعول، حيث قد يؤثر هذا على طريقة عمل الدواء.

لا تتوقف عن تناول الأقراص حتى لو شعرت بتحسن، إلا إذا أخبرك طبيبك بذلك.

 مشاكل الكبد

إذا كنت تعاني من مشاكل في الكبد، قد يقوم طبيبك بتغيير جرعتك.

كبار السن

إذا كنت من كبار السن قد يقوم طبيبك بتغيير جرعتك.

الأطفال و المراهقون

يجب عدم استعمال فرينو® طويل المفعول للأطفال والمراهقين الذين تقل أعمارهم عن 18 عام.

إذا تناولت فرينو® طويل المفعول أكثر مما يجب

إذا تناولت فرينو® طويل المفعول أكثر مما وصفه لك الطبيب، قد تشعر بالنعاس، بالدوار و تعاني من اضطراب نبضات القلب.

اتصل مع طبيبك أو مع أقرب مستشفى فورا، اصطحب أقراص فرينو® طويل المفعول معك.

إذا نسيت تناول جرعة فرينو® طويل المفعول

إذا نسيت تناول الجرعة، تناولها فور تذكرك، إذا اقترب موعد الجرعة التالية، انتظر إلى أن يحين موعد تناولها. لا تتناول جرعة مضاعفة لتعويض الجرعة التي نسيتها.

إذا توقفت عن تناول فرينو® طويل المفعول

إذا توقفت بشكل مفاجئ عن تناول فرينو® طويل المفعول، قد تعاني من عدم القدرة على النوم (القلق)، أو قد تشعر بالغثيان، أو قد تعاني من الصداع، الإسهال، القئ، الشعور بالدوار أو سرعة الغضب. قد يقترح عليك طبيبك تقليل الجرعة بشكل تدريجي قبل إيقاف العلاج.

إذا كان لديك أي أسئلة إضافية عن استعمال هذا الدواء، اسأل طبيبك أو الصيدلي.

مثل كل الأدوية قد يسبب هذا الدواء آثار جانبية على الرغم من عدم حدوثها لدى الجميع.

شائعة جدا (قد تؤثر على أكثر من 1 من كل 10 أشخاص)

الشعور بالدوار (من الممكن أن يؤدي إلى السقوط)، صداع، جفاف الفم.

الشعور بالنعاس (قد يذهب هذا الأثر الجانبي مع مرور الوقت، طالما أنت مستمر في تناول فرينو® طويل المفعول) (من الممكن أن يؤدي إلى السقوط).

تتضمن أعراض التوقف عن تناول الدواء (وهي أعراض تحدث عندما تتوقف عن تناول فرينو® طويل المفعول) عدم القدرة على النوم (القلق)، أو الشعور بالغثيان، الصداع، الإسهال، القئ، الشعور بالدوار وسرعة الغضب. ينصح بالتوقف عن تناول الدواء بشكل تدريجي خلال مدة تتراوح بين أسبوع إلى أسبوعين على الأقل.

زيادة في الوزن.

حركات غير طبيعية في العضلات، و هذه تتضمن صعوبة في بداية تحريك العضلات، رجفان، الشعور بعدم الراحة أو تصلب العضلات من دون ألم.

تغير في كمية بعض الدهون (الدهون ثلاثية الجليسيريد و مستوى الكوليستيرول الكلي).

شائعة (قد تؤثر على1 أو أقل من كل 10 أشخاص)

تسارع في نبضات القلب.

الشعور كأن قلبك ينبض بقوة، بتسارع أو التوقف المؤقت عن النبض.

إمساك، عدم راحة في المعدة (عسر الهضم).

الشعور بالضعف.

تورم اليدين او الساقين.

انخفاض في ضغط الدم عند الوقوف، هذا قد يجعلك تشعر بالدوار أو الإغماء (من الممكن أن يؤدي إلى السقوط).

ارتفاع مستوى السكر في الدم.

ضبابية الرؤية.

أحلام غير طبيعية و كوابيس.

الشعور بالجوع أكثر.

الشعور بالهياج.

اضطراب في الكلام و اللغة.

أفكار انتحارية و ازدياد حالة الاكتئاب سوءا.

قصر في النفس.

قئ (بشكل رئيسي عند كبار السن).

حمى.

تغيرات في كمية هرمون الغدة الدرقية في الدم.

انخفاض في عدد نوع معين من خلايا الدم.

زيادة كمية إنزيمات الكبد التي تقاس في الدم.

زيادة كمية هرمون البرولاكتين في الدم، إن الزيادة في هرمون البرولاكتين قد يؤدي في حالات نادرة إلى ما يلي:

تورم الثديين عند الرجال و النساء و إنتاج حليب الثدي بشكل غير متوقع.

انقطاع الدورة الشهرية عند النساء، أو عدم انتظامها.

غير شائعة (قد تؤثر على 1 أو أقل من كل 100 شخص)

نوبات ظهور أعراض مفاجئة أو نوبات الصرع.

تفاعلات تحسسية والتي قد تشمل ظهور كتل مرتفعة عن سطح الجلد، تورم في الجلد و تورم حول الفم.

شعور غير مرغوب فيه في الساقين (والذي يسمى أيضا متلازمة تململ الساقين).

صعوبة في البلع.

حركات غير مسيطر عليها، بشكل أساسي في الوجه أو اللسان.

ضعف جنسي.

داء السكري.

تغير في النشاط الكهربائي للقلب و الذي يظهر خلال التخطيط الكهربائي للقلب (إطالة في فترة  (QT.

معدل نبضات قلب أبطأ من المعتاد و الذي قد يحدث عند البدء في العلاج و الذي قد يكون مرتبط بحدوث انخفاض ضغط الدم و الإغماء.

صعوبة في التبول.

إغماء (من الممكن أن يؤدي إلى السقوط).

انسداد الأنف.

انخفاض في كمية خلايا الدم الحمراء.

انخفاض في كمية الصوديوم في الدم.

ازدياد حالة داء السكري الذي تعاني منه في الوقت الحالي سوءا.

نادرة (قد تؤثر على 1 أو أقل من كل 1000 شخص)

ظهور أعراض بشكل متزامن والتي تتضمن ارتفاع درجة الحرارة (حمى)، التعرق، تصلب العضلات، الشعور بالنعاس الشديد أو الإغماء (وهو اضطراب يسمى متلازمة مضادات الذهان الخبيثة).

اصفرار في الجلد و المنطقة البيضاء في العيون (اليرقان).

التهاب الكبد.

انتصاب مؤلم و مطوَل (قساح).

تورم الثديين و إنتاج حليب الثدي بشكل غير متوقع (تدفق الحليب بشكل تلقائي من الثدي).

اضطراب في الدورة الشهرية.

الجلطات الدموية في الأوردة، خاصة في الساقين (تتضمن الأعراض التورم، ألم و احمرار في الساقين)، و التي قد تنتقل خلال الأوعية الدموية إلى الرئيتين و تسبب ألم في الصدر، و صعوبة في التنفس. إذا لاحظت أي من هذه الأعراض اطلب النصيحة الطبية فورا.

المشي، التكلم، تناول الطعام أو القيام بأنشطة أخرى خلال نومك.

انخفاض في درجة حرارة الجسم.

التهاب في البنكرياس.

حالة (تعرف بمتلازمة الأيض) حيث تعاني من مجموعة من الأعراض التي تتضمن ثلاثة أو أكثر مما يلي: زيادة الدهون حول منطقة البطن، انخفاض مستوى «الكوليستيرول الجيد» (البروتين الدهني عالي الكثافة)، زيادة في نوع من الدهون في الدم والذي يسمى دهون ثلاثية الجليسيريد، ارتفاع ضغط الدم و ارتفاع مستوى السكر في الدم.

ظهور أعراض بشكل متزامن والتي تتضمن حمى، أعراض تشبه الإنفلونزا، التهاب الحلق، أو أي التهاب آخر يصاحبه انخفاض كبير في عدد خلايا الدم البيضاء يعرف بندرة المحببات.

انسداد الأمعاء.

ارتفاع مستوى كرياتين فوسفوكاينيز (مادة من العضلات).

نادرة جدا (قد تؤثر على 1 أو أقل من كل 10000 شخص)

طفح جلدي حاد، تنفطات، أو بقع حمراء على الجلد.

تفاعل حاد (يعرف بالحساسية المفرطة) و الذي قد يسبب صعوبة في التنفس أو صدمة.

تورم سريع في الجلد، عادة حول العينين، الشفاه و الحلق (وذمة وعائية).

حالة تنفطات خطيرة في الجلد، الفم، العيون و الأعضاء التناسلية (متلازمة ستيڤن جونسون).

إفراز غير مناسب للهرمون الذي يسيطر على حجم البول.

تحلل الألياف العضلية و ألم في العضلات (انحلال العضلات المخططة).

غير معروفة (لا يمكن تقدير تكرار حدوثها من المعلومات المتوفرة)

طفح جلدي يصاحبه ظهور بقع حمراء غير منتظمة (حمامى متعددة الأشكال).

تفاعلات تحسسية خطيرة، مفاجئة يصاحبها أعراض مثل حمى و تنفطات على الجلد و تقشير  الجلد (انحلال نخري سام في البشرة)

قد تحدث أعراض التوقف عن تناول الدواء عند الأطفال حديثي الولادة لأمهات استعملن فرينو® طويل المفعول خلال فترة الحمل.

سكتة دماغية.

قد تسبب المجموعة الدواء التي ينتمي إليها فرينو® طويل المفعول حدوث مشاكل في نظمية القلب، و التي قد تكون خطيرة و في حالات حادة قد تؤدي إلى الوفاة.

بعض الآثار الجانبية يتم ملاحظتها فقط عند الخضوع لفحص الدم.

و يشمل هذا تغيرات في كمية  بعض أنواع الدهون (الدهون ثلاثية الجليسيريد و مستوى الكوليستيرول الكلي) أو السكر في الدم، تغير في كمية هرمونات الغدة الدرقية في الدم، ارتفاع مستوى إنزيمات الكبد، انخفاض في عدد نوع معين من خلايا الدم، انخفاض في كمية خلايا الدم الحمراء في الدم، ارتفاع مستوى كرياتين فوسفوكيناز (مادة في العضلات)، انخفاض كمية الصوديوم في الدم، و زيادة كمية هرمون البرولاكتين في الدم. إن زيادة هرمون البرولاكتين قد يؤدي في حالات نادرة إلى ما يلي:

تورم الثديين عند الرجال و النساء و إنتاج حليب الثدي بشكل غير متوقع.

انقطاع الدورة الشهرية عند النساء، أو عدم انتظامها.

قد يطلب منك الطبيب القيام بفحص الدم من وقت لآخر.

آثار جانبية إضافية عند الأطفال و المراهقين

نفس الآثار الجانبية التي قد تحدث عند البالغين من الممكن أن تحدث أيضا عند الأطفال و المراهقين.

تم ملاحظة حدوث الآثار الجانبية التالية بشكل أكبر عند الأطفال و المراهقين أو لم يتم ملاحظتها عند البالغين:

شائعة جدا (قد تؤثر على أكثر من 1 من كل 10 أشخاص)

زيادة كمية هرمون البرولاكتين في الدم، إن زيادة هرمون البرولاكتين قد يؤدي في حالات نادرة إلى ما يلي:

تورم الثديين عند الذكور والإناث و إنتاج الحليب بشكل غير متوقع.

انقطاع الدورة الشهرية عند الإناث، أو عدم انتظامها.

زيادة الشهية.

القئ.

حركات غير طبيعية في العضلات، وهذا يشمل صعوبة في بداية تحريك العضلات، رجفان، الشعور بعدم الراحة أو تصلب العضلات بدون الشعور بالألم.

ارتفاع ضغط الدم.

شائعة (قد تؤثر على1 أو أقل من كل 10 أشخاص)

الشعور بالضعف، الإغماء (من الممكن أن يؤدي إلى السقوط).

انسداد الأنف.

الشعور بالهياج.

إذا حصل لديك أي من الآثار الجانبية، تحدث مع طبيبك أو الصيدلي. هذا يتضمن الآثارالجانبية المحتملة غير المذكورة في هذه النشرة.

يحفظ بعيدا عن متناول الأطفال و نظرهم.

لا تستخدم أقراص فرينو® طويل المفعول  بعد تاريخ انتهاء الصلاحية المذكورعلى الشريط و الكرتونة.

تاريخ الانتهاء يشير إلى اليوم الأخير من ذلك الشهر.

فرينو® طويل المفعول أقراص: يحفظ  بدرجة حرارة دون 30 °م.

يجب أن لا يتم التخلص من الأدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد مطلوبة. وسوف تساعد هذه التدابير في حماية البيئة.

المادة الفعالة هي كويتيابين (فيوماريت) 

المكونات الأخرى هي حمض الميثا أكرليك-إيثيل أكريليت كوبوليمر، لاكتوز غير مائي، كريستالين مالتوز، ماء نقي، تالك، ستيرات المغنيسيوم، ثلاثي إيثيل ستيريت، إيثانول.

كيف تبدو أقراص فرينو® طويل المفعول و ما هي محتويات العلبة

أقراص فرينو® طويل المفعول 50  ملغم هي أقراص ذات لون أبيض إلى أبيض مصفر، دائرية الشكل، محدبة الوجهين، محفور على أحد الأوجه 50، معبأة  في أشرطة بي ڤي سي/بي سي تي إف إي/ألومنيوم معدة للاستعمال عن طريق الفم.

 حجم العبوة: 30 و 60  قرص.

أقراص فرينو® طويل المفعول 200 ملغم هي أقراص  ذات لون أبيض إلى أبيض مصفر، مستطيلة الشكل، محدبة الوجهين، محفور على أحد الأوجه 200، معبأة  في أشرطة بي ڤي سي/ بي سي تي إف إي/ألومنيوم معدة للاستعمال عن طريق الفم.

 حجم العبوة: 30 و 60  قرص.

أقراص فرينو® طويل المفعول 300 ملغم هي أقراص ذات لون أبيض إلى أبيض مصفر، مستطيلة الشكل، محدبة الوجهين، محفور على أحد الأوجه 300، معبأة  في أشرطة بي ڤي سي/ بي سي تي إف إي/ألومنيوم معدة للاستعمال عن طريق الفم.

 حجم العبوة: 30 و 60  قرص.

أقراص فرينو® طويل المفعول 400 ملغم هي أقراص ذات لون أبيض إلى أبيض مصفر، بيضوية الشكل، محدبة الوجهين، محفور على أحد الأوجه 400، معبأة  في أشرطة بي ڤي سي/ بي سي تي إف إي/ألومنيوم معدة للاستعمال عن طريق الفم.

 حجم العبوة: 30 و 60  قرص.

مدينة الدواء للصناعات الدوائية - المملكة العربية السعودية.

المدينة الصناعية الأولى، المرحلة الخامسة، جدة - المملكة العربية السعودية.

هاتف: 00966920003288

جوال: 00966555786968

ص.ب: 4072 - جدة 22429

بريد الكتروني: info@medcitypharma.com

تصنيع: فارماثن الدولية س.أاليونان.

11/2023
 Read this leaflet carefully before you start using this product as it contains important information for you

Phreno® XR 50 mg prolonged release tablets. Phreno® XR 200 mg prolonged release tablets. Phreno® XR 300 mg prolonged release tablets. Phreno® XR 400 mg prolonged release tablets. Quetiapine (Fumarate) 50 mg prolonged release tablets. Quetiapine (Fumarate) 200 mg prolonged release tablets. Quetiapine (Fumarate) 300 mg prolonged release tablets. Quetiapine (Fumarate) 400 mg prolonged release tablets.

Phreno® XR 50 mg: Each prolonged release tablets contains 50 mg quetiapine (as fumarate). Phreno® XR 200 mg: Each prolonged release tablets contains 200 mg quetiapine (as fumarate). Phreno® XR 300 mg: Each prolonged release tablets contains 300 mg quetiapine (as fumarate). Phreno® XR 400 mg: Each prolonged release tablets contains 400 mg quetiapine (as fumarate).

Prolonged Release Tablets. Phreno® XR 50 mg prolonged release: white to off white, round biconvex tablets, engraved with “50” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use. Phreno® XR 200 mg prolonged release: white to off white, oblong biconvex tablets, engraved with “200” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use. Phreno® XR 300 mg prolonged release: white to off white, oblong biconvex tablets, engraved with “300” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use. Phreno® XR 400 mg prolonged release: white to off white, oval biconvex tablets, engraved with “400” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use.

Phreno® XR is indicated for:
 treatment of schizophrenia
 treatment of bipolar disorder:
o For the treatment of moderate to severe manic episodes in bipolar disorder.
o For the treatment of major depressive episodes in bipolar disorder.
o For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder who previously responded to quetiapine treatment.
 Add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy . Prior to initiating treatment, clinicians should consider the safety profile of Phreno® XR


Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition.
Phreno® XR should be administered once daily, without food. The tablets should be swallowed whole and not split, chewed or crushed.
Adults
For the treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder
Phreno® XR should be administrated at least one hour before a meal. The daily dose at the start of therapy is 300 mg on Day 1 and 600 mg on Day 2. The recommended daily dose is 600 mg, however if clinically justified the dose may be increased to 800 mg daily. The dose should be adjusted within the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of the patient. For maintenance therapy in schizophrenia no dosage adjustment is necessary.
For the treatment of major depressive episodes in bipolar disorder
Phreno® XR should be administered at bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group (see section 5.1).
Individual patients may benefit from a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered.
For preventing recurrence in bipolar disorder
For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue on quetiapine at the same dose administered at bedtime. Phreno® XR dose can be adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day. It is important that the lowest effective dose is used for maintenance therapy.
For add-on treatment of major depressive episodes in MDD
Phreno® XR should be administered prior to bedtime. The daily dose at the start of therapy is 50 mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect was seen at 150 and 300 mg/day in short-term trials as add-on therapy (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine - see section 5.1) and at 50 mg/day in short-term monotherapy trials. There is an increased risk of adverse events at higher doses.
Clinicians should therefore ensure that the lowest effective dose, starting with 50 mg/day, is used for treatment. The need to increase the dose from 150 to 300 mg/day should be based on individual patient evaluation.
Switching from quetiapine immediate-release tablets
For more convenient dosing, patients who are currently being treated with divided doses of immediate-release quetiapine tablets may be switched to Phreno® XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.
Elderly
As with other antipsychotics and antidepressants, quetiapine should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of quetiapine may need to be slower, and the daily therapeutic dose lower, than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients.
Elderly patients should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
In elderly patients with major depressive episodes in MDD, dosing should begin with 50 mg/day on Days 1-3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. The lowest effective dose, starting from 50 mg/day should be used. Based on individual patient evaluation, if dose increase to 300 mg/day is required this should not be prior to Day 22 of treatment.
Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.
Paediatric population
Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. The available evidence from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1 and 5.2.
Renal impairment
Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment
Quetiapine is extensively metabolised by the liver. Therefore, quetiapine should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.


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.

As quetiapine has several indications, the safety profile should be considered with respect to the individual patient’s diagnosis and the dose being administered.
Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however long-term efficacy and safety has been evaluated in adult patients as monotherapy (see section 5.1).
Paediatric population
Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials with quetiapine have shown that in addition to the known safety profile identified in adults (see section 4.8), certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope), or may have different implications for children and adolescents (extrapyramidal symptoms and irritability) and one was identified that has not been previously seen in adult studies (increases in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.
Furthermore, the long-term safety implications of treatment with quetiapine on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.
In placebo-controlled clinical trials with children and adolescent patients, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and bipolar depression (see section 4.8).
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs.
As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be co-morbid with major depressive episodes. The same precautions observed when treating patients with major depressive episodes should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25 years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). In clinical studies of
patients with MDD the incidence of suicide-related events observed in young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo. 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 x109/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 x109/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x109/L) (see section 5.1).
Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence of obvious predisposing factor(s), and should be managed as clinically appropriate.
Patients should be advised to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore throat) at any time during quetiapine therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.
Anti-cholinergic (muscarinic) effects
Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to ADRs reflecting anti cholinergic effects when quetiapine is used at recommended doses, when used concomitantly with other medications having anti-cholinergic effects, and in the setting of overdose. Quetiapine should be used with caution in patients receiving medications having anti-cholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma (see sections 4.5, 4.8, 5.1, and 4.9.).
Interactions
See 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, diarrhea, 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
Phreno® 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.


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

Caution should be exercised treating patients receiving other medications having anti cholinergic (muscarinic) effects (see section 4.4).

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.

In a multiple-dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, which could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate) (see section 4.4).

The pharmacokinetics of quetiapine were not significantly altered by co administration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).

The pharmacokinetics of quetiapine were not significantly altered by co administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.

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

The pharmacokinetics of lithium were not altered when co-administered with quetiapine. In a 6-week, randomised, study of lithium and quetiapine versus placebo and quetiapine in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particulartremor), 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


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 quetiapine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
The effects of quetiapine on human fertility have not been assessed. Effects related to elevated prolactin levels were seen in rats, although these are not directly relevant to humans (see section 5.3).


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.


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).

SOC

Very  Common

Common

Uncommon

Rare

Very Rare

Not know

Blood and

lymphatic system

disorders

Decreased

haemoglobin22

Leucopenia 1,28,

decreased

neutrophil

count,

eosinophils

increased27

Neutropenia1,

Thrombocytopenia

, Anaemia,

platelet count

decreased13

Agranulocytosis26

 

 

Immune system

disorders

 

 

 

Hypersensitivity

(including

allergic skin

reactions)

 

 

 

Anaphylactic

reaction5

 

 

Endocrine disorders

 

Hyperprolactinaemia15,

decreases in total

T424,

decreases in

free T424,

decreases in

total T324,

increases in

TSH 24

Decreases in

Free T324,

Hypothyroidism21

 

 

Inappro riate

antidiuretic

hormone

secretion

 

 

Metabolism and nutritinal

Disorders

Elevations in serum

triglyceride levels10,30

Elevations in total cholesterol

(predominantly LDL

cholesterol) 11,30

Decreases in HDL

cholesterol17,30,

Weight gain8,30

Increased

appetite, blood

glucose

increased to

hyperglycaemic

levels6, 30

Hyponatraemia19,

Diabetes1,5

Mellitus

Exacerbation of pre-existing

diabetes

Metabolic

syndrome29

 

 

Psychiatric disorders

 

 

 

Abnormal

dreams and

nightmares,

Suicidal

ideation and

suicidal

behaviour20

 

Somnambulism

and related

reactions such as

sleep talking and sleep related eating disorder

 

 

Nervous system

disorders

Dizziness4,16,

somnolence2,16

headache,

Extrapyramidal

symptom1,21

 

Dysarthria

 

Seizure1,

Restless legs

syndrome,

Tardive

dyskinesia1,5

Syncope4,16

 

 

 

Cardiac disorders

 

 

Tachycardia4,

Palpitations23

QT

prolongation1,12, 18

Bradycardia32

 

 

 

Eye

disorders

 

Vision blurred

 

 

 

 

Vascular disorders

 

Orthostatic

hypotension4,16

 

Venous

thromboembolism

1

 

Stroke33

 

Respiratory,

thoracic and

mediastinal

disorder

 

Dyspnoea23

 

Rhinitis

 

 

 

 

Gastrointe

stinal

disorders

Dry mouth

 

Constipation,

dyspepsia,

vomiting25

Dysphagia7

 

Pancreatitis1,

Intestinal

obstruction/Ileus

 

 

Hepato-biliary

disorders

 

Elevations in

serum alanine

aminotransferas

e (ALT)3, Elevations in

gamma-GT levels3

Elevations in

serum aspartate

aminotransferas

e (AST) 3

Jaundice5

Hepatitis

 

 

Skin and

subcutaneous tissue

disorders

 

 

 

 

Angioedema5,

Stevens-

Johnson

syndrome5

Toxic

Epidermal

Necrolysis,

Erythema

Multiforme

Drug Rash

Eosinophil

and System

Symptoms

(DRESS)

Musculoskeletal

and connective

tissue disorders 

 

 

 

 

Rhabdomyoly

sis

 

Renal and urinary

disorders

 

 

Urinary

retention

 

 

 

Pregnancy,

puerperium and

perinatal conditions

 

 

 

 

 

Drug

withdrawal

syndrome

neonatal31

Reproductive

system and breast

disorders

 

 

 

Sexual

dysfunction

Priapism,

galactorrhoea,

breast swelling,

menstrual disorder

 

 

General disorders

and administration

site conditions

Withdrawal (dis

continuation)

symptoms1,9

Mild asthenia,

peripheral

oedema,

irritability,

pyrexia

 

Neuroleptic

malignant

syndrome1,

hypothermia

 

 

Investigations

ons

 

 

 

 

Elevations in

blood creatine

phosphokinase14

 

 

 

(1) See section 4.4.
(2) Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine.
(3) Asymptomatic elevations (shift from normal to =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.
(4) As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period. (see section 4.4).
(5) Calculation of Frequency for these ADR’s have only been taken from postmarketing data with the immediate release formulation of quetiapine.
(6) 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.
(7) An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.
(8) Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.
(9) The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability.
The incidence of these reactions had decreased significantly after 1 week post discontinuation.
(10) Triglycerides ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150 mg/dL (≥1.694 mmol/L) (patients <18 years of age) on at least one occasion.
(11) Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL (≥5.172 mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥30 mg/dL (□0.769 mmol/L) has been very commonly observed.(Mean change among patients who had this increase was 41.7 mg/dL (□1.07 mmol/L).
(12) See text below.
(13) Platelets ≤100 x109/ L on at least one occasion.
(14) Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
(15) Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time.
(16) May lead to falls.
(17) HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L) females at any time.
(18) Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to a clinically significant level is similar between quetiapine and placebo.
(19) Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.
(20) Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation (see sections 4.4 and 5.1).
(21) See section 5.1.
(22) Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was -1.50 g/dL.
(23) These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.
(24) Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
(25) Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
(26) Based on shift in neutrophils from > = 1.5 x109/L at baseline to <0.5 x109/L at any time during treatment and based on patients with severe neutropenia (<0.5 x109/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 x109 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 x109 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 prolactin1

 

Metabolism and nutritional disorders

Increased appetite

 

Nervous system disorders

Symptoms Extrapyramidal3,4

Syncope

Vascular disorders

Increases in blood pressure 2

 

Respiratory, thoracic and

mediastinal disorders

 

Rhinitis

Gastrointestinal disorders

Vomiting

 

General disorder and administration site conditions

 

Irritability3

(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 Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.
(3) Note: The frequency is consistent to that observed in adults, but might be associated with different clinical implications in children and adolescents as compared to adults.
(4) See section 5.1.
To report any side effect(s):
•Saudi Arabia:
The National Pharmacovigilance and Drug Safety Center (NPC):
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
Reporting hotline: 19999
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
•Other GCC States:
Please contact the relevant competent authority.


Symptoms

In general, reported signs and symptoms were those resulting from an exaggeration of the active substance’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia, hypotension and anti-cholinergic effects. Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (See section 4.4, Orthostatic hypotension).

Management of overdose

There is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Based on public literature, patients with delirium and agitation and a clear anti cholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because 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.


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 (5HT2) and dopamine D1- and D2 -receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2 -receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Quetiapine compared to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic 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 quetiapine therapeutic efficacy as an antidepressant.
Pharmacodynamic effects
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance.
It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2 -receptor blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol sensitized or drug-naive Cebus monkeys after acute and chronic administration (see section 4.8).
Clinical efficacy
Schizophrenia
The efficacy of quetiapine in the treatment of schizophrenia was demonstrated in one 6-week placebo-controlled trial in patients who met DSM-IV criteria for schizophrenia, and one active-controlled quetiapine IR-to- Quetiapine switching study in clinically stable outpatients with schizophrenia.
The primary outcome variable in the placebo-controlled trial was change from baseline to final assessment in the PANSS total score. Quetiapine 400 mg/day, 600 mg/day and 800 mg/day were associated with statistically significant improvements in psychotic symptoms compared to placebo. The effect size of the 600 mg and 800 mg doses was greater than that of the 400 mg dose.
In the 6-week active-controlled switching study the primary outcome variable was the proportion of patients who showed lack of efficacy, i.e. who discontinued study treatment due to lack of efficacy or whose PANSS total score increased 20% or more from randomisation to any visit. In patients stabilised on quetiapine immediate release 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of quetiapine given once daily.
In a long-term study in stable schizophrenic patients who had been maintained on
Quetiapine for 16 weeks, quetiapine was more effective than placebo in preventing relapse. The estimated risks of relapse after 6 months treatments was 14.3% for the quetiapine treatment group compared to 68.2% for placebo. The average dose was 669 mg. There were no additional safety findings associated with treatment with quetiapine for up to 9 months (median 7 months). In particular, reports of adverse events related to EPS and weight gain did not increase with longer term treatment with quetiapine.
Bipolar disorder
In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. The efficacy of quetiapine was further demonstrated with significance versus placebo in an additional 3-week study. Quetiapine was dosed in the range of 400 to 800 mg/day and the mean dose was approximately 600 mg/day.
Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.
In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300 mg/day quetiapine showed superior efficacy to placebo in reduction of MADRS total score.
In 4 additional clinical trials with quetiapine, with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, quetiapine 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 quetiapine 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 quetiapine 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 quetiapine versus placebo and quetiapine in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).
In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium,
the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.
Major depressive episodes in MDD
Two short-term (6-week) studies enrolled patients who had shown an inadequate response to at least one antidepressant. Quetiapine 150 mg and 300 mg/day, given as add-on treatment to ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine) demonstrated superiority over antidepressant therapy alone in reducing depressive symptoms as measured by improvement in MADRS total score (LS mean change vs. placebo of 2-3.3 points).
Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however long-term efficacy and safety has been evaluated in adult patients as monotherapy (see below).
The following studies were conducted with quetiapine as monotherapy treatment, however quetiapine is only indicated for use as add-on therapy:
In three out of four short term (up to 8-weeks) monotherapy studies, in patients with major depressive disorder, quetiapine 50 mg, 150 mg and 300 mg/day demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (LS mean change vs. placebo of 2-4 points.
In a monotherapy relapse prevention study, patients with depressive episodes stabilized on open-label quetiapine treatment for at least 12 weeks were randomized to either quetiapine once daily or placebo for up to 52 weeks. The mean dose of quetiapine during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for quetiapine treated patients and 34.4% for placebo-treated patients.
In a short-term (9 week) study non-demented elderly patients (aged 66 to 89 years) with major depressive disorder, quetiapine dosed flexibly in the range of 50 mg to 300 mg/day demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by improvement in MADRS total score (LS mean change vs placebo -7.54). In this study patients randomised to quetiapine received 50 mg/day on Days 1-3, the dose could be increased to 100 mg/day on Day 4, 150 mg/day on Day 8 and up to 300 mg/day depending on clinical response and tolerability. The mean dose of quetiapine was 160 mg/day. Other than the incidence of extrapyramidal symptoms (see section 4.8 and ‘Clinical safety’ below) the tolerability of quetiapine once daily in elderly patients was comparable to that seen in adults (aged 18-65 years). The proportion of randomised patients over 75 years of age was 19%.
Clinical safety
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for quetiapine and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was
9.0% for quetiapine 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 quetiapine versus placebo and quetiapine in adult patients with acute mania indicated that the combination of quetiapine with lithium leads to more adverse events (63% versus 48% in quetiapine in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the quetiapine with lithium add-on group (12.7%) compared to the quetiapine with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).
Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were 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 x109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x109/L, was 1.9% in patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5 - <1.0 x109/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 x109/ L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x109/L was 2.9% and to <0.5 x109/L was 0.21% in patients treated with quetiapine.
Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. The incidences of shifts in TSH was 3.2 % for quetiapine versus 2.7 % for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about 2/3 of all cases, cessation of
quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.
Cataracts/lens opacities
In a clinical trial to evaluate the cataractogenic potential of quetiapine (200- 800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in quetiapine (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.
Paediatric population
Clinical efficacy
The efficacy and safety of quetiapine was studied in a 3-week placebo controlled study for the treatment of mania (n= 284 patients from the US, aged 10-17). About 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n= 222 patients, aged 13- 17) was performed. In both studies, patients with known lack of response to quetiapine were excluded. Treatment with quetiapine was initiated at 50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given two or three times daily.
In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was -5.21 for quetiapine 400 mg/day and -6.56 for quetiapine 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for = quetiapine 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.
In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was -8.16 for quetiapine 400 mg/day and -9.29 for quetiapine 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the percentage of patients achieving response, defined as ≥30% reduction from baseline in PANSS total = score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.
In a third short-term placebo-controlled monotherapy trial with quetiapine in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.
No data are available on maintenance of effect or recurrence prevention in this age group.
Clinical safety
In the short-term paediatric trials with quetiapine described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs. 1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain ≥7% of baseline body weight in the active arm vs. placebo were =17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7% vs. 6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended post treatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.
Long-term safety
A 26-week open-label extension to the acute trials (n=380 patients), with quetiapine flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see sections 4.4 and 4.8).
With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.


Absorption
Quetiapine is well absorbed following oral administration. Quetiapine achieves peak quetiapine and norquetiapine plasma concentrations at approximately 6 hours after administration (Tmax). Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear and dose proportional for doses up to 800 mg administered once daily. When quetiapine administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate (Quetiapine immediate release) administered twice daily, the area under the plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower at steady state. When quetiapine is compared to quetiapine immediate release, the norquetiapine metabolite AUC is 18% lower.
In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the quetiapine 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 quetiapine is taken once daily without food.
Distribution
Quetiapine is approximately 83% bound to plasma proteins.
Biotransformation
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.


Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at a dose range of 300 to 800 mg/day in humans.


Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450
mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
Elimination
The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of a radiolabelled drug was excreted in the urine and 21% in the faeces with less than 5% of the total radioactivity representing unchanged drug-related material. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.

Special populations


Gender
The pharmacokinetics of quetiapine does not differ between men and women.
Elderly
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
Renal impairment
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/ 1.73 m2), but the individual clearance values are within the range for normal subjects.
Hepatic impairment
The mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see section 4.2).
Paediatric population
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.
No information is available for quetiapine in children and adolescents.


There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long-term clinical research:
In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased
haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts (for cataracts/lens opacities, see section 5.1).
In an embryofoetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal exposure levels similar or slightly above those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.
In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction.


Methacrylic acid-ethyl acrylate copolymer, lactose anhydrous, crystalline maltose, purified water, talc, magnesium stearate, triethyl citrate and ethanol.


None.


36 months.

Store below 30°C.


Phreno® XR 50 mg prolonged release are white to off white, round biconvex tablets, engraved with “50” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use.
Pack size: 30 and 60 tablets.
Phreno® XR 200 mg prolonged release are white to off white, oblong biconvex tablets, engraved with “200” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use.
Pack size: 30 and 60 tablets.
Phreno® XR 300 mg prolonged release are white to off white, oblong biconvex tablets, engraved with “300” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use.
Pack size: 30 and 60 tablets.
Phreno® XR 400 mg prolonged release are white to off white, oval biconvex tablets, engraved with “400” on one side, presented in PVC/PCTFE- Aluminum foil blisters, intended for oral use.
Pack size: 30 and 60 tablets.


No special requirements.


Med City Pharma-KSA. 1st Industrial city, Phase 5, Jeddah –KSA. Tel: 00966920003288 Mobile: 00966555786968 P.O .Box: 4072 - Jeddah 22429 E-mail: info@medcitypharma.com Manufactured by: Pharmathen International S.A-Greece

01/2024
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