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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)

Reagila contains the active substance cariprazine and belongs to a group of medicines called antipsychotics. It is used to treat adults with schizophrenia.

Schizophrenia is a disease characterised by symptoms such as hearing, seeing or sensing things which are not there (hallucination), suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with this condition may also feel depressed, guilty, anxious, tense, or not being able to start or keep up planned activities, unwillingness to speak, lack of emotional response to a situation that would normally stimulate feelings in others.


Do not take Reagila

  • If you are allergic to cariprazine or any of the other ingredients of this medicine (listed in section 6).
  • If you are taking medicines used to treat:
    • Hepatitis caused by the hepatitis C virus (medicines containing boceprevir and telaprevir)
    • Bacterial infections (medicines containing clarithromycin, telithromycin, erythromycin and nafcillin)
    • Tuberculosis (medicines containing rifampicin)
    • HIV infections (medicines containing cobicistat, indinavir, nelfinavir, ritonavir, saquinavir, efavirenz and etravirine)
    • Fungal infections (medicines containing itraconazole, posaconazole, voriconazole and fluconazole)
    • Cushing’s syndrome - when the body produces an excess of cortisol (medicines containing ketoconazole)
    • Depression (herbal therapy containing St. John's wort (Hypericum perforatum) and medicines containing nefazodone)
    • Epilepsy and seizures (medicines containing carbamazepine, phenobarbital and phenytoin)
    • Heart disease (medicines containing diltiazem and verapamil)
    • Sleepiness (medicines containing modafinil)
    • High blood pressure in the lungs (medicines containing bosentan).

Warnings and precautions

Tell your doctor immediately:

  • If you are having any thoughts or feelings about harming yourself or to commit suicide. Suicidal thoughts and behaviours are more likely at the beginning of the treatment.
  • ·If you experience a combination of fever, sweating, faster breathing, muscle stiffness and drowsiness or sleepiness (may be signs of neuroleptic malignant syndrome).

Talk to your doctor or pharmacist before taking Reagila, or during treatment if you have:

  • Ever experienced or start to experience restlessness and inability to sit still. These symptoms may occur early during treatment with Reagila. Tell your doctor if this happens.
  • Ever experienced or start to experience abnormal, involuntary movements, most commonly of the tongue or face. Tell your doctor if this happens.
  • Visual impairment. Your doctor will advise you to visit an ophthalmologist.
  • Irregular heartbeat or if someone else in your family has a history of irregular heartbeat (including so called QT prolongation seen with ECG monitoring), and tell your doctor if you are taking other medicines, because they might cause or worsen this ECG change.
  • High or low blood pressure, cardiovascular disease. Your doctor will need to check your blood pressure regularly.
  • Dizziness on standing up due to a drop in your blood pressure, which may cause fainting.
  • A history of blood clots, or if someone else in your family has a history of blood clots, as medicines for schizophrenia have been associated with formation of blood clots.
  • A history of stroke, especially if you are elderly or know that you have other risk factors for stroke. Tell your doctor immediately if you notice any signs of a stroke.
  • Dementia (loss of memory and other mental abilities) especially if you are elderly.
  • Parkinson’s disease.
  • If you have diabetes or risk factors for diabetes (e.g. obesity, or someone else in your family has diabetes). Your doctor will need to check your blood sugar regularly since it may be increased by Reagila. Signs of high blood sugar level are excessive thirst, passing of large amounts of urine, increase in appetite and feeling weak.
  • A history of seizures (fits) or epilepsy.

Weight increase

Reagila may cause significant weight increase which may affect your health. Your doctor will therefore check your weight regularly.

Children and adolescents

This medicine is not recommended for children and adolescents under 18 years due to the lack of data in these patients.

Other medicines and Reagila

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. You cannot take certain medicines together with Reagila (see section “Do not take Reagila”).

Taking Reagila together with some medicines may require a dose adjustment of Reagila or the other medicine. These are medicines used to treat heart diseases containing digoxin, blood thinners containing dabigatran, or medicines affecting your mental functions.

Reagila with drink and alcohol

You should not drink grapefruit juice during treatment with Reagila.

Alcohol should be avoided when taking Reagila.

Pregnancy, breast-feeding and fertility

Women of childbearing potential/Contraception

Women of childbearing potential must use effective contraception during Reagila treatment. Even after treatment is stopped, contraception must be used for at least 10 weeks after your last dose of Reagila. This is because the medicine will stay in your body for some time after the last dose was taken.

Pregnancy

Do not take this medicine during pregnancy unless your doctor has told you to do so.

If your doctor decides that you should take this medicine during pregnancy, your doctor will monitor your baby closely after birth. This is because the following symptoms may occur in newborn babies of mothers who have used this medicine 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 should contact your doctor.

Breast-feeding

Do not breast-feed if you are taking Reagila because a risk for the baby cannot be excluded. Contact your doctor for advice.

Driving and using machines

There is a minor or moderate risk that the medicine could affect the ability to drive and use machines. Drowsiness, dizziness and vision problems may occur during treatment with this medicine (see section 4). Do not drive or use any tools or machines until you know that this medicine does not affect you in a negative way.

Reagila 3 mg, 4.5 mg and 6 mg Hard Capsules contain Allura red  

Reagila 3 mg, 4.5 mg and 6 mg Hard Capsules contain Allura red. Each hard capsule of Reagila 3 mg, 4.5 mg and 6 mg Hard Capsules contains 0.0003 mg, 0.0008 mg or 0.0096 mg Allura red; respectively. Allura red is a coloring agent, which may cause allergic reactions


Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The recommended starting dose is 1.5 mg once a day by mouth. Thereafter, the dose may be slowly adjusted by your doctor, in steps of 1.5 mg, depending on how the treatment works for you.

The maximum dose should not exceed 6 mg once a day.

Take Reagila at the same time each day with or without food.

If you were taking another medicine to treat schizophrenia before starting Reagila, your doctor will decide whether to stop the other medicine gradually or immediately and how to adjust the dose of Reagila. Your doctor will also inform you how to act if you switch from Reagila to another medicine.

Patients with kidney or liver problems

If you have serious kidney or liver problems Reagila may not be appropriate for you. Talk to your doctor.

Elderly patients

Your doctor will carefully select the appropriate dose for your needs.

Reagila should not be used by elderly patients with dementia (loss of memory).

If you take more Reagila than you should

If you have taken more Reagila than your doctor has recommended or if, for example, a child has taken it by mistake, contact your doctor or go to the nearest hospital right away and take the pack of the medicine with you.

You may experience dizziness from low blood pressure, or have abnormal heartbeats, you may feel sleepy, tired, or have abnormal body movements and find it difficult to stand or walk.

If you forget to take Reagila

If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue as usual.

Do not take a double dose to make up for a forgotten dose.

If you miss two or more doses, contact your doctor.

If you stop taking Reagila

If you stop taking this medicine you will lose the effects of the medicine. Even if you feel better, do not alter or stop your daily dose of Reagila unless told to do so by your doctor as your symptoms may return.

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


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

Tell your doctor immediately if you have:

  • A severe allergic reaction seen as fever, swollen mouth, face, lip or tongue, shortness of breath, itching, skin rash and sometimes a drop in blood pressure. (Rare side effect)
  • Combination of fever, sweating, muscle stiffness, and drowsiness or sleepiness. These can be the signs of the so-called neuroleptic malignant syndrome. (Side effect with frequency not known)
  • Inexplicable muscle pains, muscle cramps or muscle weakness. These may be signs of muscle damage which can cause very serious kidney problems. (Rare side effect)
  • Symptoms related to 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. (Side effect with frequency not known)
  • Thoughts or feelings about harming yourself or to commit suicide, suicide attempt. (Uncommon side effect)

Other side effects

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

  • Feeling of restlessness and inability to sit still
  • Parkinsonism - a medical condition with many various symptoms which include decreased or slow movements, slowness of thought, jerks when bending the limbs (cogwheel rigidity), shuffling steps, shaking, little or no facial expression, muscle stiffness, drooling

Common side effects (may affect up to 1 in 10 people)

  • Anxiety
  • Sleepiness, difficulty in sleeping, abnormal dreams, nightmare, sleepwalking
  • Dizziness
  • Involuntary twisting movements and strange postures
  • Excessive teeth grinding or jaw clenching, drooling, persistent blinking in response to tapping of the forehead (an abnormal reflex), movement problems, tongue movement disturbance (these are called extrapyramidal symptoms)
  • Blurred vision
  • High blood pressure
  • Fast, irregular heartbeat
  • Decreased or increased appetite
  • Nausea, vomiting, constipation
  • Weight increased
  • Tiredness
  • The following can be seen in laboratory tests:
    • Increases in liver enzymes
    • Increases in the level of creatine phosphokinase in the blood
    • Abnormal amount of lipids (e.g. cholesterol and/or fat) in the blood

Uncommon side effects (may affect up to 1 in 100 people)

  • Depression
  • Sudden and severe confusion
  • Spinning sensation
  • Unpleasant, abnormal sense of touch
  • Drowsiness, lack of energy or a lack of interest in doing things
  • Involuntary movements, most commonly of the tongue or face. This can appear after short or long-term use
  • Decreased or increased sexual desire, erectile problems
  • Eye irritation, high pressure in the eye, poor vision
  • Focusing problems seeing at a distance to or seeing close-to
  • Low blood pressure
  • Abnormal ECG reading, abnormal nerve impulses in the heart
  • Slow, irregular heart rate
  • Hiccups
  • Heartburn
  • Thirst
  • Pain when passing urine
  • Abnormally frequent and large urinations
  • Itching, rash
  • Diabetes
  • The following can be seen in laboratory tests:
    • Abnormal sodium level in the blood
    • Increased blood glucose (blood sugar), increased bile pigment (bilirubin) in the blood
    • Anaemia (reduced levels of red blood cells)
    • Increase in a type of white blood cells
    • Decreased level of thyroid stimulating hormone (TSH) in the blood

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

  • Seizure
  • Loss of memory, loss of speech
  • Eye discomfort in bright light
  • Clouding of the lens in the eye leading to a decrease in vision (cataract)
  • Difficulty in swallowing
  • Reduced levels of a type of white blood cells, this can make you more susceptible to infections
  • Underactive thyroid gland

Side effects with not known frequency (frequency cannot be estimated from the available data)

  • Inflammation of the liver (pain in the upper right abdomen, yellowing of the eye and skin, weakness, fever

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

Do not store above 30°C.

Store in the original package in order to protect from light.

Do not use this medicine after the expiry date which is stated on the package after “EXP”. The expiry date refers to the last day of that month.

Do not use this medicine if you notice any visible signs of deterioration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.


The active substance is cariprazine hydrochloride.

Each hard capsule of Reagila 1.5 mg Hard Capsules contains 1.635 mg cariprazine hydrochloride equivalent to 1.5 mg cariprazine.

Each hard capsule of Reagila 3 mg Hard Capsules contains 3.27 mg cariprazine hydrochloride equivalent to 3 mg cariprazine.

Each hard capsule of Reagila 4.5 mg Hard Capsules contains 4.905 mg cariprazine hydrochloride equivalent to 4.5 mg cariprazine.

Each hard capsule of Reagila 6 mg Hard Capsules contains 6.54 mg cariprazine hydrochloride equivalent to 6 mg cariprazine.

The other ingredients are: Capsule content: Pregelatinized maize starch and magnesium stearate. Capsule shell: Titanium dioxide, gelatin, Allura red (only in 3 mg, 4.5 mg, 6 mg capsules), Brilliant blue (only in 3 mg, 4.5 mg, 6 mg capsules) and yellow iron oxide (only in 3 mg, 4.5 mg capsules). Printing ink:  Black ink (only in 1.5 mg, 3 mg, 6 mg capsules) and white ink (only in 4.5 mg capsules).


Reagila 1.5 mg Hard Capsules are white opaque cap/white opaque body hard gelatin capsules imprinted with “GR 1.5” on the capsule body with black ink containing white to yellowish white powder in transparent hard PVC/PE/PVDC-aluminum foil blisters. Reagila 3 mg Hard Capsules are green opaque cap/white opaque body hard gelatin capsules imprinted with “GR 3” on the capsule body with black ink containing white to yellowish white powder in transparent hard PVC/PE/PVDC-aluminum foil blisters. Reagila 4.5 mg Hard Capsules are green opaque cap/green opaque body hard gelatin capsules imprinted with “GR 4.5” on the capsule body with white ink containing white to yellowish white powder in transparent hard PVC/PE/PVDC-aluminum foil blisters. Reagila 6 mg Hard Capsules are purple opaque cap/white opaque body hard gelatin capsules imprinted with “GR 6” on the capsule body with black ink containing white to yellowish white powder in transparent hard PVC/PE/PVDC-aluminum foil blisters. Pack size: 28 Hard capsules.

Marketing Authorization Holder

Jazeera Pharmaceutical Industries
Al-Kharj Road
P.O. Box 106229
Riyadh 11666, Saudi Arabia
Tel: + (966-11) 8107023, + (966-11) 2142472
Fax: + (966-11) 2078170
e-mail: SAPV@hikma.com

Manufacturer and Under licensed from

Gedeon Richter Plc.

Gyömrői út 19-21

1103 Budapest

Hungary

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects, you can also help provide more information on the safety of this medicine.

  • Saudi Arabia

The National Pharmacovigilance Centre (NPC)

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

  • Other GCC States

Please contact the relevant competent authority


This leaflet was last revised in 03/2023; version number SA2.0.
  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 رياجيلا على المادة الفعّالة كاريبرازين وينتمي إلى مجموعة من الأدوية يطلق عليها مضادات الذهان. يستخدم في علاج البالغين المصابين بالفصام.

الفصام هو مرض يتسم بأعراض مثل سماع أشياء غير حقيقية، رؤيتها أو الشعور بها (الهلوسة)، الارتياب، الاعتقادات الخاطئة، كلام غير متناسق وبلادة في السلوك والعاطفة. قد يشعر المصابون بهذه الحالة أيضاً بالاكتئاب، الذنب، القلق، التوتر أو عدم القدرة على بدء الأنشطة المخطط لها أو مواصلتها، عدم الرغبة في الحديث، افتقار الاستجابة العاطفية تجاه موقف عادة ما قد يثير مشاعر الآخرين.

لا تتناول رياجيلا

  • إذا كنت تعاني من حساسية لكاريبرازين أو لأي من المواد الأخرى المستخدمة في تركيبة هذا الدواء (المذكورة في القسم 6).
  • إذا كنت تتناول أدوية تستخدم في علاج ما يلي:
    • التهاب الكبد بسبب فيروس التهاب الكبد ج (أدوية تحتوي على بوسبريفير وتيلابريفير)
    • العدوى البكتيرية (أدوية تحتوي على كلاريثروميسين، تيليثروميسين، إريثروميسين ونافسيلين)
    • السّل (أدوية تحتوي على ريفامبيسين)
    • عدوى فيروس العوز المناعي البشري (أدوية تحتوي على كوبيسيستات، إندينافير، نيلفينافير، ريتونافير، ساكوينافير، إيفافيرينز، وإيترافيرين)
    • العدوى الفطرية (أدوية تحتوي على إيتراكونازول، بوساكونازول، فوريكونازول، وفلوكونازول)
    • متلازمة كوشينغ - عندما ينتج الجسم الكورتيزول بشكل مفرط (أدوية تحتوي على كيتوكونازول)
    • الاكتئاب (العلاج بالأعشاب الذي يحتوي على نبتة سانت جون (عشبة العرن) وأدوية تحتوي على نيفازودون)
    • الصرع والتشنجات (أدوية تحتوي على كاربامازيبين، فينوباربيتال وفينيتوين)
    • مرض في القلب (أدوية تحتوي على ديلتيازيم وفيراباميل)
    • النعاس (أدوية تحتوي على مودافينيل)
    • ارتفاع ضغط الدم في الرئتين (أدوية تحتوي على بوسينتان).

الاحتياطات والتحذيرات

أخبر طبيبك فوراً:

  • إذا كانت تراودك أي أفكار أو مشاعر عن إيذاء نفسك أو الانتحار. يزداد احتمال وجود الأفكار والتصرفات الانتحارية في بداية العلاج.
  • إذا كنت تعاني من الحمّى، التعرّق، سرعة التّنفس، تيبّس العضلات والخمول أو النعاس في وقت واحد (قد يكون ذلك علامات للمتلازمة الخبيثة للأدوية المضادة للذهان).

تحدث مع طبيبك أو الصيدلي قبل تناول رياجيلا، أو أثناء العلاج إذا:

  • عانيت في السابق من التململ وعدم القدرة على الجلوس أو بدأت تشعر بهما. قد تحدث هذه الأعراض مبكراً أثناء العلاج باستخدام رياجيلا. أخبر طبيبك إذا حدثت هذه الأعراض.
  • عانيت في السابق من حركات غير عادية، لا إرادية، يكثر شيوعها في اللسان أو الوجه، أو بدأت تشعر بذلك. أخبر طبيبك إذا حدثت هذه الأعراض.
  • كنت تعاني من قصور في البصر. سينصحك طبيبك بزيارة طبيب عيون.
  • كنت تعاني من عدم انتظام في نبضات القلب أو لدى أحد أفراد أسرتك تاريخ مرضي لعدم انتظام في نبضات القلب، (يشمل ذلك ما يطلق عليه إطالة فترة QT التي تلاحظ في مخطط كهربية القلب)، وأخبر طبيبك إذا كنت تتناول أدوية أخرى، لأنها قد تتسبب بهذا التغيير في مخطط كهربية القلب أو تفاقمه.
  • كنت تعاني من ارتفاع ضغط الدم أو انخفاضه، أمراض القلب والأوعية الدموية. سيحتاج طبيبك إلى فحص ضغط دمك بانتظام.
  • كنت تعاني من دوخة عند الوقوف بسبب هبوط في ضغط الدم، الذي قد يسبب الإغماء.
  • كان لديك تاريخ مرضي لحالات تجلط الدم، أو لدى أحد أفراد أسرتك تاريخ مرضي لحالات تجلط الدم، حيث إن الأدوية المستخدمة في علاج الفصام مرتبطة بتكون الجلطات الدموية.
  • كان لديك تاريخ مرضي للسكتة الدماغية، خاصةً إذا كنت من كبار السن أو تعلم وجود عوامل خطورة أخرى تؤدي إلى الإصابة بالسكتة الدماغية. أخبر طبيبك على الفور إذا لاحظت أي علامات للسكتة الدماغية.
  • كنت تعاني من الخرف (فقدان الذاكرة والقدرات الذهنية الأخرى) خاصةً إذا كنت من كبار السن.
  • كنت تعاني من مرض باركنسون.
  • كنت مصاباً بمرض السكري أو لديك عوامل خطورة للإصابة بمرض السكري (مثل: السمنة، أو أن أحد أفراد أسرتك يعاني من مرض السكري). سيحتاج طبيبك إلى فحص مستوى السكر في دمك بانتظام نظراً إلى أن رياجيلا قد يتسبب في ارتفاعه. تشمل علامات ارتفاع مستوى سكر الدم العطش المفرط، إخراج كميات كبيرة من البول، زيادة الشهية والشعور بالضعف.
  • كان لديك تاريخ مرضي للتشنجات (النوبات) أو الصرع. 

زيادة الوزن

قد يتسبب رياجيلا في زيادة في الوزن بشكل ملحوظ والذي قد يؤثر على صحتك. سيقوم طبيبك بفحص وزنك بانتظام.

الأطفال والمراهقون

لا يوصى بإعطاء هذا الدواء للأطفال والمراهقين الذين تقل أعمارهم عن 18 عاماً نظراً لعدم وجود بيانات عن هؤلاء المرضى.

الأدوية الأخرى ورياجيلا

أخبر طبيبك أو الصيدلي إذا كنت تتناول، تناولت مؤخراً، أو قد تتناول أي أدوية أخرى. لا يمكنك تناول أدوية معينة مع رياجيلا (انظر قسم "لا تتناول رياجيلا").

قد يتطلب تناول رياجيلا مع بعض الأدوية إلى تعديل جرعة رياجيلا أو الدواء الآخر. تستخدم هذه الأدوية في علاج أمراض القلب التي تحتوي على ديجوكسين، مرققات الدم التي تحتوي على دابيجاتران، أو الأدوية التي تؤثر على وظائفك العقلية.

رياجيلا مع الشراب والكحول

يجب عليك عدم شرب عصير الجريب فروت أثناء العلاج برياجيلا.

يجب تجنب شرب الكحول عند تناول رياجيلا.

الحمل، الرضاعة والخصوبة

النساء المحتمل حملهنّ/منع الحمل

يجب أن تستخدم النساء المحتمل حملهنّ وسيلة فعّالة لمنع الحمل أثناء العلاج باستخدام رياجيلا. حتى بعد توقف العلاج، يجب استخدام وسيلة منع الحمل لمدة 10 أسابيع على الأقل بعد آخر جرعة من رياجيلا. السبب في هذا أن الدواء سيبقى في الجسم لبعض الوقت بعد تناول آخر جرعة.

الحمل

لا تتناولي هذا الدواء أثناء الحمل ما لم يطلب منك طبيبكِ تناوله.

إذا قرر طبيبكِ أنه يجب عليكِ تناول هذا الدواء أثناء الحمل، فسيقوم بمراقبة طفلك عن قرب بعد الولادة. هذا لأن الأعراض التالية قد تحدث لدى حديثي الولادة للأمهات اللواتي استخدمن هذا الدواء في آخر ثلث (آخر 3 أشهر) من حملهنّ:

  • الارتعاش، تيبس العضلات و/أو الضعف، النعاس، الهياج، مشاكل في التنفس، وصعوبة في الرضاعة.

يجب عليكِ الاتصال بطبيبك إذا ظهرت أي من هذه الأعراض على طفلك.

الرضاعة الطبيعية

لا ترضعي طفلك رضاعة طبيعية إذا كنتِ تتناولين رياجيلا لأن خطر الإضرار بالجنين لا يمكن استبعاده. استشيري طبيبك للحصول على النصيحة.

القيادة واستخدام الآلات

هناك خطر طفيف أو متوسط يتمثل في أن الدواء قد يؤثر على قدرتك على القيادة واستخدام الآلات. قد يحدث خمول، دوخة، مشاكل في الرؤية أثناء العلاج باستخدام هذا الدواء (انظر القسم 4). لا تقم بالقيادة أو استخدام أي أدوات أو آلات حتى تعلم أن هذا الدواء لا يؤثر عليك بشكل سلبي.

يحتوي رياجيلا 3 ملغم، 4,5 ملغم و6 ملغم كبسولات صلبة على ألورا أحمر

يحتوي رياجيلا 3 ملغم، 4,5 ملغم و6 ملغم كبسولات صلبة على ألورا أحمر. تحتوي كل كبسولة صلبة من رياجيلا 3 ملغم، 4,5 ملغم و6 ملغم كبسولات صلبة على 0,0003 ملغم، 0,0008 ملغم أو 0,0096 ملغم ألورا أحمر؛ على التوالي. ألورا أحمر هو عامل ملوّن، قد يسبب ردود فعل تحسسية

https://localhost:44358/Dashboard

قم دائماً بتناول هذا الدواء كما وصفه لك طبيبك تماماً. تحقق من طبيبك أو الصيدلي إذا لم تكن متأكداً.

جرعة البداية الموصى بها هي 1,5 ملغم مرة واحدة يومياً تؤخذ عن طريق الفم. يمكن بعد ذلك أن يعدل الطبيب الجرعة ببطء، وذلك بالتدريج بمقدار 1,5 ملغم، وذلك بالاعتماد على مدى فعالية العلاج معك.

يجب ألا تتجاوز الجرعة القصوى 6 ملغم يومياً.

تناول رياجيلا مرة واحدة يومياً في نفس الوقت مع الطعام أو بدونه.

إذا كنت تتناول دواءً آخر لعلاج الفصام قبل البدء في تناول رياجيلا، فسيقرر طبيبك إذا ما كنت ستتوقف عن تناول الدواء الآخر تدريجياً أو فوراً وكيفية تعديل جرعة رياجيلا. سيخبرك طبيبك أيضاً بكيفية التصرف عند تبديل رياجيلا بدواء آخر.

المرضى الذين يعانون من مشاكل في الكلى أو الكبد

إذا كنت تعاني من مشاكل خطيرة في الكلى أو الكبد، فقد لا يناسبك رياجيلا. تحدث إلى طبيبك.

المرضى كبار السن

سيحدد طبيبك الجرعة المناسبة لاحتياجاتك بعناية.

ينبغي عدم استخدام رياجيلا لدى المرضى المسنين المصابين بالخرف (فقدان الذاكرة).

إذا تناولت رياجيلا أكثر من اللازم

إذا تناولت جرعة رياجيلا تزيد عن ما أوصى به طبيبك أو، على سبيل المثال، إذا أخذ طفل جرعة عن طريق الخطأ، تواصل مع طبيبك أو اذهب إلى أقرب مستشفى على الفور وخذ عبوة الدواء معك.

قد تعاني من دوخة بسبب انخفاض ضغط الدم، أو عانيت من عدم انتظام نبضات القلب، تشعر بالنعاس، التعب، أو قد تعاني من حركات جسم غير طبيعية وتعاني من صعوبة في الوقوف أو المشي.

إذا نسيت تناول رياجيلا

في حال نسيانك تناول الجرعة، تناولها فور تذكرها. ولكن إذا اقترب موعد تناول الجرعة التالية، فتجاوز الجرعة المنسية وتابع كالمعتاد.

لا تقم بتناول جرعة مضاعفة للتعويض عن الجرعة المنسية.

إذا فاتتك جرعتان أو أكثر، فتواصل مع طبيبك.

إذا توقفت عن تناول رياجيلا

إذا توقفت عن تناول هذا الدواء، فستفقد تأثيراته. حتى لو شعرت بتحسن، لا تغيّر جرعتك اليومية من رياجيلا أو تتوقف عنها إلا إذا طلب منك طبيبك ذلك حيث قد تعود الأعراض.

يرجى استشارة الطبيب، إذا كان لديك أي أسئلة إضافية حول استخدام هذا الدواء.

مثل جميع الأدوية، قد يسبب هذا الدواء آثاراً جانبيةً، إلا أنه ليس بالضرورة أن تحدث لدى جميع مستخدمي هذا الدواء.

أخبر طبيبك فوراً إذا كنت تعاني من:

  • رد فعل تحسسي شديد على شكل حمّى، تورم في الفم، الوجه، الشفة أو اللسان، ضيق في التنفس، حكة، طفح جلدي وفي بعض الأحيان انخفاض في ضغط الدم. (آثار جانبية نادرة)
  • حدوث حمّى، تعرّق، تيبس في العضلات وخمول أو نعاس في وقت واحد. يمكن أن تكون هذه علامات ما يسمى بالمتلازمة الخبيثة للأدوية المضادة للذهان. (آثار جانبية غير معروفة التكرار)
  • آلام العضلات غير المبررة، تقلصات عضلية أو ضعف العضلات. قد تكون هذه علامات تلف العضلات التي يمكن أن تسبب مشاكل خطيرة جداً في الكلى. (آثار جانبية نادرة)
  • أعراض مرتبطة بتجلطات الدم في الأوردة وخاصة في الساقين (تشمل الأعراض تورم، ألم واحمرار في الساق)، والتي يمكنها أن تنتقل عن طريق الأوعية الدموية إلى الرئتين مسببة ألماً في الصدر وصعوبة في التنفس. (آثار جانبية غير معروفة التكرار)
  • أفكار أو مشاعر حول إيذاء نفسك أو الانتحار، محاولة الانتحار. (آثار جانبية غير شائعة)

آثار جانبية أخرى

آثار جانبية شائعة جداً (قد تؤثر على أكثر من شخص واحد من كل 10 أشخاص)

  • الشعور بالتململ وعدم القدرة على الجلوس
  • أعراض مشابهة لمرض الباركنسون - حالة طبية تتضمن الكثير من الأعراض المختلفة التي تشمل انخفاض الحركات أو بطئها، بطء التفكير، نفضات عند ثني الأطراف (صمل متقطّع)، خطوات متثاقلة، الارتعاش، انخفاض القدرة على التعبير بالوجه أو انعدامها، تيبس العضلات، سيلان اللعاب

آثار جانبية شائعة (قد تؤثر على ما يصل إلى شخص واحد من كل 10 أشخاص)

  • قلق
  • نعاس، صعوبة النوم، أحلام غير عادية، كوابيس، السير أثناء النوم
  • دوخة
  • حركات التواء لاإرادية وأوضاع غريبة
  • صرير الأسنان البليغ أو شدّ الفك، سيلان اللعاب، غمز مستمر كرد فعل على نقر الجبهة (رد فعل غير طبيعي)، مشاكل في الحركة، اضطراب في حركة اللسان (تسمى هذه أعراض خارج السبيل الهرمي)
  • تغيم الرؤية
  • ارتفاع ضغط الدم
  • نبضات قلب سريعة، غير منتظمة
  • انخفاض الشهية أو زيادتها
  • غثيان، قيء، إمساك
  • زيادة الوزن
  • التعب
  • يمكن ملاحظة ما يلي في فحوصات المختبر:
    • زيادة في إنزيمات الكبد
    • ارتفاع مستوى إنزيم فوسفوكيناز الكرياتين في الدم
    • كمية دهون غير طبيعية (مثل الكوليسترول و/أو الدهون) في الدم

آثار جانبية غير شائعة (قد تؤثر على ما يصل إلى شخص واحد من كل 100 شخص)

  • اكتئاب
  • تشوش مفاجئ وشديد
  • الإحساس بالدوار
  • إحساس لمس مزعج وغير طبيعي
  • خمول، فقدان الطاقة أو الرغبة في إنجاز الأمور
  • حركات لا إرادية، تكون أكثر شيوعاً في اللسان أو الوجه. يمكن أن تظهر هذه الأعراض بعد استخدام الدواء على المدى القصير أو الطويل
  • انخفاض أو زيادة الرغبة الجنسية، مشاكل في الانتصاب
  • تهيج العين، ارتفاع ضغط العين، ضعف الرؤية
  • مشاكل في التركيز على الرؤية من مسافة بعيدة أو مسافة قريبة
  • انخفاض ضغط الدم
  • قراءة غير طبيعية في مخطط كهربية القلب، نبضات عصبية غير طبيعية في القلب
  • بطء، عدم انتظام معدل نبضات القلب
  • الفواق
  • حرقة في المعدة
  • عطش
  • ألم عند التبول
  • تبول متكرر وبكميات كبيرة بشكل غير طبيعي
  • حكة، طفح
  • مرض السكري
  • يمكن ملاحظة ما يلي في فحوصات المختبر:
    • مستوى صوديوم غير طبيعي في الدم
    • زيادة نسبة الجلوكوز في الدم (سكر الدم)، زيادة صبغة الصفراء (بيليروبين) في الدم
    • فقر الدم (انخفاض مستويات خلايا الدم الحمراء)
    • زيادة في أحد أنواع خلايا الدم البيضاء
    • انخفاض مستوى هرمون الغدة الدرقية في الدم

آثار جانبية نادرة (قد تؤثر على ما يصل إلى شخص واحد من كل 1000 شخص)

  • تشنج
  • فقدان الذاكرة، فقدان القدرة على الكلام
  • عدم ارتياح العينين في الضوء الساطع
  • تغيم العدسة في العين مما يؤدي إلى انخفاض الرؤية (الساد)
  • صعوبة في البلع
  • انخفاض مستويات أحد أنواع خلايا الدم البيضاء، وهذا يمكن أن يجعلك أكثر عرضة للعدوى
  • انخفاض نشاط الغدة الدرقية

الآثار الجانبية غير معروفة التكرار (لا يمكن تقدير التكرار من البيانات المتاحة)

  • التهاب الكبد (ألم في أعلى يمين البطن، اصفرار العين والجلد، ضعف، حمّى

احفظ هذا الدواء بعيداً عن مرأى ومتناول الأطفال.

لا يحفظ عند درجة حرارة أعلى من 30° مئوية.

يحفظ داخل العبوة الأصلية للحماية من الضوء.

لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المذكور على العبوة الخارجية بعد “EXP”. يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

لا تستخدم هذا الدواء إذا لاحظت أي علامات تلف واضحة عليه.

لا تتخلص من أي أدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد بحاجة إليها. هذه الإجراءات ستساعد في الحفاظ على سلامة البيئة.

المادة الفعّالة هي هيدروكلوريد الكاريبرازين.

تحتوي كل كبسولة صلبة من رياجيلا 1,5 ملغم كبسولات صلبة على 1,635 ملغم هيدروكلوريد الكاريبرازين يكافئ 1,5 ملغم كاريبرازين.

تحتوي كل كبسولة صلبة من رياجيلا 3 ملغم كبسولات صلبة على 3,27 ملغم هيدروكلوريد الكاريبرازين يكافئ 3 ملغم كاريبرازين.

تحتوي كل كبسولة صلبة من رياجيلا 4,5 ملغم كبسولات صلبة على 4,905 ملغم هيدروكلوريد الكاريبرازين يكافئ 4,5 ملغم كاريبرازين.

تحتوي كل كبسولة صلبة من رياجيلا 6 ملغم كبسولات صلبة على 6,54 ملغم هيدروكلوريد الكاريبرازين يكافئ 6 ملغم كاريبرازين.

المواد الأخرى المستخدمة في التركيبة التصنيعية هي: محتوى الكبسولة: نشا الذرة المعدل وستیرات المغنيسيوم. غلاف الكبسولة: ثاني أكسيد التيتانيوم، جيلاتين، ألورا أحمر (فقط في كبسولات 3 ملغم، 4,5 ملغم، 6 ملغم)، أزرق لامع (فقط في كبسولات 3 ملغم، 4,5 ملغم، 6 ملغم) وأكسيد الحديد الأصفر (فقط في كبسولات 3 ملغم، 4,5 ملغم). حبر الطباعة: حبر أسود (فقط في كبسولات 1,5 ملغم، 3 ملغم، 6 ملغم) وحبر أبيض (فقط في كبسولات 4,5 ملغم).

رياجيلا 1,5 ملغم كبسولات صلبة هي كبسولات جيلاتينية صلبة ذات غطاء أبيض معتم/جسم أبيض معتم مطبوع عليها "GR 1.5" على جسم الكبسولة بحبر أسود تحتوي على مسحوق أبيض إلى أبيض مصفر في أشرطة شفافة صلبة من كلوريد متعدد الڤينيل/متعدد الإيثيلين/ثنائي كلوريد متعدد الڤينيليدين-رقائق الألمنيوم.

رياجيلا 3 ملغم كبسولات صلبة هي كبسولات جيلاتينية صلبة ذات غطاء أخضر معتم/جسم أبيض معتم مطبوع عليها "GR 3" على جسم الكبسولة بحبر أسود تحتوي على مسحوق أبيض إلى أبيض مصفر في أشرطة شفافة صلبة من كلوريد متعدد الڤينيل/متعدد الإيثيلين/ثنائي كلوريد متعدد الڤينيليدين-رقائق الألمنيوم.

رياجيلا 4,5 ملغم كبسولات صلبة هي كبسولات جيلاتينية صلبة ذات غطاء أخضر معتم/جسم أخضر معتم مطبوع عليها "GR 4.5" على جسم الكبسولة بحبر أبيض تحتوي على مسحوق أبيض إلى أبيض مصفر في أشرطة شفافة صلبة من كلوريد متعدد الڤينيل/متعدد الإيثيلين/ثنائي كلوريد متعدد الڤينيليدين-رقائق الألمنيوم.

رياجيلا 6 ملغم كبسولات صلبة هي كبسولات جيلاتينية صلبة ذات غطاء بنفسجي معتم/جسم أبيض معتم مطبوع عليها "GR 6" على جسم الكبسولة بحبر أسود تحتوي على مسحوق أبيض إلى أبيض مصفر في أشرطة شفافة صلبة من كلوريد متعدد الڤينيل/متعدد الإيثيلين/ثنائي كلوريد متعدد الڤينيليدين-رقائق الألمنيوم.

حجم العبوة: 28 كبسولة صلبة.

مالك رخصة التسويق

شركة الجزيرة للصناعات الدوائية
طريق الخرج
صندوق بريد 106229
الرياض 11666، المملكة العربية السعودية
هاتف: 8107023 (11-966) +، 2142472 (11-966) +
فاكس: 2078170 (11-966) +
البريد الإلكتروني: SAPV@hikma.com

الشركة المصنعة وبترخيص من

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طريق جومرو 21-19

1103 بودابست

هنغاريا

 للإبلاغ عن الآثار الجانبية

تحدث إلى الطبيب، الصيدلي، أو الممرض إذا عانيت من أية آثار جانبية. وذلك يشمل أي آثار جانبية لم يتم ذكرها في هذه النشرة. كما أنه يمكنك الإبلاغ عن هذه الآثار مباشرةً (انظر التفاصيل المذكورة أدناه). من خلال الإبلاغ عن الآثار الجانبية، يمكنك المساعدة بتوفير معلومات مهمة عن سلامة الدواء.

  • المملكة العربية السعودية

المركز الوطني للتيقظ الدوائي

مركز الاتصال الموحد: 19999

البريد الإلكتروني: npc.drug@sfda.gov.sa

الموقع الإلكتروني: https://ade.sfda.gov.sa

  • دول الخليج العربي الأخرى

الرجاء الاتصال بالجهات الوطنية في كل دولة

تمت مراجعة هذه النشرة بتاريخ 2023/03؛ رقم النسخة SA2.0.
 Read this leaflet carefully before you start using this product as it contains important information for you

Reagila 1.5 mg Hard Capsules

Each hard capsule contains 1.635 mg cariprazine hydrochloride equivalent to 1.5 mg cariprazine. For the full list of excipients, see section 6.1.

Hard capsules. White to yellowish white powder in white opaque cap and white opaque body hard gelatin capsule imprinted with “GR 1.5” on the capsule body with black ink.

Reagila is indicated for the treatment of schizophrenia in adult patients.


Posology

The recommended starting dose of cariprazine is 1.5 mg once daily. Thereafter the dose can be increased slowly in 1.5 mg increments to a maximum dose of 6 mg/day, if needed. The lowest effective dose should be maintained according to the clinical judgement of the treating physician. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after starting cariprazine and after each dosage change (see section 5.2).

Switching from other antipsychotics to cariprazine

When switching from another antipsychotic to cariprazine gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while cariprazine treatment is initiated.

Switching to another antipsychotic from cariprazine

When switching to another antipsychotic from cariprazine, no gradual cross-titration is needed, the new antipsychotic should be initiated in its lowest dose while cariprazine is discontinued. It should be considered that plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week (see section 5.2).

Special population

Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment (Creatinine Clearance (CrCl) ≥ 30 mL/min and < 89 mL/min). Safety and efficacy of cariprazine have not been evaluated in patients with severe renal impairment (CrCl < 30 mL/min). Use of cariprazine is not recommended in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5-9). Safety and efficacy of cariprazine have not been evaluated in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Use of cariprazine is not recommended in patients with severe hepatic impairment (see section 5.2).

Elderly

Available data in elderly patients aged ≥65 years treated with cariprazine are not sufficient to determine whether or not they respond differently from younger patients (see section 5.2). Dose selection for an elderly patient should be more cautious.

Paediatric population

The safety and efficacy of cariprazine in children and adolescents aged less than 18 years have not been established. No data are available.

Method of administration

Reagila is for oral use, to be taken once daily at the same time of the day with or without food.


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration of strong or moderate CYP3A4 inhibitors (see section 4.5). Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).

Suicidal ideation and behaviour

The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent in psychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy.

Akathisia, restlessness

Akathisia and restlessness is a frequently occurring adverse reaction of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-EPS medication. The dose can be modified based on individual response and tolerability (see section 4.8).

Tardive dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntary movements, predominantly of the tongue and/or face that can develop in patients treated with antipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated with cariprazine, discontinuation should be considered.

Parkinson's disease

If prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate the underlying disease and worsen symptoms of Parkinson's disease. Physicians should, therefore, weigh the risks versus the benefits when prescribing cariprazine to patients with Parkinson's disease.

Ocular symptoms/cataract

In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs (see sections 4.8 and 5.3). However, a causal relationship between lenticular changes / cataracts observed in human studies and cariprazine use has not been established. Nevertheless, patients who would develop symptoms potentially related to cataract should be advised to ophthalmologic examination and re-evaluated for treatment continuation.

Neuroleptic malignant syndrome (NMS)

A potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic treatment. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, elevated serum creatine phosphokinase levels, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, cariprazine must be discontinued immediately.

Seizures and convulsions

Cariprazine should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold.

Elderly patients with dementia

Cariprazine has not been studied in elderly patients with dementia and is not recommended to treat elderly patients with dementia due to increased risk of overall mortality.

Risk of cerebrovascular accidents (CVA)

An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo controlled clinical 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. Cariprazine should be used with caution in patients with risk factors for stroke.

Cardiovascular disorders

Blood pressure changes

Cariprazine can cause orthostatic hypotension as well as hypertension (see section 4.8). Cariprazine should be used with caution in patients with known cardiovascular disease predisposing to blood pressure changes. Blood pressure should be monitored.

ECG changes

  • QT prolongation can develop in patients treated with antipsychotics.

With cariprazine no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In clinical trials, only a few, non-serious, QT-prolongations have been reported with cariprazine (see section 4.8). Therefore, cariprazine should be used cautiously in patients with known cardiovascular disease or in patients with a family history of QT prolongation and in patients treated with medicinal products that might cause QT prolongation (see section 5.1).

Venous thromboembolism (VTE)

Cases of venous thromboembolism have been reported with antipsychotic medicinal products. 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 cariprazine and preventive measures undertaken.

Hyperglycaemia and diabetes mellitus

Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for serum glucose levels. In clinical trials, glucose-related adverse reactions have been reported with cariprazine (see section 5.1).

Women of childbearing potential

Women of childbearing potential must use highly effective contraception while taking cariprazine and at least for 10 weeks after stopping treatment (see sections 4.5 and 4.6). Women using systemically acting hormonal contraceptives should add a second barrier method.

Weight change

Significant weight gain has been observed with the use of cariprazine. Patients should have their weight monitored regularly (see section 4.8).


Potential for other medicinal products to affect cariprazine

Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6.

CYP3A4 inhibitors

Ketoconazole, a strong CYP3A4 inhibitor, caused two fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered.

Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong or moderate inhibitors of CYP3A4 (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole verapamil) is contraindicated (see section 4.3). Consumption of grapefruit juice should be avoided.

CYP3A4 inducers

Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section 4.3).

CYP2D6 inhibitors

CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway is via CYP3A4 (see section 5.2). Therefore CYP2D6 inhibitors are unlikely to have a clinically relevant effect on cariprazine metabolism.

Potential for cariprazine to affect other medicinal products

P-glycoprotein (P-gp) substrates

Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinical consequences of this effect is not fully understood, however the use of P-gp substrates with narrow therapeutic index such as dabigatran and digoxin could require extra monitoring and dose adjustment.

Hormonal contraceptives

It is currently unknown whether cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a second barrier method.

Pharmacodynamic interactions

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


Women of childbearing potential/contraception

Women of childbearing potential must be advised to avoid pregnancy while on Reagila. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of Reagila. It is currently unknown if cariprazine may reduce the effectiveness of systemically acting hormonal contraceptives and therefore women using systemically acting hormonal contraceptives should add a barrier method (see section 4.5).

Pregnancy

There are no or limited amount of data from the use of cariprazine in pregnant women.

Studies in animals have shown reproductive toxicity including developmental malformations in rats (see section 5.3).

Reagila is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties.

Neonates exposed to antipsychotics (including cariprazine) 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. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be monitored carefully.

Breast-feeding

It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cariprazine.

Fertility

The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed (see section 5.3).

 


Cariprazine has minor or moderate influence on the ability to drive and use machines. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Reagila does not affect them adversely.


Summary of the safety profile

The most frequently reported ADRs with cariprazine in the dose range (1.5-6 mg) were akathisia (19%) and parkinsonism (17.5%). Most events were mild to moderate in severity.

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term.

Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions occurring in patients with schizophrenia

MedDRA

System Organ Class

Very common

(1/10)

Common

(1/100 to <1/10)

Uncommon

(1/1,000 to <1/100)

Rare

(1/10,000 to <1/1,000)

Frequency not known

Blood and lymphatic system disorders

  

Anaemia

Eosinophilia

Neutropenia

 

Immune system disorders

   

Hypersensitivity

 

Endocrine disorders

  

Blood thyroid stimulating hormone decreased

Hypothyroidism

 

Metabolism and nutrition disorders

 

Weight increased

Decreased appetite

Increased appetite

Dyslipidaemia

Blood sodium abnormal

Blood glucose increased

Diabetes mellitus

  

Psychiatric disorders

 

Sleep disorders1

Anxiety

Suicidal behaviour

Delirium

Depression

Libido decreased

Libido increased

Erectile dysfunction

  

Nervous system disorders

Akathisia2

Parkinsonism3

Sedation

Dizziness

Dystonia4

Other extrapyramidal diseases and abnormal movement disorders5

Lethargy

Dysaesthesia

Dyskinesia6

Tardive dyskinesia

Seizures/ Convulsion

Amnesia

Aphasia

Neuroleptic malignant syndrome

Eye disorders

 

Vision blurred

Eye irritation

Intraocular pressure increased

Accommodation disorder

Visual acuity reduced

Photophobia

Cataract

 

Ear and labyrinth disorders

  

Vertigo

  

Cardiac disorders

 

Tachyarrhytmia

Cardiac conduction disorders

Bradyarrhytmia

Electrocardiogram QT prolonged

Electrocardiogram T wave abnormal

  

Vascular disorders

 

Hypertension

Hypotension

  

Respiratory, thoracic and mediastinal disorders

  

Hiccups

  

Gastrointestinal disorders

 

Nausea

Constipation

Vomiting

Gastrooesophageal reflux disease

Dysphagia

 

Hepatobiliary disorders

 

Hepatic enzymes increased

Blood bilirubin increased

 

Toxic hepatitis

Skin and subcutaneous tissue disorders

  

Pruritus

Rash

  

Musculoskeletal and connective tissue disorders

 

Blood creatine phosphokinase increased

 

Rhabdomyolysis

 

Renal and urinary disorders

  

Dysuria Pollakisuria

  

Pregnancy, puerperium and perinatal conditions

    

Drug withdrawal syndrome neonatal (see section 4.6)

General disorders and administration site conditions

 

Fatigue

Thirst

  

1Sleep disorders: Insomnia, Abnormal dreams/nightmare, Circadian rhythm sleep disorder, Dyssomnia, Hypersomnia, Initial insomnia, Middle insomnia, Nightmare, Sleep disorder, Somnambulism, Terminal insomnia

2Akathisia: Akathisia, Psychomotor hyperactivity, Restlessness

3Parkinsonism: Akinesia, Bradykinesia, Bradyphrenia, Cogwheel rigidity, Extrapyramidal disorder, Gait disturbance, Hypokinesia, Joint stiffness, Tremor, Masked facies, Muscle rigidity, Musculoskeletal stiffness, Nuchal rigidity, Parkinsonism

4Dystonia: Blepharospasm, Dystonia, Muscle tightness, Oromandibular dystonia, Torticollis, Trismus

5Other extrapyramidal diseases and abnormal movement disorders: Balance disorder, Bruxism, Drooling, Dysarthria, Gait deviation, Glabellar reflex abnormal, Hyporeflexia, Movement disorder, Restless legs syndrome, Salivary hypersecretion, Tongue movement disturbance

6Dyskinesia: Choreoathetosis, Dyskinesia, Grimacing, Oculogyric crisis, Protrusion tongue

Description of selected adverse reactions

Lens opacity/Cataract

Development of cataracts was observed in cariprazine non-clinical studies (see section 5.3). Therefore, cataract formation was closely monitored with slit lamp examinations in the clinical studies and patients with existing cataracts were excluded. During the schizophrenia clinical development program of cariprazine, few cataract cases were reported, characterized with minor lens opacities with no visual impairment (13/3192; 0.4%). Some of these patients had confounding factors. The most commonly reported ocular adverse event was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%).

Extrapyramidal symptoms (EPS)

In the short term studies the incidence of EPS was observed in 27%; 11.5%; 30.7% and 15.1% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Akathisia was reported in 13.6%; 5.1%; 9.3% and 9.9% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Parkinsonism was experienced in 13.6%; 5.7%; 22.1% and 5.3% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Dystonia was observed in 1.8%; 0.2%; 3.6% and 0.7% in patients on cariprazine, placebo, risperidone and aripiprazole, respectively.

In the placebo-controlled part of the long-term maintenance of effect study EPS was 13.7% in the cariprazine group compared to 3.0% in the placebo treated patients. Akathisia was reported in 3.9% in patients treated with cariprazine, versus 2.0% in the placebo group. Parkinsonism was experienced in 7.8% and 1.0% in cariprazine and placebo group respectively.

In the negative symptom study EPS was reported in 14.3% in the cariprazine group and 11.7% in the risperidone treated patients. Akathisia was reported in 10.0% in patients treated with cariprazine and 5.2% in the risperidone group. Parkinsonism was experienced in 5.2% and 7.4% in cariprazine and risperidone treated patients respectively. Most EPS cases were mild to moderate in intensity and could be handled with common anti-EPS medicinal products. The rate of discontinuation due to EPS related ADRs was low.

Venous thromboembolism (VTE)

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotics - Frequency unknown.

Elevated liver transaminases

Elevated liver transaminases (ALT, AST) are frequently observed with antipsychotic treatment. In the cariprazine clinical studies the incidence of ALT, AST elevation ADRs occurred in 2.2% of cariprazine-, 1.6% of risperidone- and 0.4% of placebo-treated patients. None of the cariprazine-treated patients had any liver damage.

Weight changes

In the short term studies, there were slightly greater mean increases in body weight in the cariprazine group compared to the placebo group; 1 kg and 0.3 kg, respectively. In the long term maintenance of effect study, there was no clinically relevant difference in change of body weight from baseline to end of treatment (1.1 kg for cariprazine and 0.9 kg for placebo). In the open-label phase of the study during 20 weeks cariprazine treatment 9.0% of patients developed potentially clinically significant (PCS) weight gain (defined as increase ≥ 7%) while during the double-blind phase, 9.8 % of the patients who continued with cariprazine treatment had PCS weight gain versus 7.1% of the patients who were randomized to placebo after the 20 week open-label cariprazine treatment. In the negative symptom study, the mean change of body weight was -0.3 kg for cariprazine and +0.6 kg for risperidone and PCS weight gain was observed in 6% of the cariprazine group while 7.4% of the risperidone group.

QT- prolongation

With cariprazine no QT interval prolongation was detected compared to placebo in a clinical trial designed to assess QT prolongation (see section 5.1). In other clinical trials, only a few, non-serious, QT-prolongations have been reported with cariprazine. During the long-term, open-label treatment period in, 3 patients (0.4%) had QTcB > 500 msec, one of whom also had QTcF > 500 msec. A > 60 msec increase from baseline was observed in 7 patients (1%) for QTcB and in 2 patients (0.3%) for QTcF. In the long-term , maintenance of effect study, during the open-label phase, > 60 msec increase of from baseline was observed in 12 patients (1.6%) for QTcB and in 4 patients (0.5%) for QTcF. During the double-blind treatment period, > 60 msec increases from baseline in QTcB were observed in 3 cariprazine-treated patients (3.1%) and 2 placebo-treated patients (2%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

  • Saudi Arabia

The National Pharmacovigilance Center (NPC)

Fax: + (966-11) 2057662

Call NPC at: + (966-11) 2038222, Exts: 2317-2356-2340.

SFDA Call Center: 19999

e-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

  • Other GCC States

Please contact the relevant competent authority

 


Symptoms

Accidental acute overdose (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day.

Management of overdose

Management of overdose should concentrate on supportive therapy including maintenance of an adequate airway, oxygenation and ventilation and management of symptoms. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. In case of severe extrapyramidal symptoms, anticholinergic medicinal products should be administered. Since cariprazine is highly bound to plasma proteins, haemodialysis is unlikely to be useful in the management of overdose. Close medical supervision and monitoring should continue until the patient recovers.

There is no specific antidote to cariprazine.


Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15

Mechanism of action

The mechanism of action of cariprazine is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D3, D2 (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5-HT1A receptors (Ki values of 1.4-2.6 nM), and antagonist activity at serotonin 5-HT2B, 5-HT2A and histamine H1 receptors (Ki values of 0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5-HT2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar in vitro receptor binding and functional activity profile as the parent drug.

Pharmacodynamic effects

In vivo non-clinical studies demonstrated that cariprazine occupies D3 receptors to a similar extent as D2 receptors at pharmacologically effective doses. There was a dose-dependent occupancy of brain dopamine D3 and D2 receptors (with preferential occupancy in regions with higher D3 expression) in patients with schizophrenia within the therapeutic dose range of cariprazine for 15 days.

The effects of cariprazine on the QT interval were evaluated in patients with schizophrenia or schizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in 129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation was detected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated with cariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTc of > 500 msec in the study.

Clinical efficacy

Efficacy with short-term use

The efficacy of cariprazine for the treatment of acute schizophrenia was studied in three multi-center, multinational, randomized, double-blind, placebo-controlled 6-week trials including 1,754 patients with the age of 18 to 60 years. The primary endpoint was change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score and the secondary endpoint was change from baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acute schizophrenia studies. In a multinational placebo controlled study using fixed doses of 1.5 mg, 3.0 mg and 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In another multinational placebo controlled study using fixed doses of 3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In a third multinational placebo controlled study using fixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo.

Results for the primary outcome parameter are summarized in Table 1 below. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint.

Table 1. Change From Baseline to Week 6 in the PANSS Total Score in Studies of Acute Exacerbations of Schizophrenia—ITT Population

 

Baseline Mean ± SD

Change LS mean (SE)

Treatment difference versus placebo (95% CI)

P-value

PANSS total (MMRM)

RGH-MD-16 (n=711)

Placebo

97.3 ± 9.22

–13.29 (1.82)

Cariprazine 1.5 mg/day

97.1 ± 9.13

–21.27 (1.77)

–7.97 (–12.94, –3.01)

0.0017

Cariprazine 3 mg/day

97.2 ± 8.66

–21.45 (1.74)

–8.16 (–13.09, –3.22)

0.0013

Cariprazine 4.5 mg/day

96.7 ± 9.01

–23.77 (1.74)

–10.48 (–15.41, –5.55)

< 0.0001

Risperidone 4 mg/day

98.1 ± 9.50

–29.27 (1.74)

–15.98 (–20.91, –11.04)

< 0.0001*

RGH-MD-04 (n=604)

Placebo

96.5 ± 9.1

–14.3 (1.5)

Cariprazine 3 mg/day

96.1 ± 8.7

–20.2 (1.5)

–6.0 (–10.1, –1.9)

0.0044

Cariprazine 6 mg/day

95.7 ± 9.4

–23.0 (1.5)

–8.8 (–12.9, –4.7)

< 0.0001

Aripiprazole 10 mg/day

95.6 ± 9.0

–21.2 (1.4)

–7.0 (–11.0, –2.9)

0.0008*

RGH-MD-05 (n=439)

Placebo

96.6 ± 9.3

–16.0 (1.6)

Cariprazine 3 to 6 mg/day

96.3 ± 9.3

–22.8 (1.6)

–6.8 (–11.3, –2.4)

0.0029

Cariprazine 6 to 9 mg/day

96.3 ± 9.0

–25.9 (1.7)

–9.9 (–14.5, –5.3)

< 0.0001

CI = confidence interval; ITT = intent to treat; LS mean = least squares mean; PANSS = Positive and Negative Syndrome Scale.

*compared to placebo

Efficacy with long-term use

The efficacy of cariprazine for maintaining antipsychotic effect was investigated in a randomized-withdrawal, long-term clinical study. Totally, 751 patients with acute symptoms of schizophrenia received cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of 3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mg cariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary outcome of the study was time to relapse. By the end of the trial 49.0% of placebo-treated patients versus 21.6% of cariprazine-treated patients had a relapse of schizophrenic symptoms. Time to relapse (92 vs. 326 days-based on the 25th percentile) was therefore significantly longer in the cariprazine group than in the placebo group (p=0.009).

Efficacy in predominantly negative symptoms of schizophrenia

The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophrenia was investigated in a 26-week, multi-centre, double-blind, and active-controlled clinical trial. Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was investigated compared to risperidone (dose range 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms of schizophrenia (n=461). 86% of patients were less than 55 years old, 54% of them were male.

Persistent predominant negative symptoms were defined as symptoms lasting for a period of at least 6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factor score for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flat affect, N4: avolition, and N6: poverty of speech) and PANSS factor score for positive symptoms ≤ 19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptoms and clinically relevant parkinsonism (EPS) were excluded.

Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the primary efficacy parameter, PANSS factor score for negative symptoms (PANSS-FSNS) (p< 0.001). However, a statistically significant difference (p=0.002) in favour of cariprazine over risperidone was observed from Week 14 onward (Table 2). Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the secondary efficacy parameter, Personal and Social Performance (PSP) total score (p< 0.001). However, a statistically significant difference (p< 0.001) in favour of cariprazine over risperidone was observed from Week 10 onward (Table 2).

Differences on the Clinical Global Impression Severity (p=0.005) and Improvement (p<0.001) scales, as well as PANSS-FSNS response rates (PANSS FSNS ≥ 30% improvement at Week 26; p= 0.003) were supportive of findings on the primary and secondary efficacy parameters.

Table 2 Summary of results in study RGH-188-005

Efficacy parameter

Cariprazine LS mean

Risperidone LS mean

Estimated Treatment Difference

95%CI

p-value

PANSS-FSNS at Baseline

27.8

27.5

-

-

-

PANSS-FSNS at Week 26

18.5

19.6

-

-

-

PANSS-FSNS CfB to Week 26

-8.9

-7.4

-1.5

-2,4; -0.5

0.002

Total PSP at Baseline

48.8

48.2

-

-

-

Total PSP at Week 26

64.0

59.7

-

-

-

Total PSP CfB to Week 26

14.3

9.7

4.6

2.7; 6.6

<0.001

CfB= change from baseline

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with cariprazine in paediatric population. See section 4.2 for information on paediatric use.


Cariprazine has two pharmacologically active metabolites with similar activites as cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum of cariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week of daily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure.

Absorption

Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple-dose administration, peak plasma concentrations for cariprazine and the major active metabolites generally occur at approximately 3-8 hours post dose.

Administration of a single dose of 1.5 mg cariprazine with a high-fat meal (900 to 1,000 calories) did not significantly affect the Cmax or AUC of cariprazine (AUC0-∞ increased by 12%, Cmax decreased by < 5% under fed condition versus fasting). The effect of food on the exposure of the metabolites DCAR and DDCAR was also minimal.

Cariprazine can be administered with or without food.

Distribution

Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 L for cariprazine, 475 L for DCAR and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.

Biotransformation

The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxy cariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethyl cariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR, HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate and glucuronide conjugates. An additional metabolite, desdichlorophenyl piperazine cariprazine (DDCPPCAR) acid, is produced by dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by CYP3A4 and, to a lesser extent, by CYP2D6, to DCAR and HCAR. DCAR is further metabolized by CYP3A4 and to a lesser extent by CYP2D6 into DDCAR and HDCAR. DDCAR is further metabolised to HDDCAR by CYP3A4.

Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.

Elimination

Elimination of cariprazine and its major active metabolites is mainly through hepatic metabolism. Following administration of 12.5 mg/day cariprazine to patients with schizophrenia, 20.8% of the dose was excreted in urine as cariprazine and its metabolites.

Unchanged cariprazine is excreted by 1.2% of the dose in urine and 3.7% of the dose in feces.

The mean terminal half-life (1 to 3 days for cariprazine and DCAR and 13 to 19 days for DDCAR) is not predictive of time to reach steady state or plasma concentration decline after treatment discontinuation. For the management of patients treated with cariprazine, the effective half-life is more relevant than the terminal half-life. The effective (functional) half-life is ~ 2 days for cariprazine and DCAR, 8 days for DDCAR and is ~1 week for total cariprazine. The plasma concentration of total cariprazine will gradually decline following dose discontinuation or interruption. The plasma concentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in total cariprazine concentration occurs in ~3 weeks.

Linearity

After repeated administration plasma exposure of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally over the therapeutic dose range of 1.5 to 6 mg.

Special populations

Renal impairment

Population pharmacokinetic modelling was performed using data from patients enrolled in the schizophrenia cariprazine clinical program with differing levels of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found between cariprazine plasma clearance and creatinine clearance.

Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (see section 4.2).

Hepatic impairment

A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 days [Part B] was conducted in patients with varying degrees of impaired hepatic function (Child-Pugh Classes A and B). Compared to healthy subjects, patients with either mild or moderate hepatic impairment had up to approximately 25% higher exposure (Cmax and AUC) for cariprazine and up to approximately 45% lower exposure for the major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days.

The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and Cmax) decreased by 21-22% and 13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects if unbound + bound concentrations were considered, while for unbound total moiety a decrease of 12-13% and an increase of 20-25% were calculated in mild HI patients and in moderate HI patients, respectively, after multiple dosing of cariprazine.

Cariprazine has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.2).

Age, gender and race

In the population PK analysis there were no clinically relevant differences in the PK parameters (AUC and Cmax of the sum of cariprazine and its major active metabolites) based on age, gender and race. This analysis included 2,844 patients of different races, involving 536 patients between the ages of 50 and 65. Of the 2,844 patients 933 were female (see section 4.2). In elderly patients above 65 years of age data are limited.

Smoking status

Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine.

Potential for cariprazine to affect other medicinal products

Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymes and were not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP219, CYP2D6, CYP2E1 and CYP3A4 in vitro. Cariprazine and its major active metabolites are not inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR were not inhibitors of transporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).


Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cystic degeneration) in the dog. The exposure (AUC of total cariprazine) at the no-observed-adverse-effect-level (NOAEL) for ocular toxicity is 4.2-fold the clinical AUC exposure at the maximal recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in albino rats in the 2-year study at clinically relevant exposures.

Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in the lungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) times the clinical exposure at the MRHD. No inflammation was observed at the end of 2-month drug-free period at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was still present at higher doses.

Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHD in rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. In dogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed with a NOAEL 4.2 times the clinical exposure at the MRHD.

In female rats, lower fertility and conception indices were observed at clinically relevant exposures based on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.8 times the clinical exposure at the MRHD.

Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures 5.8 times the clinical exposure at the MRHD.

Administration of cariprazine to pregnant rats during the period of organogenesis, throughout pregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, and post-weaning body weight of first generation pups. In addition, pale, cold bodies and developmental delays (renal papillae not developed/underdeveloped and decreased auditory startle response in males) were observed in the absence of maternal toxicity. Reproductive performance of the first generation pups was unaffected; however, second generation pups also had similar clinical signs and lower body weight.

Cariprazine and its metabolites were excreted in milk of rats during lactation.


Capsule content:

  • Pregelatinized maize starch
  • Magnesium stearate

Capsule shell:

  • Titanium dioxide
  • Gelatin

Printing ink:

  • Black ink

Not applicable.


5 years.

Do not store above 30°C.

Store in the original package in order to protect from light.

 


Transparent hard PVC/PE/PVDC/aluminum foil blisters in carton box.

Pack size: 28 hard capsules.


Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


Jazeera Pharmaceutical Industries Al-Kharj Road P.O. BOX 106229 Riyadh 11666, Saudi Arabia Tel: + (966-11) 8107023, + (966-11) 2142472 Fax: + (966-11) 2078170 e-mail: jpimedical@hikma.com

28 October 2019
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