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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)

What Exelon is:

Exelon belongs to a class of substances called cholinesterase inhibitors. The active substance of Exelon is rivastigmine.

What is Exelon used for:

It is used for the treatment of memory disorders and dementia in patients with Alzheimer’s disease or with Parkinson’s disease.

In patients with Alzheimer’s dementia or Parkinson’s disease dementia, certain nerve cells die in the brain, resulting in low levels of the neurotransmitter acetylcholine (a substance that allows nerve cells to communicate with each other). Rivastigmine works by blocking the enzymes that break down acetylcholine: acetylcholinesterase and butyrylcholinesterase. By blocking these enzymes, Exelon allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of Alzheimer’s disease or Parkinson’s disease dementia.


Follow all the doctor’s instructions carefully. They may differ from the general information contained in this leaflet.

Read the following information before you take Exelon.

a. Do not take Exelon

If you know that you are allergic (hypersensitive) to rivastigmine (the active substance in

   Exelon) or to any of the other ingredients listed at the end of this leaflet.

·          If you have ever had an allergic reaction to a similar type of medicine, (carbamate derivative).

If  any of these  apply to you, do not take Exelon, and tell your doctor

 

b. Take special care with Exelon

If you experience gastro-intestinal reactions such as nausea (feeling sick), vomiting (being sick) and diarrhoea. You may become dehydrated (losing too much fluid) if vomiting or diarrhoea are prolonged,

If you have, or have ever had heart conditions such as an irregular or slow heartbeat, QTc prolongation, a family history of QTc prolongation, torsade de pointes, or have low potassium or magnesium

If you have, or have ever had an active stomach ulcer,

If you have, or have ever had difficulties in passing urine,

If you have, or have ever had seizures (fits or convulsions),

If you have, or have ever had asthma or severe respiratory disease,

If you suffer from trembling,

If you have a low body weight (less than 50 kg),

If you have kidney or liver problems.

If any of these apply to you, your doctor may need to monitor you more closely while you are on this medicine.

If you have not been taking Exelon for more than three days do not take the next dose until you have talked to your doctor.

 

c. Taking other medicines, herbal or dietary supplements

Tell your doctor or pharmacist about any other medicines you are taking or have recently taken, including any you have bought without a prescription.

Exelon should not be given at the same time as other medicines with similar effects (cholinomimetic agents) or with anticholinergic medications (such as medicines used to relieve stomach cramps or spasms or to prevent travel sickness).

Exelon should not be given together with metoclopramide (a medicine used to alleviate or prevent nausea and vomiting). There may be additive effects such as stiff limbs and trembling hands.

If you have to undergo surgery whilst taking Exelon, you should inform your doctor before you are given any anaesthetics because Exelon may exaggerate the effects of some muscle relaxants during anaesthesia.

Caution when Exelon is taken together with beta-blockers (medicines such as atenolol used to treat hypertension, angina, and other heart conditions). There may be additive effects such as bradycardia (slow heartbeat) that may result in syncope (fainting, loss of consciousness).

 

Caution when Exelon is taken together with medicinal products know to prolong the heart’s electrical system (QT interval) (including but not limited to quinidine (medicine used to treat irregular heartbeat), amiodarone (medicine used to treat serious /fatal irregular heartbeat), pimozide (medicine works on central nervous system), halofantrine (antimalaria medicine), cisapride (medicine used to treat symptoms of night-time heartburn), citalopram (medicine used to treat depression), mizolastin (antihistamine medicine), medicine used to treat bacterial infection such as moxifloxacin, erythromycin). Your doctor may also monitor your clinical condition as needed.

 

 

d. Taking Exelon with food and drink

You should take Exelon twice a day, once with your breakfast and once with your evening meal.

Exelon capsules: swallow the capsules whole with a drink, without opening or crushing them.

 

e. Older people (age 65 years and over)

Exelon can be used by elderly patients.

 

f. Children and adolescents (below 18 years of age)

The use of Exelon in children and adolescents has not been studied and is therefore not recommended.

 

g. Pregnancy and breast-feeding

In the event of pregnancy, the benefits of Exelon must be assessed against the possible effects on your unborn child.

Tell your doctor if you are pregnant or planning to become pregnant.

Ask your doctor , pharmacist , or healthcare provider for advice before taking any medicine during pregnancy.

You should not breast-feed during treatment with Exelon.

Ask your doctor, pharmacist , or healthcare provider for advice before taking any medicine while you are breast-feeding.

 

h. Driving and using machines

Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. Exelon may cause dizziness and somnolence, mainly at the start of treatment or when increasing the dose. Therefore, you should wait to know what effects the drug may cause before engaging in such activities. If you feel dizzy or drowsy, do not drive, use machines or perform any other tasks that require your attention.


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

Do not exceed the recommended dose.

How much Exelon to take

 

Your doctor will tell you what dosage of Exelon to take, starting with a low dose and gradually increasing, depending on how you respond to the treatment. The highest dose that should be taken is 6 mg twice a day.

 When to take Exelon:

You should take Exelon twice a day, once with your breakfast and once with your evening meal. Taking Exelon at the same time each day will help you remember when to take your medicine.

 How to take Exelon:

Hard capsules: swallow the capsules whole with a drink, without opening or crushing them.

 How long to take Exelon:

To benefit from your medicine you must take it every day.

Tell your caregiver that you are taking Exelon. Also tell your caregiver if you have not been taking Exelon for more than three days.

The prescription of this medicine needs specialized advice before its initiation and a periodic assessment of therapeutic benefits. Your doctor will also monitor your weight whilst you are taking this medicine.

If you have questions about how long to take Exelon, talk to your doctor , pharmacist or healthcare provider.

 

a. If you take more Exelon than you should

Tell your doctor if you find you have accidentally taken more Exelon than you are instructed to. You may require medical attention. Some people who have accidentally taken too much Exelon have experienced nausea, vomiting, diarrhoea, high blood pressure and hallucinations. Slow heart beat and fainting may also occur.

 

b. If you forget to take Exelon

If you find you have forgotten to take your dose of Exelon, wait and take the next dose at the usual time. Do not take a double dose of Exelon to make up for the one that you missed.

c. If you stop taking Exelon

Do not stop taking Exelon or change your dose without talking with your doctor.

If you have not been taking Exelon for more than 3 days do not take the next dose until you have talked to your doctor.


As with all medicines, patients taking Exelon may experience side effects, although not everybody gets them.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

You may tend to see side effects more frequently when you start your medication or increase to a higher dose. Side effects will gradually disappear most probably as your body becomes used to the medicine.

Some side effects could be serious

If you experience any serious side effects, stop taking this medicine and tell your doctor immediately.

Uncommon: may affect up to 1 in every 100 people

·         depression

·         fainting

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

·         fits or convulsions (seizures)

·         chest pain

·         crushing chest pain (heart attack)

·         gastric and duodenal ulcers.

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

·         hallucinations

·         irregular or fast or slow heartbeat (problems with heart rhythm)

·         blood in stools or when vomiting (gastrointestinal haemorrhage)

·         severe upper stomach pain, often with nausea and vomiting (inflammation of the pancreas)

·         severe vomiting that can lead to a rupture of the oesophagus

Frequency not known:

·         losing too much fluid (dehydration)

·         yellow skin, yellowing of the whites of eyes, abnormal darkening of the urine or unexplained nausea, vomiting, tiredness, and loss of appetite (liver disorders)

·         skin inflammation, blisters or swelling of the skin that are increasing and spreading

·         stiff limbs, trembling hands (extrapyramidal symptoms)

 

Other possible side effects

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

·           feeling sick (gastrointestinal reactions such as nausea), being sick (vomiting), diarrhoea, dizziness and loss of appetite.

Common (may affect up to1 in every 10 people):

·           agitation,

·           confusion,

·           nightmares,

·           anxiety,

·           headache,

·           drowsiness,

·           trembling,

·           stomach pains,

·           stomach discomfort after meal,

·           excessive sweating,

·           fatigue,

·           weakness, a general feeling of being unwell

·           weight loss.

Uncommon: may affect up to 1 in every 100 people

·           difficulty in sleeping

·           abnormal results of liver function tests

·           accidental fall

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

·         rash

·         itching

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

·         high blood pressure

·         urinary tract infection

·         muscle stiffness, difficulty in carrying out movements (worsening of Parkinson’s disease symptoms or development of similar symptoms)

Frequency not known:

·           aggression

·           restlessness

 

Additional information for patients with Parkinson’s disease

Some side effects are less frequent in patients with dementia associated with Parkinson’s disease: loss of appetite, dizziness and diarrhoea (common).

Some side effects are more frequent in patients with dementia associated with Parkinson’s disease: trembling, accidental falls (very common); losing too much fluid (dehydration), difficulty in sleeping, restlessness, worsening of Parkinson’s disease symptoms or development of similar symptoms (abnormally slow movements, uncontrollable movement of mouth, tongue and limbs, muscle stiffness, abnormally decreased muscular movement), slow heart beat, high blood pressure (common); abnormal posture with poor control of movements and problems with heart rhythm (both fast and slow) (uncommon).

Some additional side effects in patients with dementia associated with Parkinson’s disease are: too much saliva, abnormal way of walking and dizziness, light-headedness due to low blood pressure (common).


- Do not use Exelon after the expiry date shown on the box.

- Do not store Exelon above 30°C.

- Store Exelon in the original package.

- Do not use any Exelon pack that is damaged or shows signs of tampering.

- Keep Exelon out of the reach and sight of children.


Hard Capsules:

- The active substance of Exelon is rivastigmine.

The other ingredient are:

Capsule content:  magnesium stearate, microcrystalline cellulose, Silica.

Capsule shell: gelatin, yellow iron oxide (E 172), printing ink, based on red iron oxide (E 172), and titanium dioxide (E 171) and shellac.


Hard capsules Each hard capsule contains 1.5 mg, 3.0 mg, or 6.0 mg of rivastigmine. Exelon hard capsules are supplied in blister strips of 14 capsules packed in boxes containing 2 strips (=28 capsules). This information might differ in some countries.

The Marketing Authorization Holder for this Product is Novartis Pharma.

www.Novartis.com


This leaflet was last approved by Novartis Pharmaceutical Company in 12/2022.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

  ماهو دواء إكسيلون:

ينتمي إكسيلون إلى فئة من المواد تُسمى مثبطات الكولين استيراز. المادة الفعالة لإكسيلون هي ريفاستيجمين.

  مادواعي استعمال إكسيلون:

يُستخدم لعلاج اضطرابات الذاكرة والخرف لدى المرضى المُصابين بمرض الزهايمر أو داء باركنسون.

لدى المرضى المصابين بخرف الزهايمر أو داء باركنسون، تموت بعض الخلايا العصبية في الدماغ، مما يؤدي إلى انخفاض مستويات الناقل العصبي أسيتيل كولين (مادة تسمح للخلايا العصبية بالتواصل مع بعضها البعض). يعمل ريفاستيجمين عن طريق منع الإنزيمات التي تُكسّر الأسيتيل كولين: أسيتيل كولين استيراز وبوتيريل كولين استيراز. من خلال حجب هذه الإنزيمات، يسمح إكسيلون بزيادة مستويات الأسيتيل كولين في الدماغ، مما يساعد على تقليل أعراض مرض الزهايمر أو الخرف الناجم عن داء باركنسون.

اتبع جميع تعليمات الطبيب بعناية. فقد تختلف عن المعلومات العامة الواردة في هذه النشرة.

اقرأ المعلومات التالية قبل تناول إكسيلون.

 

أ‌.          موانع استعمال إكسيلون

 لا تتناول إكسيلون

إذا كنت على علم بأنك مصاب بالحساسية (فرط حساسية) تجاه ريفاستيجمين (المادة الفعالة في دواء إكسيلون) أو لأي من المكونات الأخرى المدرجة في نهاية هذه النشرة.

·          إذا سبق أن عانيت من رد فعل تحسسي لنوع مماثل من الأدوية، (مشتق الكربامات).

إذا انطبق عليك أي من هذه الأعراض، فلا تتناول إكسيلون، وأخبر طبيبك

 

ب‌.      الاحتياطات عند استعمال إكسيلون

 إذا عانيت من ردود فعل معدية معوية مثل الغثيان (الشعور بالإعياء)، والتقيؤ (المرض)، والإسهال. قد تُصاب بالجفاف (فقدان الكثير من السوائل) إذا استمر القيء أو الإسهال لفترة طويلة،

 إذا كنت تعاني ، أو سبق أن عانيت من أمراض قلبية مثل عدم انتظام ضربات القلب أو بطء ضربات القلب ، أو إطالة QTc ، أو تاريخ عائلي من إطالة QTc ، أو torsade de Points ، أو انخفاض البوتاسيوم أو المغنيسيوم.

 إذا كنت تعاني، أو سبق لك الإصابة، بقرحة نشطة في المعدة،

 إذا كنت تعاني، أو سبق لك أن عانيت، من صعوبات في التبول،

 إذا كنت تعاني، أو سبق أن عانيت من نوبات (اختلاجات أو تشنجات)،

 إذا كنت مصابًا بالربو أو مرض تنفسي شديد أو سبق لك الإصابة به،

  إذا كنت تعاني من الارتعاش،

 إذا كان وزن جسمك منخفضًا (أقل من 50 كلغ)،

 إذا كنت تعاني من مشاكل في الكبد أو الكلى

إذا انطبق عليك أي من هذه الأعراض، فقد يحتاج طبيبك إلى مراقبتك عن كثب أثناء تناول هذا الدواء.

إذا لم تكن تتناول دواء إكسيلون لأكثر من ثلاثة أيام، فلا تتناول الجرعة التالية حتى تتحدث إلى طبيبك.

 

ج.  التداخلات الدوائية من أخذ هذا المستحضر مع أدوية أخرى أو أعشاب أو مكملات غذائية

أخبر الطبيب المُتابع لك أو الصيدلي بأي أدوية أخرى تتناولها أو تناولتها مؤخرًا، بما في ذلك تلك التي تحصل عليها من دون وصفة طبية.

يجب عدم إعطاء دواء إكسيلون في نفس الوقت مع أدوية أخرى ذات آثار مماثلة (عوامل مُحاكية للكولين) أو مع أدوية مضادة للكولين (مثل الأدوية المستخدمة لتخفيف تقلصات المعدة أو التشنجات أو لمنع غثيان السفر).

يجب عدم إعطاء إكسيلون مع ميتوكلوبراميد (دواء يُستخدم لتخفيف الغثيان والقيء أو الوقاية منهما). قد تكون هناك آثار إضافية مثل تصلّب الأطراف وارتعاش اليدين.

إذا اضطررت إلى الخضوع لجراحة أثناء تناول إكسيلون، فيجب عليك إبلاغ طبيبك قبل إعطائك أي مواد تخدير لأن إكسيلون قد يزيد من آثار بعض مُرخيات العضلات أثناء التخدير.

تنبيه - عند تناول إكسيلون مع حاصرات بيتا (أدوية مثل أتينولول تُستخدم لعلاج ارتفاع ضغط الدم والذبحة الصدرية وحالات القلب الأخرى). قد تكون هناك آثار إضافية مثل بطء القلب (بطء ضربات القلب) قد تؤدي إلى الإغماء (الإغماء، فقدان الوعي).

 

يرجى أخذ الحيطة عند تناول إكسيلون مع منتجات طبية يعرف أنها تطيل من النظام الكهربائي للقلب (فاصل QT) (بما في ذلك على سبيل المثال لا الحصر كينيدين (دواء يُستخدم لعلاج ضربات القلب غير المنتظمة)، أميودارون (دواء يُستخدم لعلاج ضربات القلب غير المنتظمة الخطيرة/المميتة)، بيموزيد (دواء يعمل على الجهاز العصبي المركزي)، هالوفانترين (دواء مضاد للملاريا)، سيسابريد (دواء يُستخدم لعلاج أعراض حرقة المعدة ليلاً)، سيتالوبرام (دواء يُستخدم لعلاج الاكتئاب)، ميزولاستين (دواء مضاد للهيستامين)، دواء يُستخدم لعلاج العدوى البكتيرية مثل موكسيفلوكساسين، إريثرومايسين). قد يراقب طبيبك أيضًا حالتك السريرية حسب الحاجة.

 

د. تناول إكسيلون مع الطعام والشراب

يجب أن تتناول إكسيلون مرتين يوميًا، مرة مع الإفطار ومرة مع وجبة المساء.

كبسولات إكسيلون: ابتلع الكبسولات كاملة مع مشروب، دون فتحها أو سحقها.

 

هـ. كبار السن (65 عامًا وما فوق)

يمكن للمرضى كبار السن استخدام إكسيلون.

 

و. الأطفال والمراهقين (أقل من 18 عامًا)

لم تتم دراسة استخدام إكسيلون مع الأطفال والمراهقين، وبالتالي لا يوصى باستخدامه.

 

ز. الحمل والرضاعة

في حالة الحمل، يجب تقييم فوائد إكسيلون مقابل الآثار المحتملة على الجنين.

أبلغي طبيبك إذا كنت حاملاً أو تخططين للحمل.

استشر طبيبك أو الصيدلي أو مقدم الرعاية الصحية للحصول على المشورة قبل أخذ أي دواء خلال الحمل.

يجب ألا تُرضعي طفلك رضاعة طبيعية خلال فترة العلاج بدواء إكسيلون.

اطلبي المشورة من طبيبكِ أو الصيدلي أو مقدم الرعاية الصحية المُتابع لكِ قبل تناول أي دواء أثناء الرضاعة الطبيعية.

 

ح. تأثير إكسيلون على القيادة واستخدام الآلات

سوف يُخبرك طبيبك بما إذا كان مرضك يسمح لك بقيادة المركبات واستخدام الآلات بأمان. قد يُسبب إكسيلون الدوخة والنعاس، بشكل أساسي في بداية العلاج أو عند زيادة الجرعة. لذلك، يجب عليك الانتظار لمعرفة الآثار التي قد يُسببها العقار قبل المشاركة في مثل هذه الأنشطة. إذا شعرت بالدوار أو النعاس، فلا تقود السيارة أو تستخدم الآلات أو تؤدي أي مهام أخرى تتطلب انتباهك.

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احرص دائمًا على تناول هذا الدواء تمامًا كما أخبرك طبيبك أو الصيدلي. استشر طبيبك أو الصيدلي أو مقدم الرعاية الصحية إذا كنت غير متأكد.

لا تتجاوز الجرعة المُوصى بها.

ما مقدار جرعة إكسيلون الذي يجب تناولها

 

سوف يُخبرك طبيبك بجرعة إكسيلون التي يجب تناولها، بدايةً بجرعة منخفضة وزيادتها تدريجيًا، اعتمادًا على مدى استجابتك للعلاج، علمًا بأن أعلى جرعة يجب تناولها هي 6 ملغ مرتين يوميًا.

متى يجب تناول إكسيلون:

يجب أن تتناول إكسيلون مرتين يوميًا، مرة مع الإفطار ومرة مع وجبة المساء. سوف يساعدك تناول إكسيلون في نفس الوقت كل يوم على تذكر موعد تناوله.

 كيفيةتناول إكسيلون:

كبسولات إكسيلون: ابتلع الكبسولات كاملة مع مشروب، دون فتحها أو سحقها.

 كممن الوقت يجب تناول إكسيلون:

للاستفادة من دوائك، يجب عليك تناوله كل يوم.

أخبر مقدم الرعاية أنك تتناول إكسيلون. أخبر كذلك مقدم الرعاية إذا لم تكن تتناول إكسيلون لأكثر من ثلاثة أيام.

إن وصف هذا الدواء يحتاج إلى مشورة متخصصة قبل البدء في استخدامه وتقييم دوري للفوائد العلاجية. سوف يُراقب طبيبك أيضًا وزنك أثناء تناول هذا الدواء.

إذا كانت لديك أسئلة حول مدة تناول دواء إكسيلون، فتحدث إلى طبيبك أو الصيدلي أو مقدم الرعاية.

 

أ‌.         الجرعة الزائدة من إكسيلون

أخبر طبيبك إذا وجدت أنك تناولت عن طريق الخطأ جرعة من إكسيلون أكثر مما هو موصوف لك. فقد تحتاج إلى رعاية طبية. إذ عانى بعض الأشخاص الذين تناولوا جرعات كثيرة من إكسيلون عن طريق الخطأ من الغثيان، والقيء، والإسهال، وارتفاع ضغط الدم، والهلاوس. قد يحدث أيضًا بطء في ضربات القلب والإغماء.

 

ب‌.      نسيان تناول جرعة من إكسيلون

إذا وجدت أنك نسيت تناول جرعتك من إكسيلون، فانتظر وتناول الجرعة التالية في الوقت المعتاد. لا تتناول جرعة مضاعفة من إكسيلون لتعويض الجرعة التي فاتتك.

ج. التوقف عن تناول إكسيلون

لا تتوقف عن تناول إكسيلون أو تُغيّر جرعتك دون التحدث إلى طبيبك.

إذا لم تكن تتناول دواء إكسيلون لأكثر من 3 أيام، فلا تتناول الجرعة التالية حتى تتحدث إلى طبيبك.

كما هو الحال مع جميع الأدوية، قد يعاني المرضى الذين يتناولون إكسيلون من آثار جانبية، على الرغم من أنها لا تُصيب الجميع.

لا تنزعج من قائمة الآثار الجانبية المحتملة هذه. فقد لا تُعاني من أي منها.

قد تميل إلى رؤية الآثار الجانبية بشكل أكثر تكرارًا عندما تبدأ في تناول دوائك أو تزيده إلى جرعة أعلى. وستختفي الآثار الجانبية تدريجيًا على الأرجح مع اعتياد جسمك على الدواء.

قد تكون بعض الآثار الجانبية خطيرة

إذا عانيتَ من أيّة آثار جانبية خطيرة، فتوقف عن تناول هذا الدواء وأخبر طبيبك على الفور.

غير شائعة: قد تصيب ما يصل إلى شخص واحد (1) من كل 100 شخص

·         الاكتئاب

·         الإغماء

نادرة: قد تصيب ما يصل إلى شخص واحد (1) من كل 1000 شخص

·         نوبات أو تشنجات (اختلاجات)

·         ألم في الصدر

·         ألم شديد في الصدر (نوبة قلبية)

·         قرح المعدة والإثني عشر.

نادرة جدًا: قد تصيب ما يصل إلى شخص واحد (1) من كل 10000 شخص

·         الهلوسة

·         ضربات قلب غير منتظمة أو سريعة أو بطيئة (مشكلات في نظم القلب)

·         دم في البراز أو عند التقيؤ (نزيف معدي معوي)

·         ألم شديد في الجزء العلوي من المعدة، غالبًا مع الغثيان والقيء (التهاب البنكرياس)

·         قيء شديد يمكن أن يؤدي إلى تمزق المريء

معدل التكرار غير معروف:

·         فقدان الكثير من السوائل (الجفاف)

·         اصفرار الجلد، اصفرار بياض العينين، تحول لون البول إلى اللون الغامق بشكل غير طبيعي أو غثيان غير مبرر والتقيؤ والتعب وفقدان الشهية (اضطرابات الكبد)

·         التهاب الجلد، أو بثور أو تورم يتزايد وينتشر في الجلد

·         تيبّس الأطراف، ارتعاش اليدين (أعراض خارج السبيل الهرمي)

 

الآثار الجانبية الأخرى المحتملة

شائعة جدًا (قد تصيب أكثر من 1 من كل 10 أشخاص):

·           الشعور بالإعياء (ردود فعل معدية معوية مثل الغثيان)، والإعياء (القيء)، والإسهال، والدوخة، وفقدان الشهية.

شائعة: قد تصيب ما يصل إلى شخص واحد (1) من كل 10 أشخاص

·           الهياج،

·           الارتباك،

·           الكوابيس،

·           القلق،

·           الصداع،

·           النعاس،

·           الارتعاش،

·           آلام المعدة،

·           ألم في المعدة بعد تناول الطعام،

·           التعرّق المفرط،

·           الإجهاد،

·           ضعف، شعور عام بأنك لست على ما يرام

·           فقدان الوزن.

غير شائعة: قد تصيب ما يصل إلى شخص واحد (1) من كل 100 شخص

·           صعوبة النوم

·           نتائج غير طبيعية في اختبارات وظائف الكبد

·           السقوط العرضي

نادرة: قد تصيب ما يصل إلى شخص واحد (1) من كل 1000 شخص

·         الطفح الجلدي

·         حكة

نادرة جدًا: قد تصيب ما يصل إلى شخص واحد (1) من كل 10000 شخص

·         ارتفاع ضغط الدم

·         عدوى المسالك البولية

·         تيبّس العضلات، صعوبة في القيام بالحركات (تفاقم أعراض داء باركنسون أو ظهور أعراض مماثلة)

معدل التكرار غير معروف:

·           العدوانية

·           التململ

 

معلومات إضافية للمرضى المصابين بداء باركنسون

تكون بعض الآثار الجانبية أقل تكرارًا لدى المرضى المصابين بالخرف المرتبط بداء باركنسون: فقدان الشهية، والدوخة، والإسهال (شائع).

تكون بعض الآثار الجانبية أكثر تكرارًا لدى المرضى المصابين بالخرف المرتبط بداء باركنسون: الارتعاش، السقوط العرضي (شائع جدًا)؛ فقدان الكثير من السوائل (الجفاف)، صعوبة في النوم، التململ، تفاقم أعراض داء باركنسون أو ظهور أعراض مماثلة (حركات بطيئة بشكل غير طبيعي، حركة الفم واللسان والأطراف بشكل لا يمكن السيطرة عليه، تيبّس العضلات، انخفاض غير طبيعي في الحركة العضلية)، بطء ضربات القلب، ارتفاع ضغط الدم (شائع)؛ وضعية غير طبيعية مع ضعف التحكم في الحركات ومشكلات في نظم القلب (سريعة وبطيئة) (غير شائعة).

بعض الآثار الجانبية الإضافية لدى المرضى المصابين بالخرف المرتبط بداء باركنسون هي: كثرة اللعاب، وطريقة غير طبيعية للمشي والدوخة، والدوار بسبب انخفاض ضغط الدم (شائع).

- لا تستخدم إكسيلون بعد تاريخ انتهاء الصلاحية الموضح على العلبة.

- لا تخزن إكسيلون في درجة حرارة أعلى من 30 درجة مئوية.

- خزّن إكسيلون في العبوة الأصلية.

- لا تستخدم أي عبوة لدواء إكسيلون تالفة أو تظهر عليها علامات العبث بها.

- احفظ إكسيلون بعيدًا عن متناول ومرأى الأطفال.

أ. ما هي محتويات إكسيلون

الكبسولات الصلبة:

- المادة الفعالة لإكسيلون هي ريفاستيجمين.

المكونات الأخرى هي:

محتوى الكبسولة: ستيرات المغنيسيوم، سليلوز دقيق التبلور، سيليكا.

غلاف الكبسولة: جيلاتين، أكسيد الحديد الأصفر (E 172)، حبر الطباعة، بناءً على أكسيد الحديد الأحمر (E 172)، وثاني أكسيد التيتانيوم (E 171) والشيلاك.

تحتوي كل كبسولة صلبة على 1.5 ملغ أو 3.0 ملغ أو 6.0 ملغ من ريفاستيجمين.

يتم توفير كبسولات إكسيلون الصلبة في أشرطة تحتوي على 14 كبسولة معبأة في علب تحتوي على شريطين (=28 كبسولة).

 

قد تختلف هذه المعلومات في بعض البلاد.

مالك حق التَّسويق لهذا المنتج هي شركة نوفارتس فارما إيه جي.

www.Novartis.com

تم اعتماد هذه النَّشرة من قبل شركة نوفارتس للأدوية في 12/2022
 Read this leaflet carefully before you start using this product as it contains important information for you

Exelon 1.5 mg hard capsules Exelon 3.0 mg hard capsules Exelon 6.0 mg hard capsules

Each hard gelatin capsule contains rivastigmine hydrogen tartrate corresponding to 1.5 mg / 3mg / 6mg rivastigmine. For the full list of excipients, see section 6.1.

Hard capsules Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint “EXELON 1,5 mg” on body. Off-white to slightly yellow powder in a capsule with orange cap and orange body, with red imprint “EXELON 3 mg” on body. Off-white to slightly yellow powder in a capsule with red cap and orange body, with red imprint “EXELON 6 mg” on body.

Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s disease.


Dosage regimen

 

 

Initial dose

1.5 mg twice a day.

 

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

 

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose

 

Maintenance dose

1.5 mg to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose.

 

The recommended maximum daily dose

6 mg twice a day.

 

 

Re-initiation of therapy

The incidence and severity of adverse events are generally increased with higher doses.

If treatment is interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

 

Special populations

Renal and hepatic impairment

No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more dose‑dependent adverse reactions.

Patients with severe hepatic impairment have not been studied, however, Exelon capsules may be used in this patient population provided close monitoring is exercized (see sections 4.4 and 5.2).

 

Paediatric patients (below 18 years)

The use of Exelon in pediatric patients has not been studied and is therefore not recommended.

 

Method of administration

Exelon hard capsules should be administered twice a day, with morning and evening meals.

Exelon oral solution and Exelon capsules may be interchanged at equal doses.

 


The use of Exelon is contraindicated in patients with • known hypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine patch (see section 4.4).

Treatment should always be started at a dose of 1.5 mg twice daily and titrated to the patient’s maintenance dose. If treatment is interrupted for longer than three days, treatment should be re-initiated with the lowest daily dose to reduce the possibility of adverse reactions (e.g., severe vomiting) (4.2  Posology and method of administration).

 

Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose .These adverse reactions occur more commonly in women. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with serious outcomes (see section 4.8).

 

Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. The patient’s weight should be monitored during therapy with Exelon.

 

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions.

 

As with other cholinomimetics, care must be taken when using Exelon in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Cholinergic stimulation may cause increased gastric acid secretion and may exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such conditions.

 

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

 

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.

In patients with dementia associated with Parkinson’s disease who were treated with Exelon capsules worsening of parkinsonian symptoms, particularly tremor, has been observed (see section 4.8).

 

QT prolongation and torsade de pointes

Electrocardiogram QT prolongation may occur in patients treated with certain cholinesterase inhibitor products including rivastigmine. Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial infarction, bradyarrhythmias, hypokalemia or hypomagnesemia, personal or family history of QT prolongation, or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes. Clinical monitoring may also be required (see section INTERACTIONS).

 

Skin reactions

In patients who develop application site reactions suggestive of allergic contact dermatitis to Exelon Patch and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.

 

 

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued (see section 4.3).

 

 

 

There have been rare post-marketing reports of patients experiencing allergic dermatitis (disseminated) when administered rivastigmine irrespective of the route of administration (oral, transdermal). In these cases, treatment should be discontinued (see section 4.3) .Patients and caregivers should be instructed accordingly.

 

Special populations

Patients with clinically significant renal or hepatic impairment might experience more adverse reactions Dosing recommendations to titrate according to individual tolerability must be closely followed (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. However, Exelon may be used in this patient population provided and close monitoring is exercized.


Rivastigmine is metabolized mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Thus, no pharmacokinetic interactions are anticipated with other drugs metabolized by these enzymes.

Anticipated interactions resulting in a concomitant use not recommended

Metoclopramide

Considering the possibility of an additive extra-pyramidal effect the concomitant use of metoclopramide and rivastigmine is not recommended.

Drugs acting on cholinergic system

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs due to possible additive effect. Rivastigmine might also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine).

Succinylcholine-type muscle relaxants

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia

 

Anticipated interactions to be considered

Medicinal products known to prolong the QT interval

Caution is advised when rivastigmine is used in combination with other medicinal products known to prolong the QT interval (including but not limited to quinidine, amiodarone, pimozide, halofantrine, cisapride, citalopram, mizolastin, moxifloxacin, erythromycin). Clinical monitoring may also be required (see section WARNINGS AND PRECAUTIONS).

 

Observed interactions to be considered

Beta-blockers

Additive effects leading to bradycardia (which may result in syncope) have been reported with the combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta- blockers are expected to be associated with the greatest risk, but reports have also been received in patients using other beta-blockers.

Nicotine

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% in patients with Alzheimer’s dementia (n=75 smokers and 549 non-smokers) following rivastigmine oral capsule doses of up to 12 mg/day.

 

Interactions with commonly used concomitant drugs

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

 

Concomitant administration of rivastigmine with commonly prescribed medications, such as antacids, antiemetics, antidiabetics, centrally acting antihypertensives, calcium channel blockers, inotropic drugs, antianginals, non-steroidal anti-inflammatory drugs, oestrogens, analgesics, benzodiazepines, and antihistamines, was not associated with an alteration in the kinetics of rivastigmine, or an increased risk of clinically relevant untoward effects.


Pregnancy

 

Risk Summary

 

The safety of Exelon in human pregnancy has not been established. In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans. In animal studies, rivastigmine was not teratogenic. Exelon should only be given to pregnant women if the potential benefit outweighs the potential risk for the fetus.

 

 

Animal data

Embryo-fetal toxicity studies in pregnant rats and rabbits with oral dose levels up to 2.3 mg base/kg/day revealed no evidence of teratogenic potential for rivastigmine. In pre- and post-natal studies, there was no evidence of adverse effects of rivastigmine on fertility, reproductive performance or in utero or postnatal growth and development in rats at dose levels up to 1.1 mg base/kg/day.

 

Lactation

It is not known if Exelon is transferred into human milk. In animals, rivastigmine and/or metabolites were transferred into breast milk. patients on Exelon should therefore not breast-feed.

 

 

Females and males of reproductive potential

There is no information available on the effects of rivastigmine in women of child-bearing potential.

 

Fertility

There is no information available on the effect of rivastigmine on human fertility. In male and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive performance of either the parents or their offspring.


Alzheimer’s and Parkinson’s disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose Therefore, , in patients with dementia treated with Exelon ,the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician


Summary of the safety profile

The most commonly reported adverse reactions (ADRs) are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

 

Tabulated list of adverse reactions

Adverse drug reactions from clinical trials in Table 1 and Table 2 are listed according to MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on 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).

 

 

Table 1

 

Infections and infestations

            Very rare

Urinary infection

 

 

           

 

           

 

           

 

Psychiatric disorders

            Common

Agitation, Nightmares ,Confusion, Anxiety

           

 

           

 

           

 

            Uncommon

Insomnia, Depression

           

 

            Very rare

Hallucinations

           

 

Nervous system disorders

            Very common

Dizziness

            Common

Headache, Somnolence, Tremor

           

 

           

 

            Uncommon

Syncope

            Rare

Seizures

           

 (

Cardiac disorders

            Rare

Angina pectoris, myocardial infarction

            Very rare

Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)

           

 

Vascular disorders

            Very rare

Hypertension

Gastrointestinal disorders

            Very common

Nausea, Vomiting, Diarrhoea, loss of appetite

           

 

           

 

            Common

Abdominal pain and dyspepsia

            Rare

Gastric and duodenal ulcers

            Very rare

Gastrointestinal haemorrhage, Pancreatitis, severe vomiting were associated with oesophageal rupture

           

 

           

(see section 4.4).

Hepatobiliary disorders

            Uncommon

Abnormal hepatic function tests

           

 

Skin and subcutaneous tissue disorders

            Common

Hyperhydrosis

            Rare

Rash, Pruritus,

           

 

General disorders and administration site conditions

            Common

Fatigue and asthenia, Malaise

           

 

            Uncommon

Fall

Investigations

            Common

Weight loss

 

 

 

 

 

Table 2 Adverse drug reactions reported during a 24-week period in clinical studies conducted in patients with dementia associated with Parkinson’s disease treated with Exelon hard capsules

 

 

Adverse drug reactions

Study B 2315

Study B 2311

 

Exelon capsules

n (%)

Exelon capsules

n (%)

Placebo

n (%)

Total patients studied

294 (100)

362 (100)

179 (100)

Metabolism and nutritional disorders

 

 

 

Common:

Decreased appetite

14 (4.8)

28 (7.7)

8 (4.5)

Common:

Dehydration

2 (0.7)

8 (2.2)

2 (1.1)

Psychiatric disorders

 

 

 

Common:

Anxiety

13 (4.4)

11 (3.0)

1 (0.6)

Common:

Insomnia

7 (2.4)

10 (2.8)

4 (2.2)

Common:

Restlessness

1 (0.3)

10 (2.8)

3 (1.7)

Nervous system disorders

 

 

 

Very common:

Tremor

67 (22.8)

37 ( 10.2)

7 (3.9)

Common:

Dizziness

24 (8.2)

20 (5.5)

2 ( 1.1)

Common:

Somnolence

18 (6.1)

13 (3.6)

5 (2.8)

Common:

Headache

12 (4.1)

15 (4.1)

5 (2.8)

Common:

Parkinson’s disease (worsening)

*

12 (3.3)

2 (1.1)

Common:

Bradykinesia

9 (3.1)

9 (2.5)

3 (1.7)

Common:

Dyskinesia

10 (3.4)

5 (1.4)

1 (0.6)

Common:

Cogwheel rigidity

9 (3.1)

1 (0.3)

0 (0.0)

Common:

Hypokinesia

7 (2.4)

1 (0.3)

0 (0.0)

Uncommon:

Dystonia

0 (0.0)

3 (0.8)

1 (0.6)

Cardiac disorders

 

 

 

Common:

Bradycardia

2 (0.7)

5 (1.4)

1 (0.6)

Uncommon:

Atrial Fibrillation

1 (0.3)

2 (0.6)

0 (0.0)

Uncommon:

Atrioventricular block

1 (0.3)

0 (0.0)

1 (0.6)

Gastrointestinal disorders

 

 

 

Very common:

Nausea

113 (38.4)

105 (29.0)

20 (11.2)

Very common:

Vomiting

38 (12.9)

60 (16.6)

3 ( 1.7)

Common:

Diarrhoea

24 (8.2)

26 (7.2)

8 (4.5)

Common:

Abdominal pain and dyspepsia

12 (4.1)

15 (4.1)

1 (0.6)

Common:

Salivary hypersecretion

6 (2.0)

5 (1.4)

0 (0.0)

Skin and subcutaneous tissue disorders

 

 

 

Common:

Sweating increased

6 (2.0)

8 (2.2)

1 (0.6)

General disorders and administration site conditions

 

 

 

Very Common:

Fall

29 (9.9)

21 (5.8)

11 (6.1)

Common:

Fatigue

Asthenia

16 (5.4)

11 (3.7)

14 (3.9)

6 (1.7)

5 (2.8)

2 (1.1)

Common:

Gait disturbance

0 (0.0)

6 (1.7)

0 (0.0)

* Worsening of Parkinson’s disease in the study 2315 was assessed by reported pre-identified AEs (tremor, bradykinesia, cogwheel rigidity, fall), each of them listed with corresponding frequencies.

 

Additional adverse reactions observed during a 76-week prospective, open-label study in patients with dementia associated with Parkinson’s disease treated with Exelon capsules: hypertension, hypotension (common).

The following additional adverse drug reactions have been reported in a clinical study in patients with dementia associated with Parkinson’s disease treated with Exelon Patch: agitation, depression (common).

Additional adverse drug reactions from post-marketing spontaneous reports (frequency not known)

The following additional adverse drug reactions have been identified with Exelon hard capsules or Exelon oral solution based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Frequency not known: dehydration, aggression, restlessness, extrapyramidal symptoms in patients with Alzheimer’s dementia, sick sinus syndrome, hepatitis, allergic dermatitis (disseminated).

Additional adverse drug reactions which have been reported with Exelon Patch

Common: urinary incontinence.

Uncommon: cerebrovascular accident, delirium, psychomotor hyperactivity.

Rarely reported: erythema, urticaria, blister, allergic dermatitis (localized).

 

Information from clinical trials in patients with dementia associated with Parkinson’s disease

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with Exelon in patients with dementia associated with Parkinson’s disease with pre-defined events that may reflect worsening of Parkinson’s disease.

 

Table 3                Pre-defined events that may reflect worsening of Parkinson’s disease in patients with dementia associated with Parkinson’s disease (Study B2311)

 

 

Exelon

n (%)

Placebo

n (%)

Total patients studied

362 (100)

179 (100)

Total patients with pre-defined AEs

99 (27.3)

28 (15.6)

Tremor

37 (10.2)

7 ( 3.9)

Fall

21 (5.8)

11 (6.1)

Parkinson’s disease (worsening)

12 (3.3)

2 (1.1)

Salivary hypersecretion

5 (1.4)

0

Dyskinesia

5 (1.4)

1 (0.6)

Parkinsonism

8 (2.2)

1 (0.6)

Hypokinesia

1 (0.3)

0

Movement disorder

1 (0.3)

0

Bradykinesia

9 (2.5)

3 (1.7)

Dystonia

3 (0.8)

1 (0.6)

Gait abnormality

5 (1.4)

0

Muscle rigidity

1 (0.3)

0

Balance disorder

3 (0.8)

2 (1.1)

Musculoskeletal stiffness

3 (0.8)

0

Rigors

1 (0.3)

0

Motor dysfunction

1 (0.3)

0

 

Reporting of suspected adverse reactions

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

 

-To reports any side effect(s):

·    Saudi Arabia:

Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o SFDA call center: 19999

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

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

 

Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +996112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com 

 

•    Other GCC States:

-  Please contact the relevant competent authority.


Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, bradycardia, confusional state, hyperhidrosis, hypertension, hallucinations, and malaise. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, and convulsions. Muscle weakness is a possibility and may result in death if respiratory muscles are involved. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur.

Fatal outcome has been rarely reported with rivastigmine overdose and the relationship to rivastigmine was unclear. Symptoms of overdose and outcome vary from patient to patient and the severity of the outcome is not predictably related to the amount of the overdose.

 

 

 

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

 

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

 


Pharmacotherapeutic group: psychoanaleptics, anticholinesterases, ATC code: N06DA03

 

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer’s disease and Parkinson’s disease.

 

Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer’s disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.

 

Clinical studies in Alzheimer’s dementia

The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of Change-Plus, a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).

 

The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.

 

The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.

 

In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.

 

Table 4

 

 

Patients with Clinically Significant Response (%)

 

Intent to Treat

Last Observation Carried Forward

Response Measure

Rivastigmine

612 mg

N=473

Placebo

 

N=472

Rivastigmine

612 mg

N=379

Placebo

 

N=444

ADAS-Cog: improvement of at least 4 points

21***

 

12

 

25***

 

12

CIBIC-Plus: improvement

29***

18

32***

19

PDS: improvement of at least 10%

26***

17

30***

18

At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS

10*

 

6

 

12**

 

6

*p<0.05, **p<0.01, ***p<0.001

 

Clinical studies in dementia associated with Parkinson’s disease

The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change).

 

Table 5

 

Dementia associated with Parkinson’s Disease

ADAS-Cog

Exelon

 

ADAS-Cog

Placebo

 

ADCS-CGIC

Exelon

 

ADCS-CGIC

Placebo

 

ITT + RDO population

(n=329)

(n=161)

(n=329)

(n=165)

 

 

 

 

 

Mean baseline ± SD

Mean change at 24 weeks ± SD

23.8 ± 10.2

2.1 ± 8.2

24.3 ± 10.5

-0.7 ± 7.5

n/a

3.8 ± 1.4

n/a

4.3 ± 1.5

Adjusted treatment difference

 

2.881

 

n/a

p-value versus placebo

<0.0011

0.0072

 

 

 

 

 

ITT - LOCF population

(n=287)

(n=154)

(n=289)

(n=158)

 

 

 

 

 

Mean baseline ± SD

Mean change at 24 weeks ± SD

24.0 ± 10.3

2.5 ± 8.4

24.5 ± 10.6

-0.8 ± 7.5

n/a

3.7 ± 1.4

n/a

4.3 ± 1.5

Adjusted treatment difference

 

3.541

 

n/a

p-value versus placebo

<0.0011

<0.0012

 

 

 

 

 

1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

2 Mean data shown for convenience, categorical analysis performed using van Elteren test

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

 

Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).

 

Table 6

 

Dementia associated with Parkinson’s Disease

ADAS-Cog

Exelon

 

ADAS-Cog

Placebo

 

ADAS-Cog

Exelon

 

ADAS-Cog

Placebo

 

 

Patients with visual hallucinations

Patients without visual hallucinations

 

 

 

 

 

ITT + RDO population

(n=107)

(n=60)

(n=220)

(n=101)

 

 

 

 

 

Mean baseline ± SD

Mean change at 24 weeks ± SD

25.4 ± 9.9

1.0 ± 9.2

27.4 ± 10.4

-2.1 ± 8.3

23.1 ± 10.4

2.6 ± 7.6

22.5 ± 10.1

0.1 ± 6.9

Adjusted treatment difference


4.271


2.091

p-value versus placebo

0.0021

0.0151

 

Patients with moderate dementia (MMSE 10-17)

Patients with mild dementia (MMSE 18-24)

 

 

 

 

 

ITT + RDO population

(n=87)

(n=44)

(n=237)

(n=115)

 

 

 

 

 

Mean baseline ± SD

Mean change at 24 weeks ± SD

32.6 ± 10.4

2.6 ± 9.4

33.7 ± 10.3

-1.8 ± 7.2

20.6 ± 7.9

1.9 ± 7.7

20.7 ± 7.9

-0.2 ± 7.5

Adjusted treatment difference


4.731


2.141

p-value versus placebo

0.0021

0.0101

 

 

 

 

 

1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs

 

The European Medicines Agency has waived the obligation to submit the results of studies with Exelon in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for information on paediatric use).

 


Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.

 

Distribution

Rivastigmine is weakly bound to plasma proteins (approximately 40%). Rivastigmine distributes equally between blood and plasma with a blood-to-plasma partition ratio of 0.9 at concentrations ranging from 1 to 400 ng/mL. It readily crosses the blood brain barrier reaching peak concentrations in 1 to 4 hours, and with a cerebrospinal fluid-to-plasma AUC ratio of 40%. Rivastigmine has a volume of distribution after iv dosing in the range of 1.8-2.7 L/kg.

 

 

Biotranformation

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%).

 

Based on in vitro studies, no pharmacokinetic interaction is expected with medicinal products metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions relating to cytochrome P450 have been observed in humans (see section INTERACTIONS).

 

 

 

Elimination

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s disease.

 

 

Special population

Elderly subjects

In a study to assess the effect of age on the pharmacokinetics of 1 and 2.5 mg oral rivastigmine, plasma concentrations of rivastigmine tended to be higher in the elderly (n=24, aged 61 to 71 years) as compared to young subjects (n=24, aged 19 to 40 years) after the 1 mg dose. This difference was more pronounced with the higher dose (2.5 mg) at which rivastigmine plasma concentrations were 30% greater in the healthy elderly than in healthy young subjects. Plasma levels of the decarbamylated phenolic metabolite were not substantially affected by age. Studies in in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

 

Renal impairment

Plasma levels of rivastigmine were reported not to differ significantly between patients with severe renal impairment (n=10, glomerular filtration rate (GFR) <10 mL/minute) and control subjects (n=10, GFR ≥60 mL/min) given a single oral dose of 3 mg. Clearance of rivastigmine was 4.8 L/min and 6.9 L/min in patients and healthy subjects, respectively. However, in moderately impaired renal patients (n=8, GFR=10 to 50 mL/min), peak plasma concentrations of rivastigmine were increased by almost 2.5-fold and overall plasma levels (AUC) of the decarbamylated phenolic metabolite were increased by approximately 50%. Clearance of rivastigmine was 1.7 L/min. The reason for this discrepancy between severely and moderately impaired renal patients is unclear (see section DOSAGE REGIMEN AND ADMINISTRATION and section WARNINGS AND PRECAUTIONS).

 

Hepatic impairment

After oral administration, the Cmax of rivastigmine was approximately 60% higher and the AUC more than twice as high in subjects with mild to moderate hepatic impairment compared to healthy subjects. Following a single 3-mg dose or multiple 6-mg twice a day doses, the mean oral clearance of rivastigmine was approximately 60 to 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). These pharmacokinetic changes had no effect on either the incidence or severity of adverse effects (See section DOSAGE REGIMEN AND ADMINISTRATION and section WARNINGS AND PRECAUTIONS).


Clinical studies in Alzheimer’s Dementia

The efficacy of Exelon in the treatment of Alzheimer’s Disease has been demonstrated in placebo-controlled studies. The patients involved had an MMSE (Mini-Mental State Examination) of 10 to 24. Results from two pivotal 26-week multicenter studies comparing 1 to 4 mg/day and 6 to 12 mg/day with placebo, as well as pooled analysis of Phase III studies have established that Exelon produces significant improvement in the major domains of cognition, global functioning, and activities of daily living, and in disease severity. Both the low and high dose ranges showed benefit for cognition, global functioning, and disease severity; in addition, the higher dose range produced benefit in activities of daily living.

The following key outcome measures were used in these studies:

Alzheimer's Disease Assessment Scale (ADAS-Cog): a performance-based test system that measures cognitive areas relevant for patients with Alzheimer's Disease such as attention, learning, memory, and language.

Clinician Interview Based Impression of Change-Plus (CIBIC-Plus): a clinician-rated assessment of the patient’s global change in the domains of cognition, behaviour, and functioning, incorporating separate patient and caregiver inputs.

Progressive Deterioration Scale (PDS): a caregiver-rated evaluation of the patient's ability to perform activities of daily living such as toileting, washing, eating, and helping with household chores and shopping.

Study results have indicated that onset of efficacy is generally as early as week 12 and is maintained at the end of 6 months of treatment. Patients treated with 6 to 12 mg experienced improvement in cognition, activities of daily living and global functioning, while placebo patients showed deterioration. The effects of Exelon on these measures (e.g., ADAS-Cog difference from placebo 5 points at week 26) indicate a delay in the rate of deterioration of at least 6 months.

Analyses performed to detect those subtests and symptoms of the ADAS-Cog and CIBIC-Plus, respectively, which improved in patients treated with Exelon indicated that all ADAS-Cog subtests (ideational praxis, orientation, test instructions, word recall, language ability and word recognition) and all CIBIC-Plus items, except anxiety, were significantly improved at week 26 with Exelon 6 to 12 mg. Items which improved in at least 15% more Exelon than placebo patients completing treatment included word recall, functioning, agitation, tearfulness or crying, delusions, hallucinations, purposeless and inappropriate activities, and physical threats and/or violence.

Similar results were observed with Exelon capsule 6 mg twice a day in a controlled study in Chinese patients with mild to moderately severe Alzheimer’s dementia.

Clinical studies in dementia associated with Parkinson’s disease

The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in a 24-week multi-center, double blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) of 10 to 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as reported in Table 4 below: the ADAS-cog, a measure of cognition and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change).

Table 4                Dementia associated with Parkinson’s Disease

 

               ADAS-cog

Exelon                    Placebo

             ADCS-CGIC

Exelon             Placebo

 

ITT + RDO population

 

Mean baseline ± SD

 

Mean change at 24 weeks ± SD

 

p-value

(n=329)                             (n=161)

 

23.8 ± 10.2                 24.3 ± 10.5

 

2.1 ± 8.2                        -0.7 ± 7.5

 

<0.0011

 

(n=329)                            (n=165)

 

n/a                                        n/a

 

3.8 ± 1.4                         4.3 ± 1.5

 

0.0072

 

ITT + LOCF population

 

Mean baseline ± SD

 

Mean change at 24 weeks ± SD

 

p-value

(n=287)                             (n=154)

 

24.0 ± 10.3                 24.5 ± 10.6

 

2.5 ± 8.4                         -0.8 ± 7.5

 

< 0.0011

(n=289)                           (n=158)

 

n/a                                       n/a

 

3.7 ± 1.4                        4.3 ± 1.5

 

< 0.0012

 

1 ANCOVA, with treatment & country as factors and baseline ADAS-cog as a covariance

2 mean data shown for convenience, categorical analysis done using van Elteren test

ITT: Intention-To-Treat; RDO: Retrieved Dropouts; LOCF: Last Observation Carried Forward

NON-CLINICAL SAFETY DATA

Acute toxicity

The estimated oral LD50 values in mice were 5.6 mg base/kg (males) and 13.8 mg base/kg (females). The estimated oral LD50 values in rats were 8.1 mg base/kg (males) and 13.8 mg base/kg (females).

Repeated dose toxicity

Studies in rats, mice, dogs, minipigs and monkeys (maximum doses 3.8, 6.3, 2.5, 6.0 and 6.3 mg-base/kg/day, respectively) revealed evidence of cholinergic stimulation of the central and peripheral nervous systems. In-life tolerability to rivastigmine was variable between species, with the dog as the most sensitive species. No target organ toxicities or clinical pathology alterations were observed in any species, although gastro-intestinal effects were prominent in dogs.

Mutagenicity

Rivastigmine was not mutagenic in in vitro tests for gene mutations and primary DNA damage. In tests for chromosomal damage in vitro, a small increase in the number of cells carrying chromosomal aberrations occurred at very high concentrations. However, as there was no evidence of clastogenic activity in the more relevant in vivo micronucleus test assessing chromosomal damage, it is most likely that the in vitro findings were false positive observations. In addition, the major metabolite NAP226-90 did not induce structural chromosome aberrations in an in vitro test indicating that the compound has no genotoxic potential.

Carcinogenicity

No evidence of carcinogenicity was found in oral and topical studies in mice and in oral study in rats at the maximum tolerated dose. The exposure to rivastigmine and its major metabolite was approximately equivalent to human exposure with highest doses of rivastigmine capsules and patches.

Reproductive toxicity

See section PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL.

Local tolerance

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

 


Gelatin

Magnesium stearate

Hypromellose

Microcrystalline cellulose

Silica, colloidal anhydrous

Yellow iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

Shellac

 


Not applicable.


3 years

Do not store above 30°C.


-                Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 28, 56 or 112 capsules.

-                HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.

 

Not all pack sizes may be marketed.


No special requirements.


The Marketing Authorization Holder for this Product is Novartis Pharma AG. www.Novartis.com

approved by Novartis Pharmaceutical Company in 12/2022.
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