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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء

Atorva belongs to a group of medicines known as statins, which are lipid (fat) regulating medicines.  

Atorva is used to lower lipids known as cholesterol and triglycerides in the blood when a low fat diet and life style changes on their own have failed. If you are at an increased risk of heart disease, Atorva can also be used to reduce such risk even if your cholesterol levels are normal. You should maintain a standard cholesterol lowering diet during treatment.


Do not take Atorva

  • If you are allergic to atorvastatin or any of the other ingredients of this medicine (listed in section 6)  
  • If you have or have ever had a disease which affects the liver  
  • If you have had any unexplained abnormal blood tests for liver function  
  • If you are a woman able to have children and not using reliable contraception  
  • If you are pregnant or trying to become pregnant
  • If you are breast-feeding  
  • If you use the combination of glecaprevir/pibrentasvir in the treatment of hepatitis C

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Atorva:

  • If you have severe respiratory failure  
  • If you are taking or have taken in the last 7 days a medicine called fusidic acid, (a medicine for bacterial infection) orally or by injection. The combination of fusidic acid and atorvastatin can lead to serious muscle problems (rhabdomyolysis)  
  • If you have had a previous stroke with bleeding into the brain, or have small pockets of fluid in the brain from previous strokes  
  • If you have kidney problems  
  • If you have an under-active thyroid gland (hypothyroidism)  
  • If you have had repeated or unexplained muscle aches or pains, a personal history or family history of muscle problems  
  • If you have had previous muscular problems during treatment with other lipid-lowering medicines (e.g. other ‘-statin’ or ‘-fibrate’ medicines)
  • If you regularly drink a large amount of alcohol  
  • If you have a history of liver disease  
  • If you are older than 70 years

If any of these apply to you, your doctor will need to carry out a blood test before and possibly during your atorvastatin treatment to predict your risk of muscle related side effects. The risk of muscle related side effects e.g. rhabdomyolysis is known to increase when

certain medicines are taken at the same time (see section 2 “Other medicines and Atorva”).  

Also tell your doctor or pharmacist if you have a muscle weakness that is constant. Additional tests and medicines may be needed to diagnose and treat this.  

While you are on this medicine your doctor will monitor you closely if you have diabetes or are at risk of developing diabetes. You are likely to be at risk of developing diabetes if you have high levels of sugars and fats in your blood, are overweight and have high blood pressure.

Other medicines and Atorva

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. There are some medicines that may change the effect of Atorva or their effect may be changed by Atorva. This type of interaction could make one or both of the medicines less effective. Alternatively it could increase the risk or severity of side-effects, including the important muscle wasting condition known as rhabdomyolysis described in section 4:

  • Medicines used to alter the way your immune system works, e.g. ciclosporin  
  • Certain antibiotics or antifungal medicines, e.g. erythromycin, clarithromycin, telithromycin, ketoconazole, itraconazole, voriconazole, fluconazole, posaconazole, rifampin, fusidic acid  
  • Other medicines to regulate lipid levels, e.g. gemfibrozil, other fibrates, colestipol  
  • Some calcium channel blockers used for angina or high blood pressure, e.g. amlodipine, diltiazem; medicines to regulate your heart rhythm e.g. digoxin, verapamil, amiodarone  
  • Letermovir, a medicine that helps stop you from getting ill from cytomegalovirus  
  • Medicines used in the treatment of HIV e.g. ritonavir, lopinavir, atazanavir, indinavir, darunavir, the combination of tipranavir/ritonavir etc.
  • Some medicines used in the treatment of hepatitis C e.g. telaprevir, boceprevir and the combination of elbasvir/grazoprevir  
  • Other medicines known to interact with atorvastatin include ezetimibe (which lowers cholesterol), warfarin (which reduces blood clotting), oral contraceptives, stiripentol (an anti-convulsant for epilepsy), cimetidine (used for heartburn and peptic ulcers), phenazone (a painkiller), colchicine (used to treat gout), and antacids (indigestion products containing aluminium or magnesium)  
  •  Medicines obtained without a prescription: St John’s Wort  
  • If you need to take oral fusidic acid to treat a bacterial infection you will need to temporarily stop using this medicine. Your doctor will tell you when it is safe to restart Atorva. Taking atorvastatin with fusidic acid may rarely lead to muscle weakness, tenderness or pain (rhabdomyolysis). See more information regarding rhabdomyolysis in section 4.

Atorva with food, drink and alcohol

See section 3 for instructions on how to take Atorva. Please note the following:

Grapefruit juice

Do not take more than one or two small glasses of grapefruit juice per day because large quantities of grapefruit juice can change the effects of Atorva.

Alcohol

Avoid drinking too much alcohol while taking this medicine. See section 2 “Warnings and precautions” for details.

Pregnancy and breast-feeding

Do not take Atorva if you are pregnant, or if you are trying to become pregnant.

Do not take Atorva if you are able to become pregnant unless you use reliable contraceptive measures.  

Do not take Atorva if you are breast-feeding.  

The safety of atorvastatin during pregnancy and breast-feeding has not yet been proven. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines  

Normally this medicine does not affect your ability to drive or operate machines. However, do not drive if this medicine affects your ability to drive. Do not use any tools or machines if your ability to use them is affected by this medicine.

Atorva contains lactose and sodium

Atorva contains lactose. Each film-coated tablet of 10 mg, 20 mg, 40 mg and 80 mg contains 11.405 mg, 22.81 mg, 45.62 mg or 91.24 mg lactose; respectively. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 Atorva contains sodium. Each film-coated tablet of 10 mg, 20 mg, 40 mg and 80 mg contains 1.09 mg, 2.188 mg, 4.376 mg or 8.752 mg sodium; respectively. This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.


Before starting treatment, your doctor will place you on a low-cholesterol diet, which you should maintain also during therapy with Atorva.  

The usual starting dose of Atorva is 10 mg once a day in adults and children aged 10 years or older. This may be increased if necessary by your doctor until you are taking the amount you need. Your doctor will adapt the dose at intervals of 4 weeks or more. The maximum dose of Atorva is 80 mg once a day.  

Atorva tablets should be swallowed whole with a drink of water, and can be taken at any time of day, with or without food. However, try to take your tablet at the same time every day.  

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

The duration of treatment with Atorva is determined by your doctor.

Please ask your doctor if you think that the effect of Atorva is too strong or too weak.

If you take more Atorva than you should

If you accidently take too many Atorva tablets (more than your usual daily dose), contact your doctor or nearest hospital for advice.

If you forget to take Atorva

If you forget to take a dose, just take your next scheduled dose at the correct time. Do not take a double dose to make up for a forgotten dose.

 If you stop taking Atorva

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


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

If you experience any of the following serious side effects or symptoms, stop taking your tablets and tell your doctor immediately or go to the nearest hospital accident and emergency department.

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

  • Serious allergic reaction which causes swelling of the face, tongue and throat that can cause great difficulty in breathing.  
  • Serious illness with severe peeling and swelling of the skin, blistering of the skin, mouth, eyes, genitals and fever. Skin rash with pink-red blotches especially on palms of hands or soles of feet which may blister.  
  • Muscle weakness, tenderness, pain, rupture or red-brown discolouration of urine and particularly, if at the same time, you feel unwell or have a high temperature it may be caused by an abnormal muscle breakdown (rhabdomyolysis). The abnormal muscle breakdown does not always go away, even after you have stopped taking atorvastatin, and it can be life-threatening and lead to kidney problems.

 

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

  • If you experience problems with unexpected or unusual bleeding or bruising, this may be suggestive of a liver complaint. You should consult your doctor as soon as possible.  
  • Lupus-like disease syndrome (including rash, joint disorders and effects on blood cells).

Other possible side effects with Atorvastatin

Common: may affect up to 1 in 10 people

  • Inflammation of the nasal passages, pain in the throat, nose bleed  
  • Allergic reactions  
  • Increases in blood sugar levels (if you have diabetes continue careful monitoring of your blood sugar levels), increase in blood creatine kinase
  • Headache  
  • Nausea, constipation, wind, indigestion, diarrhoea  
  • Joint pain, muscle pain and back pain  
  • Blood test results that show your liver function can become abnormal

Uncommon: may affect up to 1 in 100 people

  • Anorexia (loss of appetite), weight gain, decreases in blood sugar levels (if you have diabetes you should continue careful monitoring of your blood sugar levels)  
  • Having nightmares, insomnia, dizziness  
  • Numbness or tingling in the fingers and toes, reductions of sensation to pain or touch, change in sense of taste, loss of memory, blurred vision  
  • Ringing in the ears and/or head  
  • Vomiting, belching, abdominal pain upper and lower, pancreatitis (inflammation of the pancreas leading to stomach pain)  
  • Hepatitis (liver inflammation)  
  • Rash, skin rash and itching, hives, hair loss  
  • Neck pain, muscle fatigue  
  • Fatigue, feeling unwell, weakness, chest pain, swelling especially in the ankles (oedema), raised temperature  
  • Urine tests that are positive for white blood cells

 

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

  • Visual disturbance  
  • Unexpected bleeding or bruising  
  • Cholestasis (yellowing of the skin and whites of the eyes)  
  • Tendon injury

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

  • An allergic reaction - symptoms may include sudden wheezing and chest pain or tightness, swelling of the eyelids, face, lips, mouth, tongue or throat, difficulty breathing, collapse  
  • Hearing loss  
  • Gynecomastia (breast enlargement in men).

Not known: frequency cannot be estimated from the available data:

  • Muscle weakness that is constant.  

Possible side effects reported with some statins (medicines of the same type):

  • Sexual difficulties  
  • Depression  
  • Breathing problems including persistent cough and/or shortness of breath or fever  
  • Diabetes. This is more likely if you have high levels of sugars and fats in your blood, are overweight and have high blood pressure. Your doctor will monitor you while you are taking this medicine. 

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

Do not store above 30°C.

Store in the original package.

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 atorvastatin calcium trihydrate.

Each film-coated tablet of Atorva 10 mg Film-coated Tablets contains 10.963 mg atorvastatin calcium trihydrate equivalent to 10 mg atorvastatin.

Each film-coated tablet of Atorva 20 mg Film-coated Tablets contains 21.935 mg atorvastatin calcium trihydrate equivalent to 20 mg atorvastatin. 

Each film-coated tablet of Atorva 40 mg Film-coated Tablets contains 43.85 mg atorvastatin calcium trihydrate equivalent to 40 mg atorvastatin.

Each film-coated tablet of Atorva 80 mg Film-coated Tablets contains 87.7 mg atorvastatin calcium trihydrate equivalent to 80 mg atorvastatin.

The other ingredients are: Tablet core: Calcium carbonate, microcrystalline cellulose, lactose, croscarmellose sodium, hydroxypropyl cellulose, tween 80 and magnesium stearate. Tablet coat: Opadry white and antifoam emulsion.  


Atorva 10 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 53” on one side and plain on the other side in aluminum foil blisters. Atorva 20 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 54” on one side and plain on the other side in aluminum foil blisters. Atorva 40 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 55” on one side and plain on the other side in aluminum foil blisters. Atorva 80 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 57” on one side and plain on the other side in aluminum foil blisters. Pack size: 30 and 500 Film-coated Tablets. Atorva 10 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 53” on one side and plain on the other side in aluminum foil blisters. Atorva 20 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 54” on one side and plain on the other side in aluminum foil blisters. Atorva 40 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 55” on one side and plain on the other side in aluminum foil blisters. Atorva 80 mg Film-coated Tablets are white to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 57” on one side and plain on the other side in aluminum foil blisters. Pack size: 30 and 500 Film-coated Tablets.

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


This leaflet was last revised in 06/2021; version number SA1.0.

ينتمي أتورڤا إلى مجموعة من الأدوية تُسمى الستاتين، وهي أدوية تعمل على تنظيم مستوى الدهون (الشحوم). 

يُستخدم أتورڤا لخفض مستويات الدهون المعروفة بالكولستيرول والدهون الثلاثية في الدم عند فشل النظام الغذائي منخفض الدهون وتغييرات نمط الحياة في خفض هذه المستويات بمفردها. في حالة زيادة خطورة إصابتك بأمراض القلب، يمكن استخدام أتورڤا كذلك لتقليل هذه الخطورة، حتى وإن كانت مستويات الكولستيرول لديك طبيعية. يجب أن تحافظ على نظام غذائي نموذجي لخفض الكوليسترول أثناء العلاج.  

 

لا تتناول أتورڤا

  • إذا كنت تعاني من حساسية لأتورڤاستاتين أو لأي من المواد الأخرى المستخدمة في تركيبة هذا الدواء (المذكورة في القسم 6) 
  • إذا كنت تعاني أو سبق وأن عانيت من مرض يؤثر على الكبد 
  • إذا ظهرت لديك أي فحوصات دم غير طبيعية ومجهولة السبب لوظائف الكبد 
  • إذا كنتِ امرأة قادرة على الحمل والإنجاب ولا تستخدمين وسيلة فعَّالة لمنع الحمل 
  • إذا كنتِ حاملاً أو تحاولين أن تصبحي حاملاً
  • إذا كنت ترضعين طبيعياً 
  •  إذا كنت تستخدم غليكابريڤير/بيبرنتاسفير معاً في علاج التهاب الكبد الوبائي ج

الاحتياطات والتحذيرات

تحدث مع طبيبك، الصيدلي أو الممرض قبل تناول أتورڤا:

  •  إذا كنت تعاني من الفشل التنفسي الحاد 
  • إذا كنت تستخدم أو قد استخدمت في الأيام السبعة الأخيرة دواءً يُسمى حمض الفوسيديك، (دواء لعلاج العدوى البكتيرية) عن طريق الفم أو الحقن. قد يؤدي تناول حمض الفوسيديك مع الأتورڤاستاتين إلى حدوث مشاكل خطيرة في العضلات (انحلال الربيدات) 
  • إذا سبق وأن أُصبت بسكتة دماغية مع نزيف في الدماغ، أو تكونت لديك أكياس صغيرة من السوائل في الدماغ بسبب سكتات دماغية سابقة 
  • إذا كنت تعاني من مشاكل في الكلى 
  • إذا كنت تعاني من انخفاض نشاط الغدة الدرقية (قصور الدرقية) 
  • إذا أُصبت بأوجاع أو آلام مجهولة السبب أو متكررة في العضلات، أو كان لديك تاريخ شخصي أو عائلي في مشاكل العضلات 
  • إذا سبق وأن أصبت بمشاكل عضلية أثناء العلاج بأدوية أخرى لخفض الدهون (مثل أدوية "الستاتين" أو "الفيبرات" الأخرى) 
  • إذا كنت تشرب كمية كبيرة من الكحول بانتظام 
  • إذا سبق وأن عانيت من أمراض الكبد 
  • إذا كان عمرك أكبر من 70 عاماً

إذا كان أي من ذلك ينطبق عليك، سيتعين على طبيبك إجراء فحص دم قبل علاجك بأتورڤاستاتين وربما أثنائه للتنبؤ بمدى خطورة تعرضك للآثار الجانبية المتعلقة بالعضلات. خطورة الإصابة بالآثار الجانبية المتعلقة بالعضلات مثل انحلال الربيدات تزداد عند تناول أدوية معينة في الوقت ذاته (انظر القسم 2 "الأدوية الأخرى وأتورڤا"). 

أخبر طبيبك أيضاً أو الصيدلي إذا كنت تعاني من ضعف في العضلات بشكل مستمر. قد يتعين عليك إجراء فحوصات وتناول أدوية إضافية لتشخيص ذلك وعلاجه. 

سيراقب طبيبك حالتك عن كثب أثناء تناولك هذا الدواء، إذا كنت مصاباً بمرض السكري أو عرضة لخطر الإصابة بمرض السكري. من المحتمل أن تكون عرضة لخطر الإصابة بمرض السكري إذا كان لديك مستويات عالية من السكريات والدهون في دمك، وإذا كنت تعاني من زيادة الوزن وارتفاع ضغط الدم.

الأدوية الأخرى وأتورڤا

أخبر طبيبك أو الصيدلي إذا كنت تتناول، تناولت مؤخراً، أو قد تتناول أية أدوية أخرى. توجد بعض الأدوية التي قد تغير من تأثير أتورڤا أو قد يتغير تأثيرها بفعل أتورڤا. قد يؤدي هذا النوع من التفاعل إلى تقليل فاعلية أحد الأدوية أو كليهما. وبخلاف ذلك، قد يؤدي إلى زيادة خطورة الآثار الجانبية أو شدّتها، التي من بينها حالة الهزال العضلي الخطيرة المعروفة باسم انحلال الربيدات الموضحة في القسم 4:

  •  الأدوية المستخدمة لتغيير طريقة عمل جهازك المناعي، مثل سيكلوسبورين 
  • بعض المضادات الحيوية أو الأدوية المضادة للفطريات مثل إريثروميسين، كلاريثروميسين، تيليثروميسين، كيتوكونازول، إيتراكونازول، فوريكونازول، فلوكونازول، بوساكونازول، ريفامبيسين، حمض الفوسيديك 
  • أدوية تنظيم مستويات الدهون الأخرى، مثل جيمفبروزيل، أدوية الفيبرات الأخرى، كوليستيبول 
  • بعض حاصرات قنوات الكالسيوم المستخدمة لعلاج الذبحة أو ارتفاع ضغط الدم، مثل أملوديبين، ديلتيازيم؛ أدوية تنظيم نظم القلب مثل ديجوكسين، فيراباميل، أميودارون 
  • ليتيرموڤير، دواء يساعدك على منع الإصابة بالفيروس المُضخِّم للخلايا 
  • الأدوية المستخدمة في علاج فيروس نقص المناعة البشري مثل ريتوناڤير، لوبيناڤير، أتازاناڤير، إنديناڤير، داروناڤير، وتناول تيبراناڤير/ريتوناڤير معاً وغير ذلك.
  • بعض الأدوية المستخدمة في علاج التهاب الكبد الوبائي ج، مثل تيلابريڤير، بوسبريڤير، وتناول إلباسڤير/غرازوبريڤير معاً 
  • تشمل الأدوية الأخرى المعروفة بالتفاعل مع أتورڤاستاتين إزيتمايب (الذي يخفض الكوليسترول)، الوارفارين (الذي يقلل من تجلط الدم)، ووسائل منع الحمل التي تؤخذ عن طريق الفم، ستيريبنتول (مضاد الاختلاج لعلاج الصرع)، سيميتيدين (يستخدم لعلاج حرقة المعدة والقرح المعدية)، فينازون (مسكن للألم)، كولشيسين (يستخدم لعلاج النقرس)، ومضادات الحموضة (مستحضرات عسر الهضم التي تحتوي على الألومنيوم أو المغنيسيوم) 
  •  الأدوية التي تُصرف دون وصفة طبية: نبتة القديس يوحنا 
  • إذا كنت بحاجة إلى تناول حمض الفيوسيديك عن طريق الفم لعلاج عدوى بكتيرية، سيتعين عليك إيقاف تناول هذا الدواء مؤقتاً. سيُخبرك طبيبك عندما يكون من الآمن إعادة بدء تناول أتورڤا. قد يؤدي تناول أتورڤاستاتين مع حمض الفيوسيديك نادراً إلى ضعف العضلات، الإيلام أو الألم بها (انحلال الربيدات). انظر إلى المزيد من المعلومات عن انحلال الربيدات في القسم 4.

أتورڤا مع الطعام، الشراب والكحول

انظر القسم 3 للحصول على تعليمات عن كيفية تناول أتورڤا. يُرجى ملاحظة ما يلي:

عصير الجريب فروت  

لا تتناول أكثر من كوب أو كوبين صغيرين من عصير الجريب فروت في اليوم لأن الكميات الكبيرة من عصير الجريب فروت قد تُغير من تأثير أتورڤا.

الكحول

تجنب تناول الكثير من الكحول أثناء تناول هذا الدواء. انظر القسم 2 "الاحتياطات والتحذيرات" لمعرفة التفاصيل.

الحمل والرضاعة

لا تتناولي أتورڤا إذا كنتِ حاملاً، أو تحاولين أن تصبحي حاملاً.

لا تتناولي أتورڤا إذا كنت قادرة على الحمل إلا إذا كنتِ تستخدمين وسائل منع حمل فعَّالة. 

لا تتناولي أتورڤا إذا كنتِ مرضعاً. 

لم تثبت سلامة أتورڤاستاتين أثناء الحمل والرضاعة الطبيعية بعد. استشيري طبيبك أو الصيدلي قبل تناول أي دواء.

القيادة واستخدام الآلات 

لا يؤثر هذا الدواء عادةً على قدرتك على القيادة أو تشغيل الآلات. ومع ذلك، تجنب القيادة إذا كان هذا الدواء يؤثر على قدرتك على القيادة. لا تستخدم أي أدوات أو آلات في حالة تأثير هذا الدواء على قدرتك على استخدامها.

يحتوي أتورڤا على اللاكتوز والصوديوم

يحتوي أتورڤا على اللاكتوز. يحتوي كل قرص مغطى بطبقة رقيقة من 10 ملغم، 20 ملغم، 40 ملغم و80 ملغم على 11.405 ملغم، 22.81 ملغم، 45.62 ملغم أو 91.24 ملغم لاكتوز؛ على التوالي. إذا أخبرك طبيبك أن لديك عدم تحمل تجاه بعض السكريات، تواصل مع طبيبك قبل تناول هذا المستحضر الدوائي.

يحتوي أتورڤا على الصوديوم. يحتوي كل قرص مغطى بطبقة رقيقة من 10 ملغم، 20 ملغم، 40 ملغم و80 ملغم على 1.09 ملغم، 2.188 ملغم، 4.376 ملغم أو 8.752 ملغم صوديوم؛ على التوالي. يحتوي هذا الدواء على أقل من 1 ملمول (23 ملغم) صوديوم لكل قرص مغطى بطبقة رقيقة، وبذلك يعتبر ’خالٍ من الصوديوم‘ بشكل أساسي.

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سيضع لك طبيبك، قبل بدء العلاج، نظام غذائي منخفض الكوليسترول، حيث يجب عليك اتباعه كذلك أثناء العلاج بأتورڤا. 

جرعة البداية المعتادة من أتورڤا هي 10 ملغم مرة واحدة يومياً للبالغين والأطفال بعمر 10 أعوام أو أكبر. قد يقوم الطبيب بزيادتها عند الضرورة حتى تأخذ المقدار الذي تحتاج إليه. سيعدل طبيبك الجرعة كل 4 أسابيع أو أكثر. الجرعة القصوى من أتورڤا هي 80 ملغم مرة واحدة يومياً. 

يجب بلع أقراص أتورڤا كاملة مع شرب الماء، ويمكن تناولها في أي وقت من اليوم مع الطعام أو بدونه. ومع ذلك، حاول تناول القرص في الوقت نفسه كل يوم. 

قم دائماً بتناول دوائك كما أخبرك طبيبك أو الصيدلي تماماً. تحقق من طبيبك أو الصيدلي إذا لم تكن متأكداً. 

مدة العلاج بأتورڤا يحددها الطبيب.

يُرجى إخبار طبيبك إذا كنت تعتقد بأن تأثير أتورڤا قوي جداً أو ضعيف جداً.

إذا تناولت أتورڤا أكثر من اللازم

إذا تناولت عن طريق الخطأ عدداً كبيراً من أقراص أتورڤا (أكثر من جرعتك اليومية المعتادة)، اتصل على طبيبك أو أقرب مستشفى للحصول على استشارة.

إذا نسيت تناول أتورڤا

إذا نسيت تناول جرعة، فتناول جرعتك التالية المحددة في الوقت الصحيح فحسب. لا تقم بتناول جرعة مضاعفة لتعويض الجرعة المنسية.

إذا توقفت عن تناول أتورڤا

إذا كان لديك أية أسئلة إضافية حول استخدام هذا الدواء، أو كنت ترغب في إيقاف علاجك، اسأل الطبيب أو الصيدلي. 

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

إذا أصبت بأي من الآثار الجانبية الخطيرة أو الأعراض التالية، فتوقف عن تناول أقراصك وأخبر طبيبك على الفور، أو توجه إلى قسم الحوادث والطوارئ بأقرب مستشفى.

نادرة: قد تؤثر فيما يصل إلى شخص من بين كل 1000 شخص

  • رد فعل تحسسي خطير يسبب تورماً في الوجه، اللسان، الحلق والذي قد يسبب صعوبة كبيرة في التنفس. 
  • مرض خطير يصحبه تقشير شديد وتورم في الجلد، تبثر الجلد، الفم، العينين، الأعضاء التناسلية والحمى. طفح جلدي مع وجود بقع باللون الوردي إلى الأحمر خاصة عند راحة اليدين أو أخمص القدمين حيث قد يكون بثوراً. 
  • ضعف العضلات، الإيلام، الألم، تمزق أو تغير لون البول إلى اللون الأحمر البني، وخاصة إذا شعرت، في الوقت نفسه، بالتوعك أو ارتفاع درجة الحرارة، فقد يحدث ذلك بسبب تحلل العضلات غير الطبيعي (انحلال الربيدات). لا يزول تكسير العضلات غير الطبيعي دائماً، حتى بعد التوقف عن تناول أتورڤاستاتين، وقد يكون مهدداً للحياة ويؤدي إلى مشاكل في الكلى.

نادرة جداً: قد تؤثر فيما يصل إلى شخص من بين كل 10000 شخص

  • إذا تعرضت لمشاكل نزيف أو كدمات غير متوقعة أو غير معتادة، فقد يُشير ذلك إلى وجود مرض بالكبد. يجب عليك استشارة طبيبك في أقرب وقت ممكن. 
  • متلازمة الأمراض الشبيهة بالذئبة (من بينها الطفح، اضطرابات المفاصل والتأثير على خلايا الدم)

الآثار الجانبية المحتملة الأخرى الناتجة عن تناول أتورڤاستاتين

شائعة: قد تؤثر فيما يصل إلى شخص من بين كل 10 أشخاص

  •  التهاب في الممرات الأنفية، ألم في الحلق، نزيف الأنف 
  • ردود الفعل التحسسية 
  • زيادات في مستويات سكر الدم (إذا كنت تعاني من مرض السكري استمر في مراقبة مستويات سكر الدم لديك بعناية)، زيادة في كيناز الكرياتين في الدم 
  • صداع 
  • غثيان، إمساك، غازات، عسر الهضم، إسهال 
  • ألم المفاصل، ألم العضلات وألم الظهر 
  • نتائج غير طبيبعة لفحوصات الدم الخاصة بوظائف الكبد

غير شائعة: قد تؤثر فيما يصل إلى شخص  من بين كل 100 شخص

  • القهم (فقدان الشهية)، زيادة الوزن، انخفاضات في مستويات سكر الدم (إذا كنت مصاباً بالسكري، يجب عليك الاستمرار في مراقبة مستويات سكر الدم بعناية) 
  • كوابيس، أرق، دوخة
  • تنميل أو وخز في أصابع اليدين والقدمين، انخفاضات في مستوى الإحساس بالألم أو اللمس، تغير في حاسة التذوق، فقدان الذاكرة، تشوش الرؤية 
  • طنين في الأذنين و/أو الرأس 
  • تقيؤ، تجشؤ، ألم في البطن في المنطقة العلوية والسفلية، التهاب البنكرياس (التهاب البنكرياس يؤدي إلى حدوث ألم في المعدة) 
  • التهاب الكبد
  • طفح، طفح جلدي وحكة، الشرى، تساقط الشعر 
  •  ألم في العنق، تعب عضلي 
  • إجهاد، شعور بالإعياء، ضعف، ألم بالصدر، تورم وخاصة بالكاحلين (الوذمة)، ارتفاع درجة الحرارة 
  •  نتائج إيجابية لفحوصات البول لخلايا الدم البيضاء

نادرة: قد تؤثر فيما يصل إلى شخص من بين كل 1000 شخص

  • اضطرابات بصرية 
  • كدمات أو نزيف غير متوقع 
  • الركود الصفراوي (اصفرار الجلد وبياض العينين) 
  • إصابة بالأوتار

نادرة جداً: قد تؤثر فيما يصل إلى شخص من بين كل 10000 شخص

  • رد فعل تحسسي - قد تشمل الأعراض الصفير المفاجئ وألماً أو ضيقاً في الصدر، تورم الجفون، الوجه، الشفتين، الفم، اللسان أو الحلق، صعوبة التنفس، هبوط
  • فقدان السمع 
  • تثدي الرجل (تضخم الثديين لدى الرجال).
  • غير معروف: لا يمكن تقدير التكرار من البيانات المتاحة:
  • ضعف في العضلات بشكل مستمر. 

الآثار الجانبية المحتملة التي تم الإبلاغ عنها بسبب استخدام بعض الستاتين (أدوية من النوع نفسه):

  • مشاكل جنسية 
  • الاكتئاب 
  • مشاكل في التنفس تشمل السعال المستمر و/أو ضيق التنفس أو الحمى 
  • مرض السكري. تزداد احتمالية الإصابة به إذا كان لديك مستويات عالية من السكريات والدهون في دمك، وإذا كنت تعاني من زيادة الوزن وارتفاع ضغط الدم. سيراقب طبيبك حالتك أثناء تناولك هذا الدواء. 

احفظ هذا الدواء بعيداً عن مرأى ومتناول الأطفال.

لا يحفظ عند درجة حرارة أعلى من 30° مئوية.

يحفظ داخل العبوة الأصلية.

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.

هي محتويات أتورڤا

المادة الفعالة هي أتورڤاستاتين الكالسيوم ثلاثي الماء.

يحتوي كل قرص مغطى بطبقة رقيقة من أتورڤا 10 ملغم أقراص مغطاة بطبقة رقيقة على 10.963 ملغم أتورڤاستاتين الكالسيوم ثلاثي الماء يكافئ 10 ملغم أتورڤاستاتين.

يحتوي كل قرص مغطى بطبقة رقيقة من أتورڤا 20 ملغم أقراص مغطاة بطبقة رقيقة على 21.935 ملغم أتورڤاستاتين الكالسيوم ثلاثي الماء يكافئ 20 ملغم أتورڤاستاتين. 

يحتوي كل قرص مغطى بطبقة رقيقة من أتورڤا 40 ملغم أقراص مغطاة بطبقة رقيقة على 43.85 ملغم أتورڤاستاتين الكالسيوم ثلاثي الماء يكافئ 40 ملغم أتورڤاستاتين.

يحتوي كل قرص مغطى بطبقة رقيقة من أتورڤا 80 ملغم أقراص مغطاة بطبقة رقيقة على 87.7 ملغم أتورڤاستاتين الكالسيوم ثلاثي الماء يكافئ 80 ملغم أتورڤاستاتين.

المواد الأخرى المستخدمة في التركيبة التصنيعية هي: لب القرص: كربونات الكالسيوم، سيليلوز بلوري مكروي، لاكتوز، كروسكارميللوز الصوديوم، ھيدروكسي بروبيل السيليلوز، توين 80 وستيرات المغنيسيووم. غلاف القرص: أوبادري أبيض ومستحلب مضاد للرغوة.

أتورڤا 10 ملغم أقراص مغطاة بطبقة رقيقة هي أقراص بيضاوية الشكل لونها أبيض مائل للصفرة مغطاة بطبقة رقيقة، منقوش على أحد جانبيها "JI 53" وغير منقوش على الجانب الآخر في أشرطة من رقائق الألومنيوم. 

أتورڤا 20 ملغم أقراص مغطاة بطبقة رقيقة هي أقراص بيضاوية الشكل لونها أبيض مائل للصفرة مغطاة بطبقة رقيقة، منقوش على أحد جانبيها "JI 54" وغير منقوش على الجانب الآخر في أشرطة من رقائق الألومنيوم. 

أتورڤا 40 ملغم أقراص مغطاة بطبقة رقيقة هي أقراص بيضاوية الشكل لونها أبيض مائل للصفرة مغطاة بطبقة رقيقة، منقوش على أحد جانبيها "JI 55" وغير منقوش على الجانب الآخر في أشرطة من رقائق الألومنيوم. 

أتورڤا 80 ملغم أقراص مغطاة بطبقة رقيقة هي أقراص بيضاوية الشكل لونها أبيض مائل للصفرة مغطاة بطبقة رقيقة، منقوش على أحد جانبيها "JI 57" وغير منقوش على الجانب الآخر في أشرطة من رقائق الألومنيوم. 

حجم العبوة: 30 و500 قرص مغطى بطبقة رقيقة.

قد لا يتم تسويق جميع أحجام العبوات.

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

تمت مراجعة هذه النشرة بتاريخ 06/2021؛ رقم النسخة: SA1.0.

Atorva 40 mg Film-coated Tablets

Each film-coated tablet contains 43.85 mg atorvastatin calcium trihydrate equivalent to 40 mg atorvastatinExcipients with known effect: - Each film-coated tablet contains 45.62 mg lactose. - Each film-coated tablet contains 4.376 mg sodium. For the full list of excipients, see section 6.1.

Film-coated Tablets. White to off-white oval elliptical-shaped film-coated tablets, embossed with “JI 55” on one side and plain on the other side.

Hypercholesterolaemia

Atorva is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.

Atorva is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

Prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.


Posology

The patient should be placed on a standard cholesterol-lowering diet before receiving Atorva and should continue on this diet during treatment with Atorva.

The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.

The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia

The majority of patients are controlled with Atorva 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Heterozygous familial hypercholesterolaemia

Patients should be started with Atorva 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.

Homozygous familial hypercholesterolaemia

Only limited data are available (see section 5.1).

The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Prevention of cardiovascular disease

In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines.

Renal impairment

No adjustment of dose is required (see section 4.4).

Hepatic impairment

Atorva should be used with caution in patients with hepatic impairment (see sections 4.4 and 5.2). Atorva is contraindicated in patients with active liver disease (see section 4.3).

Co-administration with other medicines

In patients taking the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus infection prophylaxis concomitantly with atorvastatin, the dose of atorvastatin should not exceed 20 mg/day (see sections 4.4 and 4.5).

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin (see sections 4.4 and 4.5).

Elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.

Paediatric population

Hypercholesterolaemia

Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.

For patients with Heterozygous Familial Hypercholesterolemia aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day (see section 5.1). The dose may be increased to 80 mg daily, according to the response and tolerability. Doses should be individualised according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more. The dose titration to 80 mg daily is supported by study data in adults and by limited clinical data from studies in children with Heterozygous Familial Hypercholesterolemia (see sections 4.8 and 5.1).

There are limited safety and efficacy data available in children with Heterozygous Familial Hypercholesterolemia between 6 to 10 years of age derived from open-label studies. Atorvastatin is not indicated in the treatment of patients below the age of 10 years. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Other pharmaceutical forms/strengths may be more appropriate for this population.

Method of administration

Atorva is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food.


Atorva is contraindicated in patients: • With hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • With active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal. • During pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6). • Treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

Liver effects

Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Atorva is recommended (see section 4.8).

Atorva should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1).

Skeletal muscle effects

Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Before the treatment

Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations:

•   Renal impairment.

•   Hypothyroidism.

•   Personal or familial history of hereditary muscular disorders.

•   Previous history of muscular toxicity with a statin or fibrate.

•   Previous history of liver disease and/or where substantial quantities of alcohol are consumed.

•   In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.

•   Situations where an increase in plasma levels may occur, such as interactions (see section 4.5) and special populations including genetic subpopulations (see section 5.2).

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.

If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.

Creatine kinase measurement

Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.

Whilst on treatment

•   Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.

•   If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped.

•   If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.

•   If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

•   Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Concomitant treatment with other medicinal products

Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin or ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.

In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see section 4.5).

Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Atorva and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Paediatric population

No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see section 4.8).

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Excipients

Atorva contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Atorva contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.


Effect of co-administered medicinal products on atorvastatin

Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see section 5.2). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe (see section 4.3 and 4.4).

 CYP3A4 inhibitors

Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 1 and specific information below). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antivirals used in the treatment of HCV (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.

 CYP3A4 inducers

Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.

 Transport inhibitors

Inhibitors of transport proteins (e.g. ciclosporin, letermovir) can increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).

Use of atorvastatin is not recommended in patients taking letermovir co-administered with ciclosporin (see section 4.4).

 Gemfibrozil / fibric acid derivatives

The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored (see section 4.4).

 Ezetimibe

The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.

 Colestipol

Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone.

 Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment (see section 4.4).

 Colchicine

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.

Effect of atorvastatin on co-administered medicinal products

Digoxin

When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.

 Oral contraceptives

Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.

 Warfarin

In a clinical study in patients receiving chronic warfarin therapy, co-administration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Paediatric population

Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Drug interactions

Table 1: Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin

Co-administered medicinal product and dosing regimen

Atorvastatin

Dose (mg)

Ratio of AUC&

Clinical Recommendation#

 

Glecaprevir 400 mg OD/ Pibrentasvir 120 mg OD, 7 days

10 mg OD for 7 days

8.3

Co-administration with products containing glecaprevir or pibrentasvir is contraindicated (see section 4.3).

 

Tipranavir 500 mg BID/ Ritonavir 200 mg BID, 8 days (days 14 to 21)

40 mg on day 1, 10 mg on day 20

9.4

In cases where co-administration with atorvastatin is necessary, do not exceed 10 mg atorvastatin daily. Clinical monitoring of these patients is recommended.

 

Telaprevir 750 mg q8h, 10 days

20 mg, SD

7.9

 

Ciclosporin 5.2 mg/kg/day, stable dose

10 mg OD for 28 days

8.7

 

Lopinavir 400 mg BID/ Ritonavir 100 mg BID, 14 days

20 mg OD for 4 days

5.9

In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 20 mg, clinical monitoring of these patients is recommended.

 

Clarithromycin 500 mg BID, 9 days

80 mg OD for 8 days

4.5

 

Saquinavir 400 mg BID/ Ritonavir (300 mg BID from days 5-7, increased to 400 mg BID on day 8), days 4-18, 30 min after atorvastatin dosing

40 mg OD for 4 days

3.9

In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 40 mg, clinical monitoring of these patients is recommended.

 

Darunavir 300 mg BID/ Ritonavir 100 mg BID, 9 days

10 mg OD for 4 days

3.4

 

Itraconazole 200 mg OD, 4 days

40 mg SD

3.3

 

Fosamprenavir 700 mg BID/ Ritonavir 100 mg BID, 14 days

10 mg OD for 4 days

2.5

 

Fosamprenavir 1400 mg BID, 14 days

10 mg OD for 4 days

2.3

 

Elbasvir 50 mg OD/ Grazoprevir 200 mg OD, 13 days

10 mg SD

1.95

The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with products containing elbasvir or grazoprevir.

 

Letermovir 480 mg OD, 10 days

20 mg SD

3.29

The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with products containing letermovir.

 

Nelfinavir 1250 mg BID, 14 days

10 mg OD for 28 days

1.74

No specific recommendation.

 

Grapefruit Juice, 240 mL OD *

40 mg, SD

1.37

Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.

 

Diltiazem 240 mg OD, 28 days

40 mg, SD

1.51

After initiation or following dose adjustments of diltiazem, appropriate clinical monitoring of these patients is recommended.

 

Erythromycin 500 mg QID, 7 days

10 mg, SD

1.33

Lower maximum dose and clinical monitoring of these patients is recommended.

 

Amlodipine 10 mg, single dose

80 mg, SD

1.18

No specific recommendation.

 

Cimetidine 300 mg QID, 2 weeks

10 mg OD for 2 weeks

1.00

No specific recommendation.

 

Colestipol 10 g BID, 24 weeks

40 mg OD for 8 weeks

0.74**

No specific recommendation

 

Antacid suspension of magnesium and aluminium hydroxides, 30 mL QID, 17 days

10 mg OD for 15 days

0.66

No specific recommendation.

 

Efavirenz 600 mg OD, 14 days

10 mg for 3 days

0.59

No specific recommendation.

 

Rifampin 600 mg OD, 7 days (co-administered)

40 mg SD

1.12

If co-administration cannot be avoided, simultaneous co-administration of atorvastatin with rifampin is recommended, with clinical monitoring.

 

Rifampin 600 mg OD, 5 days (doses separated)

40 mg SD

0.20

 

Gemfibrozil 600 mg BID, 7 days

40 mg SD

1.35

Lower starting dose and clinical monitoring of these patients is recommended.

 

Fenofibrate 160 mg OD, 7 days

40 mg SD

1.03

Lower starting dose and clinical monitoring of these patients is recommended.

 

Boceprevir 800 mg TID, 7 days

40 mg SD

2.3

Lower starting dose and clinical monitoring of these patients is recommended. The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with boceprevir.

 

& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

# See sections 4.4 and 4.5 for clinical significance.

*Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products metabolised by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of 20.4% for the active orthohydroxy metabolite. Large quantities of grapefruit juice (over 1.2 l daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold.

** Ratio based on a single sample taken 8-16 h post dose.

OD = once daily; SD = single dose; BID = twice daily; TID = three times daily; QID = four times daily.

Table 2: Effect of atorvastatin on the pharmacokinetics of co-administered medicinal products

Atorvastatin and dosing regimen

Co-administered medicinal product

Medicinal product/Dose (mg)

Ratio of AUC&

Clinical Recommendation

80 mg OD for 10 days

Digoxin 0.25 mg OD, 20 days

1.15

Patients taking digoxin should be monitored appropriately.

40 mg OD for 22 days

Oral contraceptive OD, 2 months

-    Norethindrone 1 mg

-    Ethinyl estradiol 35 µg

1.28

1.19

No specific recommendation.

80 mg OD for 15 days

* Phenazone, 600 mg SD

1.03

No specific recommendation.

10 mg, SD

Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days

1.08

No specific recommendation.

10 mg, OD for 4 days

Fosamprenavir 1400 mg BID, 14 days

0.73

No specific recommendation.

10 mg OD for 4 days

Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days

0.99

No specific recommendation.

Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

*Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.

OD = once daily; SD = single dose; BID = twice daily.


Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

Atorva is contraindicated during pregnancy (see section 4.3). Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Studies in animals have shown toxicity to reproduction (see section 5.3).

Maternal treatment with atorvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.

For these reasons, Atorva should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Atorva should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).

Breast-feeding

It is unknown whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk (see section 5.3). Because of the potential for serious adverse reactions, women taking Atorva should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breast-feeding (see section 4.3).

Fertility

In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).


Atorvastatin has negligible influence on the ability to drive and use machines.


In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for atorvastatin.

Estimated frequencies of reactions are ranked according to the following convention: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Infections and infestations

Common: Nasopharyngitis.

Blood and lymphatic system disorders

Rare: Thrombocytopenia.

Immune system disorders

Common: Allergic reactions.

Very rare: Anaphylaxis.

Metabolism and nutrition disorders

Common: Hyperglycaemia.

Uncommon: Hypoglycaemia, weight gain, anorexia.

Psychiatric disorders

Uncommon: Nightmare, insomnia.

Nervous system disorders

Common: Headache.

Uncommon: Dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.

Rare: Peripheral neuropathy.

Eye disorders

Uncommon: Vision blurred.

Rare: Visual disturbance.

Ear and labyrinth disorders

Uncommon: Tinnitus.

Very rare: Hearing loss.

Respiratory, thoracic and mediastinal disorders

Common: Pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders

Common: Constipation, flatulence, dyspepsia, nausea, diarrhoea.

Uncommon: Vomiting, abdominal pain upper and lower, eructation, pancreatitis.

Hepatobiliary disorders

Uncommon: hepatitis.

Rare: cholestasis.

Very rare: hepatic failure.

Skin and subcutaneous tissue disorders

Uncommon: Urticaria, skin rash, pruritus, alopecia.

Rare: Angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Common: Myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.

Uncommon: Neck pain, muscle fatigue.

Rare: Myopathy, myositis, rhabdomyolysis, muscle rupture, tendonopathy, sometimes complicated by rupture.

Very rare: Lupus-like syndrome.

Not known: Immune-mediated necrotizing myopathy (see section 4.4).

Reproductive system and breast disorders

Very rare: Gynecomastia.

General disorders and administration site conditions

Uncommon: Malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Common: Liver function test abnormal, blood creatine kinase increased.

Uncommon: White blood cells urine positive.

As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on atorvastatin. These elevations were dose related and were reversible in all patients.

Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% atorvastatin-treated patients (see section 4.4).

Paediatric population

Paediatric patients aged from 10 to 17 years of age treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections. No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight. The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatin in adult patients.

The clinical safety database includes safety data for 520 paediatric patients who received atorvastatin, among which 7 patients were < 6 years old, 121 patients were in the age range of 6 to 9, and 392 patients were in the age range of 10 to 17. Based on the data available, the frequency, type and severity of adverse reactions in children is similar to adults.

The following adverse events have been reported with some statins:

•   Sexual dysfunction.

•   Depression.

•   Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).

•   Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

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 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.


Specific treatment is not available for atorvastatin overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.


Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code: C10AA05.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).

Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.

Atorvastatin has been shown to reduce concentrations of total-C (30% - 46%), LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% - 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In a multicentre 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind, multicentre, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis.

The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of atorvastatin were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non-fatal myocardial infarction, coronary death) was not investigated in this study.

In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.

Acute coronary syndrome

In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due to a 26% reduction in re-hospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).

The safety profile of atorvastatin in the MIRACL study was consistent with what is described in section 4.8.

Prevention of cardiovascular disease

The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomised, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.

Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative Risk Reduction (%)

No. of Events (Atorvastatin vs Placebo)

Absolute Risk Reduction1 (%)

p-value

Fatal CHD plus non-fatal MI

Total cardiovascular events and revascularization procedures

Total coronary events

36%

20%
 

29%

100 vs. 154

389 vs. 483
 

178 vs 247

1.1%

1.9%
 

1.4%

0.0005

0.0008
 

0.0006

1Based on difference in crude events rates occurring over a median follow-up of 3.3 years.

CHD = coronary heart disease; MI = myocardial infarction.

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).

The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomised, double-blind, multicentre, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/L (160 mg/dl) and TG ≤6.78 mmol/L (600 mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.

Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative Risk Reduction (%)

No. of Events (Atorvastatin vs Placebo)

Absolute Risk Reduction1 (%)

p-value

Major cardiovascular events (fatal and non-fatal AMI, silent MI, acute CHD death, unstable angina, CABG, PTCA, revascularization, stroke)

MI (fatal and non-fatal AMI, silent MI)

Strokes (Fatal and non-fatal)

37%

42%

48%

83 vs. 127

38 vs 64

21 vs. 39

3.2%

1.9%

1.3%

0.0010

0.0070

0.0163

1Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p=0.0592).

Recurrent stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years), and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9% (211/2366) for placebo.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of haemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.

•   The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

•   The risk of haemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin 80 mg/day.

All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with prior haemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.

Paediatric population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old

An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C ≥ 4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥ 2.

The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of < 3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.

Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.

In a second open label, single arm study, 271 male and female HeFH children 6-15 years of age were enrolled and treated with atorvastatin for up to three years. Inclusion in the study required confirmed HeFH and a baseline LDL-C level ≥ 4 mmol/L (approximately 152 mg/dL). The study included 139 children at Tanner 1 developmental stage (generally ranging from 6-10 years of age). The dosage of atorvastatin (once daily) was initiated at 5 mg (chewable tablet) in children less than 10 years of age. Children age 10 and above were initiated at 10 mg atorvastatin (once daily). All children could titrate to higher doses to achieve a target of < 3.35 mmol/L LDL-C. The mean weighted dose for children aged 6 to 9 years was 19.6 mg and the mean weighted dose for children aged 10 years and above was 23.9 mg.

The mean (+/- SD) baseline LDL-C value was 6.12 (1.26) mmol/L which was approximately 233 (48) mg/dL. See table 3 below for final results.

The data were consistent with no drug effect on any of the parameters of growth and development (i.e., height, weight, BMI, Tanner stage, Investigator assessment of Overall Maturation and Development) in paediatric and adolescent subjects with HeFH receiving atorvastatin treatment over the 3 year study. There was no Investigator-assessed drug effect noted in height, weight, BMI by age or by gender by visit.

TABLE 3. Lipid-lowering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia (mmol/L)

Timepoint

N

TC (S.D.)

LDL-C (S.D.)

HDL-C (S.D.)

TG (S.D.)

Apo B (S.D.)#

Baseline

271

7.86(1.30)

6.12(1.26)

1.314(0.2663)

0.93(0.47)

1.42(0.28)**

Month 30

206

4.95(0.77)*

3.25(0.67)

1.327(0.2796)

0.79(0.38)*

0.90(0.17)*

Month 36/ET

240

5.12(0.86)

3.45(0.81)

1.308(0.2739)

0.78(0.41)

0.93(0.20)***

TC= total cholesterol; LDL-C = low density lipoprotein cholesterol-C; HDL-C = high density lipoprotein cholesterol-C; TG = triglycerides; Apo B = apolipoprotein B; “Month 36/ET” included final visit data for subjects who ended participation prior to the scheduled 36 month timepoint as well as full 36 month data for subjects completing the 36 month participation; “*”= Month 30 N for this parameter was 207; “**”= Baseline N for this parameter was 270; “***” = Month 36/ET N for this parameter was 243; “#”=g/L for Apo B.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old

In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >3.36 mmol/L. Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase. The mean achieved LDL-C value was 3.38 mmol/L (range: 1.81-6.26 mmol/L) in the atorvastatin group compared to 5.91 mmol/L (range: 3.93-9.96 mmol/L) in the placebo group during the 26-week double-blind phase.

An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) compared with colestipol (N=31).

A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was lowered by 36%.

The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 to less than 6 years in the treatment of heterozygous hypercholesterolaemia and in children aged 0 to less than 18 years in the treatment of homozygous familial hypercholesterolaemia, combined (mixed) hypercholesterolaemia, primary hypercholesterolaemia and in the prevention of cardiovascular events (see section 4.2 for information on paediatric use).


Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code: C10AA05.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).

Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.

Atorvastatin has been shown to reduce concentrations of total-C (30% - 46%), LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% - 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In a multicentre 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Atorvastatin was administered at doses up to 80 mg/day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind, multicentre, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis.

The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of atorvastatin were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non-fatal myocardial infarction, coronary death) was not investigated in this study.

In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.

Acute coronary syndrome

In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This was mainly due to a 26% reduction in re-hospitalisation for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).

The safety profile of atorvastatin in the MIRACL study was consistent with what is described in section 4.8.

Prevention of cardiovascular disease

The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomised, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.

Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative Risk Reduction (%)

No. of Events (Atorvastatin vs Placebo)

Absolute Risk Reduction1 (%)

p-value

Fatal CHD plus non-fatal MI

Total cardiovascular events and revascularization procedures

Total coronary events

36%

20%
 

29%

100 vs. 154

389 vs. 483
 

178 vs 247

1.1%

1.9%
 

1.4%

0.0005

0.0008
 

0.0006

1Based on difference in crude events rates occurring over a median follow-up of 3.3 years.

CHD = coronary heart disease; MI = myocardial infarction.

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).

The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomised, double-blind, multicentre, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/L (160 mg/dl) and TG ≤6.78 mmol/L (600 mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.

Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of atorvastatin was as follows:

Event

Relative Risk Reduction (%)

No. of Events (Atorvastatin vs Placebo)

Absolute Risk Reduction1 (%)

p-value

Major cardiovascular events (fatal and non-fatal AMI, silent MI, acute CHD death, unstable angina, CABG, PTCA, revascularization, stroke)

MI (fatal and non-fatal AMI, silent MI)

Strokes (Fatal and non-fatal)

37%

42%

48%

83 vs. 127

38 vs 64

21 vs. 39

3.2%

1.9%

1.3%

0.0010

0.0070

0.0163

1Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p=0.0592).

Recurrent stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21-92 years of age (average age 63 years), and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9% (211/2366) for placebo.

In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of haemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.

•   The risk of haemorrhagic stroke was increased in patients who entered the study with prior haemorrhagic stroke (7/45 for atorvastatin versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

•   The risk of haemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for atorvastatin versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for atorvastatin versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin 80 mg/day.

All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in the subgroup of patients with prior haemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.

Paediatric population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old

An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of atorvastatin was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C ≥ 4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage ≥ 2.

The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was permitted to be doubled if a subject had not attained target LDL-C of < 3.35 mmol/L at Week 4 and if atorvastatin was well tolerated.

Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.

In a second open label, single arm study, 271 male and female HeFH children 6-15 years of age were enrolled and treated with atorvastatin for up to three years. Inclusion in the study required confirmed HeFH and a baseline LDL-C level ≥ 4 mmol/L (approximately 152 mg/dL). The study included 139 children at Tanner 1 developmental stage (generally ranging from 6-10 years of age). The dosage of atorvastatin (once daily) was initiated at 5 mg (chewable tablet) in children less than 10 years of age. Children age 10 and above were initiated at 10 mg atorvastatin (once daily). All children could titrate to higher doses to achieve a target of < 3.35 mmol/L LDL-C. The mean weighted dose for children aged 6 to 9 years was 19.6 mg and the mean weighted dose for children aged 10 years and above was 23.9 mg.

The mean (+/- SD) baseline LDL-C value was 6.12 (1.26) mmol/L which was approximately 233 (48) mg/dL. See table 3 below for final results.

The data were consistent with no drug effect on any of the parameters of growth and development (i.e., height, weight, BMI, Tanner stage, Investigator assessment of Overall Maturation and Development) in paediatric and adolescent subjects with HeFH receiving atorvastatin treatment over the 3 year study. There was no Investigator-assessed drug effect noted in height, weight, BMI by age or by gender by visit.

TABLE 3. Lipid-lowering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia (mmol/L)

Timepoint

N

TC (S.D.)

LDL-C (S.D.)

HDL-C (S.D.)

TG (S.D.)

Apo B (S.D.)#

Baseline

271

7.86(1.30)

6.12(1.26)

1.314(0.2663)

0.93(0.47)

1.42(0.28)**

Month 30

206

4.95(0.77)*

3.25(0.67)

1.327(0.2796)

0.79(0.38)*

0.90(0.17)*

Month 36/ET

240

5.12(0.86)

3.45(0.81)

1.308(0.2739)

0.78(0.41)

0.93(0.20)***

TC= total cholesterol; LDL-C = low density lipoprotein cholesterol-C; HDL-C = high density lipoprotein cholesterol-C; TG = triglycerides; Apo B = apolipoprotein B; “Month 36/ET” included final visit data for subjects who ended participation prior to the scheduled 36 month timepoint as well as full 36 month data for subjects completing the 36 month participation; “*”= Month 30 N for this parameter was 207; “**”= Baseline N for this parameter was 270; “***” = Month 36/ET N for this parameter was 243; “#”=g/L for Apo B.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old

In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >3.36 mmol/L. Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase. The mean achieved LDL-C value was 3.38 mmol/L (range: 1.81-6.26 mmol/L) in the atorvastatin group compared to 5.91 mmol/L (range: 3.93-9.96 mmol/L) in the placebo group during the 26-week double-blind phase.

An additional paediatric study of atorvastatin versus colestipol in patients with hypercholesterolaemia aged 10-18 years demonstrated that atorvastatin (N=25) caused a significant reduction in LDL-C at week 26 (p<0.05) compared with colestipol (N=31).

A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 paediatric patients treated with atorvastatin titrated according to response (some subjects received 80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was lowered by 36%.

The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 to less than 6 years in the treatment of heterozygous hypercholesterolaemia and in children aged 0 to less than 18 years in the treatment of homozygous familial hypercholesterolaemia, combined (mixed) hypercholesterolaemia, primary hypercholesterolaemia and in the prevention of cardiovascular events (see section 4.2 for information on paediatric use).


Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females.

There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or foetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses foetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin or its metabolites are excreted in human milk.

 


Tablet core:

-    Calcium carbonate

-    Microcrystalline cellulose

-    Lactose

-    Croscarmellose sodium

-    Hydroxypropyl cellulose

-    Tween 80

-    Magnesium stearate.  

Tablet coat:

-    Opadry white

-    Antifoam emulsion.   


Not applicable.


36 months.

Do not store above 30°C.

Store in the original package.


Aluminum foil blisters. 

Pack sizes: 30 and 500 Film-coated Tablets.

Not all pack sizes may be marketed


No special 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: SAPV@hikma.com

27 June 2021

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