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Levetam 100 mg/ml oral solution is an antiepileptic medicine (a medicine used to treat seizures in epilepsy). Levetam is used:
• on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to treat partial onset seizures with or without secondary generalisation.
• as an add-on to other antiepileptic medicines to treat:
– partial onset seizures with or without generalisation in adults, adolescents, children and infants from one month of age
– myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy
– primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy
Do not take Levetam
• If you are allergic (hypersensitive) to levetiracetam or any of the other ingredients of this medicine (listed in Section 6).
Warnings and Precautions
Talk to your doctor before taking Levetam
• If you suffer from kidney problems, follow your doctor’s instructions. He/she may decide if your dose should be adjusted.
• If you notice any slow down in the growth or unexpected puberty development of your child, please contact your doctor.
• If you notice an increase in seizure severity (e.g. increased number), please contact your doctor.
• A small number of people being treated with anti-epileptics such as Levetam have had thoughts of harming or killing themselves. If you have any symptoms of depression and/or suicidal ideation, please contact your doctor.
Other medicines and Levetam
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Levetam with food, drink and alcohol
You may take Levetam with or without food. As a safety precaution, do not take Levetam with alcohol.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
If you are pregnant or if you think you may be pregnant, please inform your doctor.
Levetam should not be used during pregnancy unless clearly necessary. A risk of birth defects for your unborn child cannot be completely excluded. Levetam has shown unwanted reproductive effects in animal studies at dose levels higher than you would need to control your seizures.
Breast-feeding is not recommended during treatment.
Driving and using machines
Levetam may impair your ability to drive or operate any tools or machinery, as Levetam may make you feel sleepy. This is more likely at the beginning of treatment or after an increase in the
dose. You should not drive or use machines until it is established that your ability to perform such activities is not affected.
Levetam contains methyl parahydroxybenzoate and propyl parahydroxybenzoate.
Levetam oral solution includes methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
Levetam must be taken twice a day, once in the morning and once in the evening, at about the same time each day.
Take the oral solution following your doctor`s instructions. Monotherapy
Dose in adults and adolescents (from 16 years of age):
General dose: between 10 ml (1000 mg) and 30 ml (3,000 mg) each day, divided in 2 intakes per day.
When you will first start taking Levetam, your doctor will prescribe you a lower dose during 2 weeks before giving you the lowest general dose. Add-on therapy
Dose in adults and adolescents (12 to 17 years) weighing 50 kg or more:
General dose: between 10 ml (1,000 mg) and 30 ml (3,000 mg) each day, divided in 2 intakes per day.
Dose in infants (6 to 23 months), children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg:
Your doctor will prescribe the most appropriate pharmaceutical form of Levetam according to the age, weight and dose.
General dose: between 0.2 ml (20 mg) and 0.6 ml (60 mg) per kg bodyweight each day, divided in 2 intakes per day. The exact quantity of oral solution formulation should be delivered using the syringe provided in the cardboard box.
Weight | Starting dose: 0.1 ml/kg twice daily | Maximum dose: 0.3 ml/kg twice daily |
6 kg | 0.6 ml twice daily | 1.8 ml twice daily |
8 kg | 0.8 ml twice daily | 2.4 ml twice daily |
10 kg | 1 ml twice daily | 3 ml twice daily |
15 kg | 1.5 ml twice daily | 4.5 ml twice daily |
20 kg | 2 ml twice daily | 6 ml twice daily |
25 kg | 2.5 ml twice daily | 7.5 ml twice daily |
From 50 kg | 5 ml twice daily | 15 ml twice daily |
Dose in infants (1 month to less than 6 months):
The oral solution is more suitable dosage form for infants.
General dose: between 0.14 ml (14 mg) and 0.42 ml (42 mg) per kg bodyweight each day, divided in 2 intakes per day. The exact quantity of oral solution formulation should be delivered using the syringe provided in the cardboard box.
Weight | Starting dose: 0.07 ml/kg twice | Maximum dose: 0.21 ml/kg twice |
4 kg | 0.3 ml twice | 0.85 ml twice |
5 kg | 0.35 ml twice | 1.05 ml twice |
6 kg | 0.45 ml twice | 1.25 ml twice |
7 kg | 0.5 ml twice | 1.5 ml twice daily |
The oral solution is more suitable dosage form for infants.
Method of administration:
Levetam oral solution may be diluted in a glass of water or baby`s bottle.
Instructions for use:
Open the bottle: press the cap and turn it anticlockwise (figure 1)
• Separate the adaptor from the syringe (figure 2). Insert the adaptor into the bottle neck (figure 3). Ensure it is well fixed.
Take the syringe and put it in the adaptor opening (figure 4). Turn the bottle upside down (figure 5).
• Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then push the piston upward in order to remove any possible bubble (figure 5B). Pull the piston down to the graduation mark corresponding to the quantity in milliliters (ml) prescribed by your doctor (figure 5C).
• Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B).
• Empty the contents of the syringe in a glass of water or baby`s bottle by pushing the piston to the bottom of the syringe (figure 7).
• Drink the whole contents of the glass/baby`s bottle.
• Close the bottle with the plastic screw cap.
Wash the syringe with water only (figure 8).
Duration of treatment:
• Levetam is used as a chronic treatment. You should continue Levetam treatment for as long as your doctor has told you.
• Do not stop your treatment without your doctor`s advice as this could increase your seizures. Should your doctor decide to stop your Levetam treatment, he/she will instruct you about the gradual withdrawal of Levetam.
If you take more Levetam than you should:
The possible side effects of an overdose of Levetam are sleepiness, agitation, aggression, decrease of alertness, inhibition of breathing and coma.
Contact your doctor if you took more Levetam than you should.
Your doctor will establish the best possible treatment of overdose.
If you forget to take Levetam:
Contact your doctor if you have missed one or more doses.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Levetam:
If stopping treatment, as with other antiepileptic medicines, Levetam should be discontinued gradually to avoid an increase of seizures.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the side effects like sleepiness, tiredness and dizziness may be more common at the beginning of the treatment or at dose increase. These effects should however decrease over time.
Very common: may affect more than 1 user in 10
• nasopharyngitis;
• somnolence (sleepiness), headache.
Common: may affect 1 to 10 users in 100
• anorexia (loss of appetite);
• depression, hostility or aggression, anxiety, insomnia, nervousness or irritability;
• convulsion, balance disorder (equilibrium disorder), dizziness (sensation of unsteadiness), lethargy, tremor (involuntary trembling);
• vertigo (sensation of rotation);
• cough;
• abdominal pain, diarrhoea, dyspepsia (indigestion), vomiting, nausea;
• rash;
• asthenia/fatigue (tiredness).
Uncommon: may affect 1 to 10 users in 1000
• decreased number of blood platelets, decreased number of white blood cells;
• weight decrease, weight increase;
• suicide attempt and suicidal ideation, mental disorder, abnormal behaviour, hallucination, anger, confusion, panic attack, emotional instability/mood swings, agitation;
• amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia (impaired coordinated movements), paraesthesia (tingling), disturbance in attention (loss of concentration);
• diplopia (double vision), vision blurred;
• liver function test abnormal;
• hair loss, eczema, pruritus;
• muscle weakness, myalgia (muscle pain);
• injury.
Rare: may affect 1 to 10 users in 10,000
• Infection;
• Decreased number of all blood cell types;
• Severe hypersensitivity reactions;
• Decreased blood sodium concentration;
• Suicide, personality disorders (behavioural problems), thinking abnormal (slow thinking, unable to concentrate);
• Uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling movements, hyperkinesias (hyperactivity);
• Pancreatitis;
• Hepatic failure, hepatitis;
• Skin rash, which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme), a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens- Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body surface (toxic epidermal necrolysis).
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Keep this medicine out of the sight and reach of children.
Store below 30°C.
Do not use this medicine after the expiry date stated on the cardboard box and bottle after EXP:
The expiry date refers to the last day of the month.
Do not use after 7 months of first opening the bottle.
Due to sensitivity to light, store in the original container.
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.
What Levetam contains
The active substance is called levetiracetam. Each ml contains 100 mg of levetiracetam. The other ingredients are: sodium citrate, citric acid monohydrate, methyl
parahydroxybenzoate, propyl parahydroxybenzoate, ammonium glycyrrhizinate, glycerol, sucralose, hydrogenated glucose syrup, grape flavour, purified water.
SPIMACO
AlQassim pharmaceutical plant
Saudi Pharmaceutical Industries &
Medical Appliance Corporation
(ليفيتام 100 ملجم/مل محلول فموى هو دواء مضاد للصرع (دواء يستخدم لعلاج نوبات الصرع).
يستخدم ليفيتام فى:
• كعلاج وحيد في البالغين والمراهقين من سن 16 سنة المصابين بالصرع الذى تم تشخيصه حديثا، لعلاج النوبات الجزئية مع أو بدون تعميم ثانوي.
• كإضافة على الأدوية المضادة للصرع الأخرى:
− لعلاج النوبات الجزئية مع أو بدون تعميم ثانوي فى البالغين والمراهقين و الأطفال من سن شهر واحد.
− نوبات الرمع العضلي لدى البالغين والمراهقين من سن 12 سنة و المصابين بصرع الرمع العضلي للأحداث.
− نوبات الأولية المعممة التوترية الإرتجاجية في البالغين والمراهقين من سن 12 سنة المصابين بالصرع المعمم مجهول السبب (نوع من الصرع التي يعتقد أن يكون لها سبب وراثي)
لا تتناول ليفيتام فى الحالات الآتية:
• إذا كنت تعاني من حساسية (فرط الحساسية) تجاه ليفيتيراسيتام أو أي من المكونات الأخرى في هذا الدواء (المدرجة في القسم 6).
تحذيرات واحتياطات:
تحدث إلى طبيبك قبل تناول ليفيتام فى الحالات الآتية:
إذا كنت تعاني من مشاكل في الكلى، اتبع تعليمات الطبيب. قفد قيرر الطبيب ما إذا كان ينبغي تعديل الجرعة.
إذا لاحظت أي تباطؤ غير متوقع في نمو أو تطور فترة البلوغ لطفلك، يرجى الاتصال بالطبيب.
إذا لاحظت زيادة في شدة النوبات (على سبيل المثال زيادة العدد)، يرجى الاتصال بالطبيب.
كان هناك عدد قليل من الأشخاص الذين يعالجون مع مضادات الصرع مثل ليفيتام لديهم أفكار إيذاء أو قتل أنفسهم. إذا كان لديك أي أعراض الإكتئاب و / أو التفكير في الإنتحار، يرجى الاتصال بالطبيب.
تناول أدوية أخرى
يرجى إخبار الطبيب أو الصيدلي إذا كنت تتناول أو تناولت مؤخرا أي أدوية أخرى، بما في ذلك الأدوية التي تم الحصول عليها دون وصفة طبية.
تناول ليفيتام مع الطعام والشراب و الكحول
قد تتناول ليفيتام مع أو بدون الطعام. كإجراء احترازي، لا تأخذ ليفيتام مع الكحول.
الحمل و الرضاعة
إسأل طبيبك أو الصيدلي للحصول على المشورة قبل تناول أي دواء.
إذا كنت حاملا ً أو إذا كنت تعتقدين أنك قد تكونين حاملا ً، الرجاء إبلاغ الطبيب.
لا ينبغي أن تستخدمى ليفيتام أثناء الحمل إلا عند الضرورة بشكل واضح. الخطر المحتمل على الطفل الذي لم يولد بعد غيرمعروف. وقد أظهر ليفيتام في الدراسات على الحيوانات آثار إنجابية غير مرغوب فيها عند جرعات أعلى مما قد تحتاجينها للسيطرة على النوبات الخاصة بك.
لا ينصح الرضاعة الطبيعية أثناء العلاج.
القيادة و استخدام الآلات
قد يضعف ليفيتام من قدرتك على القيادة أو تشغيل أي أدوات أو آلات، قد يجعلك ليفيتام تشعر بالنعاس. هذا هو الأرجح في بداية العلاج أو بعد زيادة في الجرعة. يجب أن لا تقود أو تستخدم الآلات حتى يثبت أن قدرتك على أداء مثل هذه الأنشطة لا يتأثر.
يحتوى محلول ليفيتام على ميثيل باراهيدروكسى بنزوات وبروبيل باراهيدروكسى بنزوات والتى قد تسبب تفاعلات تحسسية (قد تكون متأخرة).
دائما تناول هذا الدواء تماما كما أخبرك طب بيك أو الصيدلي. استشر طبيبك أو الصيدلي إذا كنت غير متأكد.
يجب أن يؤخذ ليفيتام مرتين في اليوم، مرة في الصباح ومرة في المساء، في الوقت نفسه تقريبا كل يوم.
اتبع تعليمات طبيبك المعالج فى تناول الجرعة المحددة لك.
كعلاج وحيد
الجرعة في البالغين والمراهقين (من سن 61 سنة):
الجرعة العامة: بين 10مل (1,000 ملجم) و 30مل (3,000 ملجم) كل يوم, مقسمة على جرعتين يوميا ً.
عندما تبدأ تناول ليفيتام لأول مرة، سوف يصف لك طبيبك أقل جرعة خلال أسبوعين قبل إعطائك أقل جرعة عامة.
إضافة على علاج آخر
الجرعة في البالغين والمراهقين (12-17 نسة) ذوى وزن 50 كجم أو أكثر:
الجرعة العامة: بين 10مل (1,000 ملجم) و 30مل (3,000 ملجم) كل يوم, مقسمة على جرعتين يوميا ً.
الجرعة عند الرضع ( 6 - 23 شهرا) والأطفال ( 2 - 11 سنة) والمراهقين ( 12 - 17 سنة) ذوى وزن أقل من 50 كجم:
طبيبك سوف يصف الشكل الدوائى الأكثر ملاءمة من ليفيتيراسيتام وفقا للعمر والوزن والجرعة.
الجرعة العامة: بين 0.2 مل (20 ملجم) لكل كيلو جرام من وزن الجسم، و0.6 مل (60 ملجم) لكل كيلو جرام من وزن الجسم كل يوم, مقسمة على جرعتين يوميا ً. يتم تناول الجرعة المحددة من محلول ليفيتام عن طريق الفم باستخدام سرنجة متوفرة داخل الكرتونة.
الجرعة القصوى: 0.3 مل/كجم مرتين يوميا ً. | جرعة البداية: 0.1 مل/كجم مرتين يوميا ً. | الوزن |
1.8 مل مرتين يوميا ً. | 0.6 مل مرتين يوميا ً. | 6 كجم |
2.4 مل مرتين يوميا ً. | 0.8 مل مرتين يوميا ً. | 8 كجم |
3 مل مرتين يوميا ً. | 1 مل مرتين يوميا ً. | 10 كجم |
4.5 مل مرتين يوميا ً. | 1.5 مل مرتين يوميا ً. | 15 كجم |
6 مل مرتين يوميا ً. | 2 مل مرتين يوميا ً. | 20 كجم |
7.5 مل مرتين يوميا ً. | 2.5 مل مرتين يوميا ً. | 25 كجم |
15 مل مرتين يوميا ً. | 5 مل مرتين يوميا ً. | من 50 كجم |
الجرعة عند الرضع (1 شهر إلى أقل من 6 أشهر):
المحلول عن طريق الفم هو أكثر ملاءمة للرضع.
الجرعة العامة: تتراوح ما بين 0.14 مل (14 ملجم) و 0.42 مل (42 ملجم) لكل كجم من وزن الجسم كل يوم, مقسمة على جرعتين يوميا ً. يتم تناول الجرعة المحددة من محلول ليفيتام عن طريق الفم باستخدام سرنجة متوفرة داخل الكرتونة.
الجرعة القصوى: 0.21 مل/كجم مرتين يوميا ً. | جرعة البداية: 0.07 مل/كجم مرتين يوميا ً. | الوزن |
0.85 مل مرتين يوميا ً. | 0.3 مل مرتين يوميا ً. | 4 كجم |
1.05 مل مرتين يوميا ً. | 0.35 مل مرتين يوميا ً. | 5 كجم |
1.25 مل مرتين يوميا ً. | 0.45 مل مرتين يوميا ً. | 6 كجم |
1.5 مل مرتين يوميا ً. | 0.5 مل مرتين يوميا ً. | 7 كجم |
طريقة التناول:
قد يتم تخفيف محلول ليفيتام فى كوب من الماء أو فى الزجاجة الخاصة بالطفل.
تعليمات الاستخدام:
• افتح الزجاجة: قم بالضغط على الغطاء ولفه فى عكس اتجاه عقارب الساعة (كما هو موضح بالشكل رقم 1).
• قم بنزع المحول من السرنجة (كما هو موضح بالشكل رقم 2). أدخل المحول فى عنق الزجاجة (كما هو موضح بالشكل رقم 3).
وتأكد من تثبيته جيدا ً.
أدخل السرنجة فى فتحة المحول (كما هو موضح بالشكل رقم 4).
قم بإقلاب الزجاجة رأساً على عقب (كما هو موضح بالشكل رقم 5).
املأ السرنجة بقليل من المحلول عبر شد المكبس إلى أسفل )كما فى الشكل رقم 5A( ,ثم اضغط المكبس لأعلى للتخلص من أى فقاقيع هواء )كما بالشكل رقم 5B .(قم بسحب المكبس لأسفل إلى العلامة المقابلة لكمية الملليليترات )مل (الموصوفة من قبل الطبيب المعالج )كما بالشكل رقم 5C
أعد الزجاجة إلى وضعها الطبيعى بحيث تكون فتحة الزجاجة لأعلى )كما بالشكل رقم 6A .(قم بنزع السرنجة من المحول )كما بالشكل رقم 6B
أفرغ محتويات السرنجة فى كوب من الماء أو فى الزجاجة الخاصة بالطفل عبر الضغط على المكبس بقاع السرنجة )كما بالشكل 7
- يجب على الطفل شرب محتويات الكوب أو الزجاجة الخاصة به بالكامل
- قم بإغلاق زجاجة الدواء بالغطاء البلاستيكى
- قم بغسل السرنجة بالماء فقط (كما بالشكل رقم 8).
مدة العلاج
•يستخدم ليفيتام كعلاج مزمن .يجب أن يستمر العلاج بواسطة ليفيتام للمدة التى أقرهاطبيب الالمعالج.
•لا تتوقف عن العلاج دون استشارة الطبيب لأن ذلك قد يزيد النوبات الخاصة بك.
إذا قرر طبيبك وقف العلاج بـ ليفيتام ، فإنه سوف يقوم بسحب تدريجي لـ ليفيتام.
إذا تناولت ليفيتام أكثر مما يجب
الآثار الجانبية المحتملة للجرعة الزائدة من ليفيتام هي النعاس، والتهيج، والعدوانية، وانخفاض اليقظة، وتثبيط التنفس والغيبوبة. اتصل بالطبيب فى حالة تناول جرعة أكثر مما يجب .الطبيب يقررسوف أفضل علاج ممكن للجرعة الزائدة.
فى حالة نسيان تناول ليفيتام
اتصل بطبيبك إذا كنت قد نسيت جرعة أو أكثر.
لا تقم بمضاعفة الجرعة لتعويض الجرعة المنسية.
إذا توقفت عن تناول ليفيتام
إذا وقفت العلاج، كما هو الحال مع الأدويةالأخرىالمضادة للصرعً، ينبغي وقف ليفيتام تدريجيالتجنب زيادة النوبات.
إذا كان لديك أي أسئلة أخرى عن استخدام هذا الدواء، اسأل طبيبك أو الصيدلي.
مثل جميع الأدوية، يمكن لهذا الدواء أن يسبب آثارا جانبية، وإن لم تكن تحدث لكل من يتناول هذا الدواء. بعض الآثار الجانبية مثل النعاس والتعب والدوخة قد تكون أكثر شيوعا في بداية العلاج أو عند زيادة الجرعة .ولكن هذه الآثار قد تقل بمرور الوقت.
شائعة جدا :قد تؤثر فى أكثر من 1 من 10مستخدمين لهذا الدواء:
•التهاب البلعوم الأنفي؛
•النعاس والصداع.
شائعة: قد تؤثر فى 1 إلي 10 مستخدمين من 100 مستخدم لهذا الدواء:
• فقدان الشهية؛
• الاكتئاب أو العدوانية، أو القلق ،أو الأرق ،أو العصبية أو التهيج؛
• التشنج، واضطراب التوازن، والدوخة (الإحساس بعدم الثبات)، والخمول، ورعاش (ارتعاش لاإرادي)؛
• الدوار (الإحساس بالدوران)؛
• السعال؛
• ألم في البطن، والإسهال، وعسر الهضم (عسر الهضم)، والتقيؤ والغثيان؛
• طفح جلدي؛
• الوهن / التعب.
غير شائعة: قد تؤثر فى1 إلي 10 مستخدمين من 1,000:
• انخفاض عدد الصفائح الدموية، وانخفاض عدد خلايا الدم البيضاء؛
• انخفاض الوزن ،أو زيادة الوزن؛
• محاولة الانتحار والتفكير في الانتحار، واضطرابات عقلية، والسلوك الشاذ، هلوسة، والغضب، والارتباك، نوبة الهلع، وتقلب المزاج / عدم استقرار عاطفي، والتهيج؛
• فقدان الذاكرة، ضعف الذاكرة (النسيان)، وخلل فى التنسيق/ ترنح (ضعف فى تنسيق الحركات)، وخز ، اضطراب في الانتباه (فقدان التركيز)؛
• ازدواج الرؤية (الرؤية المزدوجة)، عدم وضوح الرؤية؛
• اختلال فى اختبار وظيفة الكبد ؛
• فقدان الشعر، الأكزيما، حكة؛
• ضعف العضلات، وألم عضلي (ألم في العضلات)؛
• الإصابة.
نادرة: قد تؤثر فى 1 إلي 10 مستخدمين من 10,000:
• العدوى,
• انخفاض عدد جميع أنواع الخلايا في الدم,
• تفاعلات تحسسية حادة,
• انخفاض مستوى الصوديوم بالدم,
• الانتحار، اضطرابات شخصية (مشكلات سلوكية)، والتفكير الغير طبيعي (ا تلفكير البطيء، عدم القدرة على التركيز),
• تشنجات عضلية لا يمكن السيطرة عليها تؤثر على الرأس والجذع والأطراف، وصعوبة في السيطرة على الحركات، فرط الحراك
(فرط النشاط),
• التهاب البنكرياس,
• الفشل الكبدي والتهاب الكبد,
• طفح جلدي، والتي قد تشكل بثور تبدو كالأهداف الصغيرة (بقع سوداء مركزية وتحيط بها منطقة أكثر شحوبا ً، مع حلقة مظلمة حول الحافة) (حمامي عديدة الأشكال)، طفح جلدي على نطاق واسع مع ظهور بثور وتقشير للجلد، وخاصة حول الفم، والأنف والعينين والأعضاء التناسلية (متلازمة ستيفنز جونسون)، وشكل أكثر شدة مما يتسبب في تقشير الجلد في أكثر من 30٪ من سطح الجسم (انحلال البشرة السمي).
إذا كان لديك أي آثار جانبية تحدث إلى طبيبك أو الصيدلي. وهذا يشمل أي آثار جانبية محتملة غير مدرجة في هذه النشرة.
يحفظ الدواء بعيدا ً عن متناول ونظر الأطفال.
يحفظ هذا الدواء فى درجة حرارة أقل من 30 درجة مئوية.
لا تستعمل هذا الدواء بعد انتهاء تاريخ الصلاحية المدون على العبوة والزجاجة بعد EXP. وتاريخ الانتهاء يشير إلى أخر يوم فى الشهر المذكور.
لا تستخدم هذا الدواء بعد 7 شهور من فتح الزجاجة أول مرة.
نظراً لحساسية الدواء تجاه الضوء, يحفظ الدواء فى عبوته الأصلية.
يجب عدم التخلص من الأدوية في مياه المجاري أو قمامة المنزل. اسأل الصيدلي كيف تتخلص من الأدوية التي لم تعد بحاجة إليها. لأن هذه الاعتبارات ستعمل على حماية البيئة.
علام يحتوى ليفيتام
- إن المادة الفعالة هي ليفيتيراسيتام. يحتوى كل مل من محلول ليفيتام على 100 ملجم من المادة الفعالة ليفيتيراسيتام.
- المكونات الأخرى هى: سيترات الصوديوم, حامض سيتريك أحادى التميه, ميثيل باراهيدروكسى بنزوات, بروبيل باراهيدروكسى بنزوات, أمونيوم جليسريزينات, جليسرول, سكرالوز, شراب جلوكوز مهدرج, نكهة العنب, ماء منقى.
ليفيتام محلول شفاف, عديم اللون ذو رائحة فاكهة مميزة ومذاق نكهة العنب, خالى من جزيئات المواد الغريبة. كل كرتونة تحتوى على ليفيتام 100 ملجم/مل محلول فموى فى زجاجة بحجم 150 مل من زجاج العنبر و 300 مل من زجاج العنبر.
الدوائية
مصنع الأدوية بالقصيم
الشركة السعودية للصناعات الدوائية والمستلزمات الطبية
المملكة العربية السعودية
Levetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
Levetam is indicated as adjunctive therapy
• In the treatment of partial onset seizures with or without secondary generalisation in adults adolescents, and children from 1 month of age with epilepsy.
• In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
• In the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.
Levetam concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.
Posology
Monotherapy for adults and adolescents from 16 years of age
The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.
Add-on therapy for adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more
The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.
Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.
Duration of treatment
There is no experience with administration of intravenous levetiracetam for longer period than 4 days.
Special populations
Elderly (65 years and older)
Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).
Renal impairment
The daily dose must be individualised according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function:
Group | Creatinine clearance (ml/min/1.73m2) | Dose and frequency |
Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis (1) | > 80 50-79 30-49 < 30 - | 500 to 1,500 mg twice daily 500 to 1,000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1,000 mg once daily (2) |
(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.
(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.
For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.
The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination using, for young adolescents and children using the following formula (Schwartz formula):
ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male
Dosing adjustment for infants, children and adolescents patients weighing less than 50 kg with impaired renal function:
Group | Creatinine clearance (ml/min/1.73 m2) | Dose and frequency (1) | |
Infants 1 to less than 6 months | Infants 6 to 23 months, children and adolescents weighing less than 50 kg | ||
Normal | > 80 | 7 to 21 mg/kg (0.07 to 0.21 ml/kg) twice daily | 10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily |
Mild | 50-79 | 7 to 14 mg/kg (0.07 to 0.14 ml/kg) twice daily | 10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily |
Moderate | 30-49 | 3.5 to 10.5 mg/kg (0.035 to 0.105 ml/kg) twice daily | 5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily |
Severe | < 30 | 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) twice daily | 5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily |
End-stage renal disease patients undergoing dialysis | -- | 7 to 14 mg/kg (0.07 to 0.14 ml/kg) once daily (2) (4) | 10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (3) (5) |
(1) Levetam oral solution should be used for doses under 250 mg and for patients unable to swallow tablets.
(2) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.
(3) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.
(4) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.
(5) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.
Hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73 m2.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
The tablet formulation is not adapted for use in infants and children under the age of 6 years. Levetam oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases Levetam oral solution should be used.
The safety and efficacy of Levetam concentrate for solution for infusion in infants and children less than 4 years have not been established.
Monotherapy
The safety and efficacy of Levetam in children and adolescents below 16 years as monotherapy treatment have not been established.
There are no data available.
Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg
Levetam oral solution is the preferred formulation for use in infants and children under the age of 6 years.
The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for infants from 6 months of age, children and adolescents:
Weight | Starting dose: 10 mg/kg twice daily | Maximum dose: 30 mg/kg twice daily |
6 kg (1) | 60 mg (0.6 ml) twice daily | 180 mg (1.8 ml) twice daily |
10 kg (1) | 100 mg (1 ml) twice daily | 300 mg (3 ml) twice daily |
15 kg (1) | 150 mg (1.5 ml) twice daily | 450 mg (4.5 ml) twice daily |
20 kg (1) | 200 mg (2 ml) twice daily | 600 mg (6 ml) twice daily |
25 kg | 250 mg twice daily | 750 mg twice daily |
From 50 kg (2) | 500 mg twice daily | 1,500 mg twice daily |
(1) Children 25 kg or less should preferably start the treatment with Levetam 100 mg/ml oral solution.
(2) Dose in children and adolescents 50 kg or more is the same as in adults.
Add-on therapy for infants aged from 1 month to less than 6 month.
The oral solution is the formulation to use in infants.
The initial therapeutic dose is 7 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 21 mg/kg twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Infants should start the treatment with Levetam 100 mg/ml oral solution.
Dose recommendations for infants aged from 1 month to less than 6 months:
Weight | Starting dose: 7 mg/kg twice daily | Maximum dose: 21 mg/kg twice daily |
4 kg | 28 mg (0.3 ml) twice daily | 84 mg (0.85 ml) twice daily |
5 kg | 35 mg (0.35 ml) twice daily | 105 mg (1.05 ml) twice daily |
7 kg | 49 mg (0.5 ml)twice daily | 147 mg (1.5 ml) twice daily |
Three presentations are available:
- A 300 ml bottle with a 10 ml oral syringe (containing up to 1000 mg levetiracetam) graduated every 0.25 ml (corresponding to 25 mg).
This presentation should be prescribed for children aged 4 years and older, adolescents and adults.
- A 150 ml bottle with a 3 ml oral syringe (containing up to 300 mg levetiracetam) graduated every 0.1 ml (corresponding to 10 mg)
In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants and young children agedfrom 6 months to less than 4 years.
- A 150 ml bottle with a 1 ml oral syringe (containing up to 100 mg levetiracetam) graduated every 0.05 ml (corresponding to 5 mg)
In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants aged 1 month to less than 6 months.
Method of administration - tablets
The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.
Method of administration
The oral solution may be diluted in a glass of water or baby's bottle and may be taken with or without food. A graduated oral syringe, an adaptor for the syringe and instructions for use in the package leaflet are provided with Levetam.
The daily dose is administered in two equally divided doses.
Method of administration – solution for infusion
Levetam therapy can be initiated with either intravenous or oral administration.
Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.
Levetam concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion (see section 6.6).
Discontinuation
In accordance with current clinical practice, if Levetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Renal insufficiency
The administration of Levetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2).
Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.
Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Paediatric population
The tablet formulation is not adapted for use in infants and children under the age of 6 years.
Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been exposed in clinical studies of which only 13 were aged < 6 months.
Excipients:
Levetam 100 mg/ml oral solution includes methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed)
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that Levetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Levetam.
As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.
Oral contraceptives and other pharmacokinetics interactions
Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
Antacids
No data on the influence of antacids on the absorption of levetiracetam are available.
Food and alcohol
The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.
Pregnancy
Pregnancy Category: C
There are no adequate data available from the use of levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.
Levetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary.
As with other antiepileptic medicinal products, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.
Fertility
No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.
No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.
Summary of the safety profile
The adverse event profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.
Tabulated list of adverse reactions
Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
MedDRA SOC | Frequency category | |||
Very common | Common | Uncommon | Rare | |
Infections and infestations | Nasopharyngitis |
|
| Infection |
Blood and lymphatic system disorders |
|
| Thrombocytopenia, leukopenia | Pancytopenia (, neutropenia, agranulocytosis |
Immune system disorders |
|
|
| Drug reaction with eosinophilia and systemic symptoms (DRESS) |
Metabolism and nutrition disorders |
| Anorexia | Weight decreased , weight increase | Hyponatraemia |
Psychiatric disorders |
| Depression, hostility/ aggression, anxiety, insomnia, nervousness/irritability | Suicide attempt), suicidal ideation psychotic disorder), abnormal behaviour), hallucination(), anger(), confusional state ,panic attack affect lability/mood swings, agitation | Completed suicide), personality disorder, thinking abnormal |
Nervous system disorders | Somnolence, headache | Convulsion, balance disorder, dizziness, lethargy, tremor | Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention | Choreoathetosis, dyskinesia), hyperkinesia |
Eye disorders |
|
| Diplopia, vision blurred |
|
Ear and labyrinth disorders |
| Vertigo |
|
|
Respiratory, thoracic and mediastinal disorders |
| Cough |
|
|
Gastrointestinal disorders |
| Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea |
| Pancreatitis |
Hepatobiliary disorders |
|
| Liver function test abnormal | Hepatic failure, hepatitis |
Skin and subcutaneous tissue disorders |
| Rash | Alopecia, eczema, pruritus, | Toxic epidermal necrolysis, Stevens-Johnson syndrome), erythema multiforme |
Musculoskeletal and connective tissue disorders |
|
| Muscular weakness, myalgia |
|
General disorders and administration site conditions |
| Asthenia/fatigue |
|
|
Injury, poisoning and procedural complications |
|
| Injury |
|
Description of selected adverse reactions
The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Bone marrow suppression was identified in some of the cases of pancytopenia.
Paediatric population
In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty (60) of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.
The adverse event profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of Levetam in children 4 to 16 years of age with partial onset seizures. It was concluded that Levetam was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in Levetam treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist). However subjects, who took Levetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.
To report any side effect(s): The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc
|
Symptoms
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levetam overdoses.
Management of overdose
After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.
Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.
In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.
Pharmacodynamic effects
Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6 % for patients on placebo.
Paediatric population
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).
44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4 % of the patients were seizure-free for at least 6 months and 7.2 % were seizure-free for at least 1 year.
In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days. In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one month to less than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and children 6 months to less than 4 years old, was use in this study. The total daily dose was administered b.i.d.
The primary measure of effectiveness was the responder rate (percent of patients with ≥ 50 % reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG. The efficacy analysis consisted of 109 patients who had at least 24 hours of video EEG in both baseline and evaluation periods. 43.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo were considered as responders. The results are consistent across age group. With continued long-term treatment, 8.6 % of the patients were seizure-free for at least 6 months and 7.8 % were seizure-free for at least 1 year.
Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.
Efficacy of levetiracetam as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 – 1200 mg/day or levetiracetam 1000 – 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response.
Six-month seizure freedom was achieved in 73.0 % of levetiracetam-treated patients and 72.8 % of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95 % CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6 % and 58.5 % of subjects on levetiracetam and on carbamazepine CR respectively).
In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients out of 69).
Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
Levetiracetam efficacy was established in a double-blind, placebo-controlled study of 16 weeks duration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy with myoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonic epilepsy.
In this study, levetiracetam, dose was 3000 mg/day given in 2 divided doses.
58.3 % of the levetiracetam treated patients and 23.3 % of the patients on placebo had at least a 50 % reduction in myoclonic seizure days per week. With continued long-term treatment, 28.6 % of the patients were free of myoclonic seizures for at least 6 months and 21.0 % were free of myoclonic seizures for at least 1 year.
Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy.
Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, levetiracetam dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.
72.2 % of the levetiracetam treated patients and 45.2 % of the patients on placebo had a 50 % or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4 % of the patients were free of tonic-clonic seizures for at least 6 months and 31.5 % were free of tonic-clonic seizures for at least 1 year.
Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. The time independent pharmacokinetic profile of levetiracetam was also confirmed following 1500 mg intravenous infusion for 4 days with b.i.d dosing.
There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.
Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam.
A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation).
The pharmacokinetic profile has been characterized following oral administration. A single dose of 1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as three 500 mg tablets.
The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9 % sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9 % sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns.
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %.
Peak plasma concentrations (Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule.
Peak concentrations (Cmax) are typically 31 and 43 µg/ml following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively.
The extent of absorption is dose-independent and is not altered by food.
Distribution
No tissue distribution data are available in humans.
Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.
Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 µg/mL (arithmetic average ± standard deviation).
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose).
Other unidentified components accounted only for 0.6 % of the dose.
No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.
In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of Levetam with other substances, or vice versa, is unlikely.
Elimination
The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.
Elderly
In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population (see section 4.2).
Renal impairment
The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Levetam, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.
Hepatic impairment
In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).
Paediatric population
Children (4 to 12 years)
Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.
Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.
Infants and children (1 month to 4 years)
Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).
In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age.
In both population pharmacokinetic analyses, there was about a 20 % increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing antiepileptic medicinal product.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity.
Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.
No adverse effects on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.
Two embryo-foetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in foetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for foetuses.
Four embryo-foetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in foetal weight associated with increased incidence of foetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the foetuses (equal to the MRHD on a mg/m2 basis).
A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was ≥ 1800 mg/kg/day for the F0 females, and for the survival, growth and development of the F1 offspring up to weaning.(x 6 the MRHD on a mg/m2 basis).
Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6-17 the MRHD on a mg/m2 basis)
Environmental Risk Assessment (ERA)
The use of Levetam in accordance with the product information is not likely to result in an unacceptable environmental impact (see section 6.6).
Sodium citrate,
Citric acid monohydrate,
Methyl parahydroxybenzoate,
Propyl parahydroxybenzoate,
Ammonium glycyrrhizinate,
Glycerol,
Sucralose,
Hydrogenated glucose syrup,
Grape flavor &
Purified water.
No idea about incompatibilities with other medicines
Do not store above 30°C.
Amber Glass bottle with child-resistant plastic cap (CRC) and syringe with adaptor:
-Glass bottle: Glass Type III (150mg & 300ml Amber glass)
-Plastic cap: polypropylene (PP) child-resistant cap
-Syringe with adaptor: 1ml, 3ml & 10ml polypropylene (PP) syringe, polyethylene (PE) low density adaptor packed in plastic (polyethylene film)pouch.
Any unused product or waste material should be disposed of in accordance with local requirements.
