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TIENAM belongs to a group of medicines called carbapenem antibiotics. It kills a wide range of bacteria (germs) that cause infections in various parts of the body in adults and children one year of age and above.
Treatment
Your doctor has prescribed TIENAM because you have one (or more) of the following types of infection:
• Complicated infections in the abdomen
• Infection affecting the lungs (pneumonia)
• Infections that you can catch during or after the delivery of your baby
• Complicated urinary tract infections
• Complicated skin and soft tissue infections
TIENAM may be used in the management of patients with low white blood cell counts, who have fever that is suspected to be due to a bacterial infection.
TIENAM may be used to treat bacterial infection of the blood which might be associated with a type of infection mentioned above.
1. Do not use TIENAM
- if you are allergic to imipenem, cilastatin or any of the other ingredients of this medicine (listed in section 6)
- if you are allergic to other antibiotics such as penicillins, cephalosporins, or carbapenems
Warnings and Precautions
Tell your doctor about any medical condition you have or have had including:
- allergies to any medicines including antibiotics (sudden life-threatening allergic reactions require immediate medical treatment)
- colitis or any other gastrointestinal disease
- kidney or urinary problems, including reduced kidney function (TIENAM blood levels increase in patients with reduced kidney function. Central nervous system adverse reactions may occur if the dose is not adjusted to the kidney function)
- any central nervous system disorders such as localized tremors or epileptic seizures (fits)
- liver problems
You may develop a positive test (Coombs test) which indicates the presence of antibodies that may destroy red blood cells. Your doctor will discuss this with you.
Children
TIENAM is not recommended in children less than one year of age or children with kidney problems.
Other medicines and TIENAM
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Tell your doctor if you are taking ganciclovir which is used to treat some viral infections.
Also, tell your doctor if you are taking valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder, migraine, or schizophrenia) or any blood thinners such as warfarin.
Your doctor will decide whether you should use TIENAM in combination with these medicines.
Pregnancy and breast-feeding
It is important that you tell your doctor if you are pregnant or are planning to become pregnant before receiving TIENAM. TIENAM has not been studied in pregnant women. TIENAM should not be used during pregnancy unless your doctor decides the potential benefit justifies the potential risk to the developing baby.
It is important that you tell your doctor if you are breast-feeding or if you intend to breast-feed before receiving TIENAM. Small amounts of this medicine may pass into breast milk and it may affect the baby. Therefore, your doctor will decide whether you should use TIENAM while breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
There are some side effects associated with this product (such as seeing, hearing, or feeling something that is not there, dizziness, sleepiness, and a spinning sensation) that may affect some patients' ability to drive or operate machinery (see section 4).
TIENAM contains sodium
This medicine contains 37.6 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 1.9% of the recommended maximum daily dietary intake of sodium for an adult.
TIENAM will be prepared and given to you by a doctor or another health care professional. Your doctor will decide how much TIENAM you need.
Use in adults and adolescents
The recommended dose for adults and adolescents is 500 mg/500 mg every 6 hours or
1,000 mg/1,000 mg every 6 or 8 hours. If you have kidney problems your doctor may lower your dose. Use in children
The recommended dose for children one year of age or older is 15/15 or 25/25 mg/kg/dose every 6 hours. TIENAM is not recommended in children under one year of age and children with kidney problems.
Method of administration
TIENAM is given intravenously (into a vein) over 20-30 minutes for a dose of ≤500 mg/500 mg or 40-60 minutes for a dose of >500 mg/500 mg. The rate of infusion may be slowed if you feel sick.
If you use more TIENAM than you should
Symptoms of overdose may include seizures (fits), confusion, tremors, nausea, vomiting, low blood pressure and slow heart rate. If you are concerned that you may have been given too much TIENAM, contact your doctor or another healthcare professional immediately.
If you forget to use TIENAM
If you are concerned that you may have missed a dose, contact your doctor or another healthcare professional immediately.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Like all medicines, this medicine can cause side effects, although not everybody gets them. The frequency of possible side effects listed below is defined using the following convention:
• very common: affects more than 1 user in 10
• common: affects 1 to 10 users in 100
• uncommon: affects 1 to 10 users in 1,000
• rare: affects 1 to 10 users in 10,000
• very rare: affects less than 1 user in 10,000
• not known: frequency cannot be estimated from the available data
The following side-effects occur rarely, however if they do occur, while receiving or after receiving TIENAM, the medicine must be stopped and your doctor contacted immediately.
• Allergic reactions including rash, swelling of the face, lips, tongue, and/or throat (with difficulty in breathing or swallowing), and/or low blood pressure
• Skin peeling (toxic epidermal necrolysis)
• Severe skin reactions (Stevens-Johnson syndrome and erythema multiforme)
• Severe skin rash with loss of skin and hair (exfoliative dermatitis) Other possible side effects:
Common
• Nausea, vomiting, diarrhoea. Nausea and vomiting appear to occur more frequently in patients with low number of white blood cells
• Swelling and redness along a vein which is extremely tender when touched
• Rash
• Abnormal liver function detected by blood tests
• Increase in some white blood cells
Uncommon
• Local skin redness
• Local pain and formation of a firm lump at the injection site
• Skin itchiness
• Hives
• Fever
• Blood disorders affecting the cell components of the blood and usually detected by blood tests (symptoms may be tiredness, paleness of skin, and prolonged bruising after injury)
• Abnormal kidney, liver and blood function detected by blood tests
• Tremors and uncontrolled twitching of muscles
• Seizures (fits)
• Psychic disturbances (such as mood swings and impaired judgment)
• Seeing, hearing or feeling something that is not there (hallucinations)
• Confusion
• Dizziness, sleepiness
• Low blood pressure
Rare
• Fungal infection (candidiasis)
• Staining of the teeth and/or tongue
• Inflammation of the colon with severe diarrhoea
• Disturbances in taste
• Inability of the liver to perform normal function
• Inflammation of the liver
• Inability of the kidney to perform normal function
• Changes in the amount of urine, changes in urine colour
• Disease of the brain, tingling sensation (pins and needles), localised tremor
• Hearing loss
Very rare
• Severe loss of liver function due to inflammation (fulminant hepatitis)
• Inflammation of stomach or intestine (gastro-enteritis)
• Inflammation of intestine with bloody diarrhoea (haemorrhagic colitis)
• Red swollen tongue, overgrowth of the normal projections on the tongue giving it a hairy appearance, heartburn, sore throat, increase in the production of saliva
• Stomach pain
• A spinning sensation (vertigo), headache
• Ringing in the ears (tinnitus)
• Pain in several joints, weakness
• Irregular heartbeat, the heart beating forcefully or rapidly
• Chest discomfort, difficulty breathing, abnormally fast and superficial breathing, pain in the upper spine
• Flushing, bluish discoloration of the face and lips, skin texture changes, excessive sweating
• Itching of the vulva in women
• Changes in the amounts of blood cells
• Worsening of a rare disease associated with muscle weakness (aggravation of myasthenia gravis)
Not known
• Abnormal movements
• Agitation
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via The National Pharmacovigilance Centre (NPC) . By reporting side effects you can help provide more information on the safety of this medicine.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the container.
Do not store above 25 °C.
After reconstitution:
Diluted solutions should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous infusion should not exceed two hours.
Do not freeze the reconstituted solution.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer used. These measures will help protect the environment.
What TIENAM contains
- The active substances are imipenem and cilastatin. Each vial contains imipenem monohydrate equivalent to 500 mg imipenem and cilastatin sodium equivalent to 500 mg cilastatin.
- The other ingredient is sodium bicarbonate.
Marketing Authorization Holder
Merck Sharp & Dohme B.V.,
Waarderweg 39, 2031 BN Haarlem,
P.O. Box 581, 2003 PC Haarlem,
The Netherlands
Manufacturer
Merck Sharp & Dohme Corp., 2778 South East Highway, Elkton, Virginia 22827, USA
ينتمي تينام إلى مجموعة من الأدوية تُسمّى المُضادّات الحيويّة من فئة الكاربابينيمات. وهو يقتل مجموعة واسعة من البكتيريا (الجراثيم) التي تُسبّب العدوى في أجزاء مُختلفة من الجسم في البالغين والأطفال من عمر سنة واحدة وما فوق.
العلاج
لقد وصف لك طبيبك تينام لأنّ لديك واحد (أو أكثر) من الأنواع التالية من العدوى:
• عدوى مُعقّدة في البطن
• العدوى التي تُصيب الرئتين (الالتهاب الرئوي)
• العدوى التي يمكن أن تُصابي بها أثناء أو بعد ولادة طفلكِ
• عدوى المسالك البوليّة المُعقّدة
• العدوى المُعقّدة في الجلد والأنسجة الرّخوة
يُمكن استخدام تينام في علاج المرضى الذين يُعانون من انخفاض في أعداد خلايا الدّم البيضاء، ويُعانون من حُمّى يُشتبه في أنها ناجِمة عن عدوى بكتيريّة.
يُمكن استخدام تينام لعلاج العدوى البكتيريّة في الدّم والتي قد تكون مُرتبطة بنوع من العدوى المذكورة أعلاه.
لا تستخدم تينام:
- إذا كنت تُعاني من حساسيّة تجاه إيميبينم، سيلاستاتين أو أي من المكونات الأخرى لهذا الدواء (المُدرجة في القسم 6)
- إذا كنت تُعاني من حساسيّة تجاه مُضادّات حيويّة أخرى مثل البنسلين أو السيفالوسبورين أو الكاربابينيمات
التّحذيرات والاحتياطات
أخبر طبيبك عن أي حالة طبيّة لديك حاليّا أو كانت لديك سابقًا بما في ذلك:
- الحساسيّة تجاه أي أدوية بما في ذلك المُضادّات الحيويّة (تتطلّب تفاعلات الحساسيّة المُفاجِئة والتي تُهدِّد الحياة علاجًا طبيًا فوريًّا)
- التهاب القولون أو أي مرض مَعوي آخر
- مشاكل الكِلى أو البول، بما في ذلك انخفاض وظائف الكِلى (ترتفع مُستويات تينام في الدّم في المرضى الذين يُعانون من انخفاض وظائف الكِلى. قد تحدث ردود فعل جانبيّة في الجهاز العصبي المركزي إذا لم يتم تعديل الجرعة تبعا لوظيفة الكِلى)
- أي اضطرابات في الجهاز العصبي المركزي مثل رُعاش موضعي أو اختلاجات صرعيّة (نوبات)
- مشاكل كبِديّة
قد يظهر لديك اختبار إيجابي (اختبار كومبس) وهو اختبار يشير إلى وجود الأجسام المُضادّة التي قد تٌدمّر خلايا الدّم الحمراء. سيُناقش طبيبك هذا الأمر معك.
الأطفال
لا يُنصح باستخدام تينام للأطفال الذين تقلّ أعمارهم عن سنة واحدة أو الأطفال الذين يُعانون من مشاكل في الكِلى.
الأدوية الأُخرى وتينام
أخبر طبيبك أو الصّيدلي إذا كنت تستخدم أو قد استخدمت مُؤخّرا أو قد تستخدم أيّ أدوية أُخرى.
أخبر طبيبك إذا كنت تستخدم غانسايكلوفير الذي يُستخدم لعلاج بعض أنواع العدوى الفيروسيّة.
أخبر طبيبك أيضًا إذا كنت تتناول حمض الفالبرويك أو فالبروات الصوديوم (يُستخدم لعلاج الصّرع أو الاضطراب ثُنائي القُطب أو الصّداع النّصفي أو الفِصام) أو أي مُميّعات للدّم مثل الوارفارين.
سيقرّر طبيبك ما إذا كان يجب عليك استخدام تينام مع هذه الأدوية.
الحمل والرّضاعة الطّبيعيّة
من المهم أن تخبري طبيبكِ إذا كنتِ حاملًا أو تخططين للحمل قبل تلقّيكِ تينام. لم تتم دراسة تينام في النّساء الحوامِل. لا ينبغي استخدام تينام أثناء الحمل إلّا إذا قرّر طبيبكِ أنّ الفائدة المُحتملة تُبرِّر الخطر المُحتمل على الجنين.
من المهم أن تخبري طبيبكِ إذا كنتِ تُرضعين رضاعة طبيعيّة أو إذا كنتِ تنوين الرّضاعة الطّبيعيّة قبل تلقّيكِ تينام. قد تُفرز كمّيّات صغيرة من هذا الدّواء في حليب الثّدي، وقد يُؤثّر ذلك على الطّفل. لذلك سيُقرّر طبيبكِ ما إذا كان عليكِ استخدام تينام أثناء الرّضاعة الطّبيعيّة.
اطلبي المشورة من طبيبكِ أو الصّيدلي قبل تناول أي دواء.
القيادة واستخدام الآلات
هناك بعض الأعراض الجانبيّة المُرتبطة بهذا المُنتج (مثل رُؤية أو سماع أو الشّعور بشيء غير موجود، والدّوخة، والنُّعاس، والإحساس بالدُّوار) والتي قد تُؤثّر على قدرة بعض المرضى على القيادة أو تشغيل الآلات ( أُنظر القسم 4).
تينام يحتوي على الصّوديوم
يحتوي هذا الدّواء على 37,6 مجم صوديوم (المُكوِّن الرّئيس للطّهي/ملح الطعام) في كلّ قارورة. وهذا يُعادِل 1,9٪ من الحد الأقصى المُوصى به من الحصّة الغذائيّة اليوميّة للصّوديوم للبالغين.
سيتم تحضير تينام وإعطاؤه لك من قبل طبيب أو أخصائي رعاية صحيّة آخر. سيقرّر طبيبك جرعة تينام التي تحتاجها.
الاستخدام في البالغين والمُراهقين
الجرعة المُوصى بها للبالغين والمُراهقين هي 500 مجم/500 مجم كل 6 ساعات أو 1,000 مجم/1,000 مجم كل 6 أو 8 ساعات. إذا كنت تُواجه مشاكل في الكِلى فقد يخفض طبيبك جرعتك.
الاستخدام في الأطفال
الجرعة المُوصى بها للأطفال من عمر سنة أو أكبر هي 15/15 أو 25/25 مجم/كجم/جرعة كلّ 6 ساعات. لا يُنصح باستخدام تينام في الأطفال الذين تقلّ أعمارهم عن سنة واحدة والأطفال الذين يُعانون من مشاكل في الكِلى.
طريقة الإعطاء
يتم إعطاء تينام عن طريق الوريد (في الوريد) على مدى 20-30 دقيقة للجرعة التي تكون ≤ 500 مجم/500 مجم أو 40-60 دقيقة للجرعة التي تكون >500 مجم/500 مجم. قد يتم إبطاء مُعدّل التّسريب إذا شعرت بالمرض "الغثيان".
إذا كنت تستخدم تينام أكثر ممّا يجب
قد تشمل أعراض الجرعة الزّائِدة: اختلاجات (نوبات)، ارتباك، رُعاش، غثيان، قيء، انخفاض ضغط الدّم وبطء مُعدّل ضربات القلب. إذا كنت قلقا من أنك قد أُعطيت الكثير من تينام، فاتّصل بطبيبك أو أخصّائي رعاية صحيّة آخر على الفور.
إذا نسيت استخدام تينام
إذا كنت قلقًا من أنّه قد فاتتك أحد الجرعات، فاتّصل بطبيبك أو أخصّائي رعاية صحيّة آخر على الفور.
إذا كان لديك أي أسئلة أُخرى حول استخدام هذا المُنتج، فاسأل طبيبك أو الصّيدلي.
كما هو الحال مع جميع الأدوية، يمكن أن يُسبِّب هذا الدّواء أعراضًا جانبيّة، مع أنها لا تحدث لدى جميع من يستخدمه.
يتم تحديد مدى تكرار الأعراض الجانبيّة المُحتملة المُدرجة أدناه باستخدام التعريفات التّالية:
• شائعة جدًّا : تُؤثّر على أكثر من مُستخدِم واحد من كل 10
• شائعة : تُؤثّر على 1 إلى 10 مُستخدِمين من كل 100
• غير شائعة : تُؤثّر على 1 إلى 10 مُستخدِمين من كل 1,000
• نادرة : تُؤثّر على 1 إلى 10 مُستخدِمين من كل 10,000
• نادرة جدًّا : تُؤثّر على أقلّ من مُستخدِم واحد من كل 10,000
• غير معروفة: لا يُمكن تقدير التّكرار من البيانات المُتاحة
نادرًا ما تحدث الأعراض الجانبيّة التّالية، ولكن إذا حدثت، أثناء تلقّي أو بعد تلقّي تينام، فيجب إيقاف الدّواء والاتّصال بطبيبك على الفور.
• الحساسيّة بما في ذلك الطّفح الجلدي، وتورّم الوجه والشّفاه واللّسان و/أو الحلق (مع صُعوبة في التّنفس أو البلع) و/أو انخفاض ضغط الدّم
• تقشُّر الجلد (تَقَشُّرُ الأَنْسِجَةِ المُتَمَوِّتَةِ البَشْرَوِيَّةِ التَّسَمُّمِيّ)
• ردود فعل جلديّة شديدة (مُتلازمة ستيفنس-جونسون وحُمامَى مُتعدِّدة الأشكال)
• طفح جلدي حاد مع فقدان الجلد والشّعر (التهاب الجلد التّقشُّري).
الأعراض الجانبيّة المُحتملة الأُخرى :
شائعة
• غثيان وقيء وإسهال. ويبدو أنّ الغثيان والقيء يحدثان أكثر في المرضى الذين يُعانون من انخفاض عدد خلايا الدّم البيضاء
• تورّم واحمرار على طول أحد الأوردة والذي يكون شديد الإيلام عند لمسه
• طفح
• خلل في وظائف الكبد يتم الكشف عنه عن طريق اختبارات الدّم
• ارتفاع في عدد بعض خلايا الدّم البيضاء
غير شائعة
• احمرار جلدي موضعي
• ألم موضعي وتكوّن كتلة صلبة في موضع الحقن
• حكة جلديّة
• شَرَى
• حُمّى
• اضطرابات الدّم والتي تُؤثّر على مُكوِّنات خلايا الدّم وعادة ما يتم الكشف عنها عن طريق اختبارات الدّم (قد تكون الأعراض هي تعب وشُحوب الجلد، وكدمات طويلة الأمد بعد التّعرّض لإصابة ما)
• خلل في وظائف الكِلى والكبد والدّم يتم الكشف عنه عن طريق اختبارات الدّم
• رُعاش واختلاجات غير مُنضبطة في العضلات
• اختلاجات (نوبات)
• اضّطرابات نفسيّة (مثل تقلُّب المزاج وخلل في الحُكْم على الأمور)
• رُؤية أو سماع أو الشُّعور بشيء غير موجود (هلوسة)
• تشوُّش
• دوخة ونُعاس
• انخفاض ضغط الدّم
نادرة
• عدوى فِطريّة (داء المُبيّضات)
• تصبُّغ الأسنان و/أو اللّسان
• التهاب القولون مع إسهال حاد
• اضّطرابات في التّذوّق
• عدم قدرة الكبد على أداء وظيفته الطّبيعيّة
• التهاب الكبد
• عدم قدرة الكِلى على أداء وظيفتها الطّبيعيّة
• تغيّرات في كميّة البول، وتغيّرات في لون البول
• مرض في الدّماغ، الإحساس بالوخز (دبابيس وإبر)، رُعاش موضعي
• فقدان السّمع
نادرة جدًّا
• تدني شديد في وظيفة الكبد بسبب الالتهاب (التهاب الكبد المُفاجئ)
• التهاب المعدة أو الأمعاء (التهاب المعدة والأمعاء)
• التهاب الأمعاء مع إسهال دموي (التهاب القولون النّزفي)
• لِسان مُتَورّم مُحمرّ، فرط نموّ النتوءات الطبيعية على اللّسان مما يُعطيه مظهرًا مُشعّرًا، حرقة في المعدة، التهاب في الحلق، زيادة في إفراز اللُّعاب
• ألم في المعدة
• إحساس بالدُّوار (دُوار)، وصُداع
• رنين في الأذنين (طنين)
• ألم في عِدّة مفاصل، ضعف
• عدم انتظام ضربات القلب، القلب ينبض بقوّة أو بسرعة
• عدم الرّاحة في الصّدر، صعوبة في التّنفّس، تنفّس سريع ضحل بشكل غير طبيعي، ألم في العمود الفقري العُلوي
• تورُّد، ازرقاق الوجه والشّفتين، تغيّر ملمس الجلد، تعرُّق مُفرط
• حكّة فرجيّة لدى النّساء
• تغيّرات في كميّات خلايا الدّم
• تفاقم مرض نادر مُرتبط بضعف العضلات (تفاقم الوهن العضلي الوبيل)
غير معروفة
• حركات غير طبيعية
• هيجان
الإبلاغ عن الأعراض الجانبية
إذا ظهرت لديك أي أعراض جانبيّة، فتحدّث إلى طبيبك أو الصّيدلي. وهذا يشمل أي أعراض جانبيّة مُحتملة غير مُدرجة في هذه النّشرة. يُمكنك أيضا الإبلاغ عن الأعراض الجانبيّة مُباشرة عن طريق المركز الوطني للتيقّظ والسّلامة الدّوائيّة (NPC) التابع للهيئة العامة للغذاء والدواء. يُمكنك المُساعدة في توفير مزيد من المعلومات عن مأمونيّة هذا الدّواء بإبلاغك عن الأعراض الجانبيّة.
احفظ هذا الدّواء بعيدًا عن مَرأى ومُتناول الأطفال.
لا تستخدم هذا الدّواء بعد تاريخ انتهاء الصلاحية المذكور على العبوّة.
احفظه في درجة حرارة أقل من 25 درجة مئوية.
بعد إعادة التّشكيل:
ينبغي استخدام المحاليل المُخفّفة على الفور. يجب ألّا يتجاوز الفاصل الزّمني بين بداية إعادة التّشكيل ونهاية التّسريب الوريدي ساعتين.
لا تقمْ بتجميد المحلول المُعاد تشكيله.
لا تتخلّص من أي أدوية عن طريق مياه الصّرف الصّحي أو النِّفايات المنزلية. اسأل الصّيدلي عن كيفية التّخلّص من الأدوية التي لم تعد مُستخدمةً. ستُساعد هذه التدابير في حماية البيئة.
ما مُحتويات تينام
- المواد الفعّالة هي إيميبينم و سيلاستاتين. تحتوي كلّ قارورة على إيميبينم مونوهيدرات ما يُعادِل 500 مجم إيميبينم، وصوديوم سيلاستاتين ما يُعادِل 500 مجم سيلاستاتين.
- المادّة الأُخرى هي بيكربونات الصّوديوم.
الشكل الصّيدلاني لتينام ومُحتويات العبوّة
تينام هو مسحوق أبيض مائل إلى أصفر فاتح مُعد لتحضير محلول للتّسريب الوريدي في قارورة زجاجيّة.
تتكوّن أحجام العبوّة إمّا من 1 أو 10 أو 25 قارورة. قد لا يتم تسويق جميع أحجام العبوّة.
الشركة المالكة لحقوق التسويق والشّركة المُصنِّعة
الشركة المالكة لحقوق التسويق
ميرك شارب آند دوم بي. في.
39 واردرويغ، 2031 بي إن هآرلم،
صندوق البريد: 581، 2003 بّي سي هآرلم،
هولندا
الشّركة المُصنِّعة
ميرك شارب آند دوم كوربوريشن؛ 2778 الطّريق السّريع الجنوب شرقي، إلكتون، فيرجينيا 22827، الولايات المتحدة الأمريكية
TIENAM is indicated for the treatment of the following infections in adults and children 1 year of age and above (see sections 4.4 and 5.1):
• complicated intra-abdominal infections
• severe pneumonia including hospital and ventilator-associated pneumonia
• intra- and post-partum infections
• complicated urinary tract infections
• complicated skin and soft-tissue infections
TIENAM may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
The dose recommendations for TIENAM represent the quantity of imipenem/cilastatin to be administered.
The daily dose of TIENAM should be based on the type of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s) and the patient's renal function (see also sections 4.4 and 5.1).
Adults and adolescents
For patients with normal renal function (creatinine clearance of ≥ 90 ml/min), the recommended dose regimens are:
500 mg/500 mg every 6 hours OR
1000 mg/1000 mg every 8 hours OR every 6 hours
It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 1000 mg/1000 mg administered every 6 hours.
A reduction in dose is necessary when creatinine clearance is < 90 ml/min. (see Table 1) The maximum total daily dose should not exceed 4000 mg/4000 mg per day.
Renal impairment
To determine the reduced dose for adults with impaired renal function:
1. The total daily dose (i.e. 2000/2000, 3000/3000 or 4000/4000 mg) that would usually be applicable to patients with normal renal function should be selected.
2. From table 1 the appropriate reduced dose regimen is selected according to the patient's creatinine clearance. For infusion times see Method of administration.
Table 1
Creatinine clearance (mL/min) is: | If TOTAL DAILY DOSE is: 2000 mg/day | If TOTAL DAILY DOSE is: 3000 mg/day | If TOTAL DAILY DOSE is: 4000 mg/day |
| |||
≥90 (normal) | 500 q6h | 1000 q8h | 1000 q6h |
reduced dosage (mg) for patients with renal impairment: | |||
<90 - ≥60 | 400 q6h | 500 q6h | 750 q8h |
<60 - ≥30 | 300 q6h | 500 q8h | 500 q6h |
<30 - ≥15 | 200 q6h | 500 q12h | 500 q12h |
Patients with a creatinine clearance of <15 ml/min
These patients should not receive TIENAM unless haemodialysis is instituted within 48 hours.
Patients on haemodialysis
When treating patients with creatinine clearances of <15 ml/min who are undergoing dialysis use the dose recommendation for patients with creatinine clearances of 15 to 29 ml/min (see table 1).
Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive TIENAM after haemodialysis and at 12 hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background central nervous system (CNS) disease, should be carefully monitored; for patients on haemodialysis, TIENAM is recommended only when the benefit outweighs the potential risk of seizures (see section 4.4).
Currently there are inadequate data to recommend use of TIENAM for patients on peritoneal dialysis.
Hepatic impairment
No dose adjustment is recommended in patients with impaired hepatic function (see section 5.2).
Elderly population
No dose adjustment is required for the elderly patients with normal renal function (see section 5.2).
Paediatric population ≥1 year of age
For paediatric patients ≥1 year of age, the recommended dose is 15/15 or 25/25 mg/kg/dose administered every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 25/25 mg/kg administered every 6 hours.
Paediatric population <1 year of age
Clinical data are insufficient to recommend dosing for children less than 1 year of age.
Paediatric population with renal impairment
Clinical data are insufficient to recommend dosing for paediatric patients with renal impairment (serum creatinine > 2 mg/dl). See section 4.4.
Method of administration
TIENAM is to be reconstituted and further diluted (see sections 6.2, 6.3 and 6.6) prior to administration. Each dose of �500 mg/500 mg should be given by intravenous infusion over 20 to 30 minutes. Each dose >500 mg/500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.
General
The selection of imipenem/cilastatin to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.
Hypersensitivity
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating therapy with TIENAM, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams and other allergens (see section 4.3). If an allergic reaction to TIENAM occurs, discontinue the therapy immediately. Serious anaphylactic reactions require immediate emergency treatment.
Hepatic
Hepatic function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure and fulminant hepatitis).
Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin. There is no dose adjustment necessary (see section 4.2).
Haematology
A positive direct or indirect Coombs test may develop during treatment with imipenem/cilastatin.
Antibacterial spectrum
The antibacterial spectrum of imipenem/cilastatin should be taken into account especially in life- threatening conditions before embarking on any empiric treatment. Furthermore, due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to imipenem/cilastatin, caution should be exercised. The use of imipenem/cilastatin is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment. Concomitant use of an appropriate anti-MRSA agent may be indicated when MRSA infections are suspected or proven to be involved in the approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications (see section 4.1).
Interaction with valproic acid
The concomitant use of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section 4.5).
Clostridium difficile
Antibiotic-associated colitis and pseudomembranous colitis have been reported with imipenem/cilastatin and with nearly all other anti-bacterial agents and may range from mild to life- threatening in severity. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of imipenem/cilastatin (see section 4.8). Discontinuation of therapy with imipenem/cilastatin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Meningitis
TIENAM is not recommended for the therapy of meningitis.
Renal impairment
Imipenem-cilastatin accumulates in patients with reduced kidney function. CNS adverse reactions may occur if the dose is not adjusted to the renal function, see sections 4.2 and 4.4 “Central nervous system” in this section.
Central nervous system
CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses based on renal function and body weight were exceeded. These experiences have been reported most commonly in patients with CNS disorders (e.g. brain lesions or history of seizures) and/or compromised renal function in whom accumulation of the administered entities could occur. Hence close adherence to recommended dose schedules is urged especially in these patients (see section 4.2). Anticonvulsant therapy should be continued in patients with a known seizure disorder.
Special awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold.
If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dose of TIENAM should be decreased or discontinued.
Patients with creatinine clearances of <15 ml/min should not receive TIENAM unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, TIENAM is recommended only when the benefit outweighs the potential risk of seizures (see section 4.2).
Paediatric population
Clinical data are insufficient to recommend the use of TIENAM in children under 1 year of age or paediatric patients with impaired renal function (serum creatinine >2 mg/dl). See also above under Central nervous system.
Sodium
This medicinal product contains 37.6 mg sodium (1.6 mmol) per vial, equivalent to 1.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This should be taken into consideration by patients on a controlled sodium diet.
Generalized seizures have been reported in patients who received ganciclovir and TIENAM. These medicinal products should not be used concomitantly unless the potential benefit outweighs the risks.
Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anti-convulsant therapies should be considered (see section 4.4).
Oral anti-coagulants
Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti- coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co- administration of antibiotics with an oral anti-coagulant agent.
Concomitant administration of TIENAM and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolized) imipenem decreased to approximately 60% of the dose when TIENAM was administered with probenecid.
Concomitant administration of TIENAM and probenecid doubled the plasma level and half-life of cilastatin but had no effect on urine recovery of cilastatin.
Paediatric population
Interaction studies have only been performed in adults.
Pregnancy
There are no adequate and well-controlled studies for the use of imipenem/cilastatin in pregnant women.
Studies in pregnant monkeys have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
TIENAM should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding
Imipenem and cilastatin are excreted into the mother’s milk in small quantities. Little absorption of either compound occurs following oral administration. Therefore, it is unlikely that the suckling infant will be exposed to significant quantities. If the use of TIENAM is deemed necessary, the benefit of breast feeding for the child should be weighed against the possible risk for the child.
Fertility
There are no data available regarding potential effects of imipenem/cilastatin treatment on male or female fertility.
No studies on the effects on the ability to drive and use machines have been performed. However, there are some side effects (such as hallucination, dizziness, somnolence, and vertigo) associated with this product that may affect some patients’ ability to drive or operate machinery (see section 4.8).
In clinical trials including 1,723 patients treated with imipenem/cilastatin intravenous the most frequently reported systemic adverse reactions that were reported at least possibly related to therapy were nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension
(0.4%), seizures (0.4%) (see section 4.4), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Similarly, the most frequently reported local adverse reactions were phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein induration (0.2%). Increases in serum transaminases and in alkaline phosphatase are also commonly reported.
The following adverse reactions have been reported in clinical studies or during post-marketing experience.
All adverse reactions are listed under system organ class and frequency: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ Class Frequency Event
Infections and infestations Rare pseudomembranous colitis, candidiasis
Very rare gastro-enteritis
Blood and lymphatic system disorders
Common eosinophilia
Uncommon pancytopenia, neutropenia, leucopenia,
thrombocytopenia, thrombocytosis
Rare agranulocytosis
Very rare haemolytic anaemia, bone marrow depression
Immune system disorders Rare anaphylactic reactions
Psychiatric disorders Uncommon psychic disturbances including hallucinations
and confusional states
System Organ Class Frequency Event
Nervous system disorders Uncommon seizures, myoclonic activity, dizziness,
somnolence
Rare encephalopathy, paraesthesia, focal tremor, taste perversion
Very rare aggravation of myasthenia gravis, headache Not known agitation, dyskinesia
Ear and labyrinth disorders Rare hearing loss
Very rare vertigo, tinnitus
Cardiac disorders Very rare cyanosis, tachycardia, palpitations Vascular disorders Common thrombophlebitis
Uncommon hypotension
Very rare flushing
Respiratory, thoracic and mediastinal disorders
Very rare dyspnoea, hyperventilation, pharyngeal pain
Gastrointestinal disorders Common diarrhoea, vomiting, nausea
Medicinal product-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non- granulocytopenic patients treated with TIENAM
Rare staining of teeth and/or tongue
Very rare haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, increased salivation
Hepatobiliary disorders Rare hepatic failure, hepatitis
Very Rare fulminant hepatitis
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Common rash (e.g. exanthematous)
Uncommon urticaria, pruritus
Rare toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis
Very rare hyperhidrosis, skin texture changes
Very rare polyarthralgia, thoracic spine pain
Renal and urinary disorders Rare acute renal failure, oligurial/anuria, polyuria,
urine discoloration (harmless and should not be confused with haematuria)
The role of TIENAM in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present.
Reproductive system and breast disorders
General disorders and administration site conditions
Very rare pruritus vulvae
Uncommon fever, local pain and induration at the
injection site, erythema at the injection site
Very rare chest discomfort, asthenia/weakness
Investigations Common increases in serum transaminases, increases in
serum alkaline phosphatase
Uncommon A positive direct Coombs' test, prolonged
prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea
nitrogen
Paediatric population (≥3 months of age)
In studies of 178 paediatric patients ≥3 months of age, the reported adverse reactions were consistent with those reported for adults.
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
To report any side effect(s):
· Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa
· Other GCC States:
Please contact the relevant competent authority.
Symptoms of overdose that can occur are consistent with the adverse reaction profile; these may include seizures, confusion, tremors, nausea, vomiting, hypotension, bradycardia. No specific information is available on treatment of overdose with TIENAM. Imipenem-cilastatin sodium is haemodialyzable. However, usefulness of this procedure in the overdose setting is unknown.
Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems, ATC code: J01D H51 Mechanism of action
TIENAM consists of two components: imipenem and cilastatin sodium in a 1:1 ratio by weight.
Imipenem, also referred to as N-formimidoyl-thienamycin, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya.
Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolizes and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Similar to other beta-lactam antibacterial agents, the time that imipenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy.
Mechanism of resistance
Resistance to imipenem may be due to the following:
• Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins)
• Imipenem may be actively removed from the cell with an efflux pump.
• Reduced affinity of PBPs to imipenem
• Imipenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do generally express co-resistance to imipenem. There is no target-based cross-resistance between imipenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes.
Breakpoints
EUCAST MIC breakpoints for imipenem to separate susceptible (S) pathogens from resistant (R) pathogens are as follows (v 1,1 2010-04-27):
• Enterobacteriaceae 1: S ≤2 mg/l, R >8 mg/l
• Pseudomonas spp. 2: S ≤4 mg/l, R >8 mg/l
• Acinetobacter spp.: S ≤2 mg/l, R >8 mg/l
• Staphylococcus spp. 3: Inferred from cefoxitin susceptibility
• Enterococcus spp.: S ≤4 mg/l, R >8 mg/l
• Streptococcus A, B, C, G: The beta-lactam susceptibility of beta-haemolytic streptococcus
groups A, B, C and G is inferred from the penicillin susceptibility.
• Streptococcus pneumoniae 4: S ≤2 mg/l, R >2 mg/l
• Other streptococci 4: S ≤2 mg/l, R >2 mg/l
• Haemophilus influenzae 4: S ≤2 mg/l, R >2 mg/l
• Moraxalla catarrhalis 4: S ≤2 mg/l, R >2 mg/l
• Neisseria gonorrhoeae: There is insufficient evidence that Neisseria gonorrhoeae is a good target for therapy with imipenem.
• Gram-positive anaerobes: S ≤2 mg/l, R >8 mg/l
• Gram-negative anaerobes: S ≤2 mg/l, R >8 mg/l
• Non-species related breakpoints 5: S ≤2 mg/l, R >8 mg/l
1 Proteus and Morganella species are considered poor targets for imipenem.
2 The breakpoints for Pseudomonas relate to high dose frequent therapy (1g every 6 hours).
3 Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.
4 Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
5 Non-species related breakpoint have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the overview of species-related breakpoints or footnotes.
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species: |
Gram-positive aerobes:
Enterococcus faecalis
Staphylococcus aureus (Methicillin-susceptible)* Staphylococcus coagulase negative (Methicillin-susceptible) Streptococcus agalactiae
Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans group
Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Serratia marcescens
Gram-positive anaerobes: Clostridium perfringens** Peptostreptococcus spp.**
Gram-negative anaerobes: Bacteroides fragilis Bacteroides fragilis group Fusobacterium spp.
Porphyromonas asaccharolytica Prevotella spp.
Veillonella spp.
Species for which acquired resistance may be a problem: |
Gram-negative aerobes: Acinetobacter baumannii Pseudomonas aeruginosa
Inherently resistant species: |
Gram positive aerobes:
Enterococcus faecium
Gram negative aerobes:
Some strains of Burkholderia cepacia (formerly Pseudomonas cepacia) Legionella spp.
Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia, formerly Pseudomonas maltophilia)
Others: |
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Ureoplasma urealyticum
* All methicillin-resistant staphylococci are resistant to imipenem/cilastatin.
** EUCAST non-species related breakpoint is used.
Imipenem
Absorption
In normal volunteers, intravenous infusion of TIENAM over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 μg/ml for the 250 mg/250 mg dose, from 21 to 58 μg/ml for the 500 mg/500 mg dose, and from 41 to 83 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of imipenem following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg /1000 mg
doses were 17, 39, and 66 μg/ml, respectively. At these doses, plasma levels of imipenem decline to below 1 μg/ml or less in four to six hours.
Distribution
The binding of imipenem to human serum proteins is approximately 20%.
Biotransformation
When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies.
Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits metabolism of imipenem so that concomitant administration of imipenem and cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both urine and plasma.
Elimination
The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10 µg/ml for up to eight hours after a
500 mg/500 mg dose of TIENAM. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.
No accumulation of imipenem in plasma or urine has been observed with regimens of TIENAM, administered as frequently as every six hours, in patients with normal renal function.
Cilastatin
Absorption
Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of TIENAM, ranged from 21 to 26 μg/ml for the 250 mg/250 mg dose, from 21 to 55 μg/ml for the 500 mg/500 mg dose and from 56 to 88 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of cilastatin following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22, 42, and
72 µg/ml respectively.
Distribution
The binding of cilastatin to human serum proteins is approximately 40%.
Biotransformation and elimination
The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10 hours of administration of TIENAM. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Activity of dehydropeptidase-I in the kidney returned to normal levels shortly after the elimination of cilastatin from the blood stream.
Pharmacokinetics in special populations Renal insufficiency
Following a single 250 mg/250 mg intravenous dose of TIENAM, the area under the curve (AUCs)
for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold in subjects with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m2), moderate (CrCL 30-<50 ml/min/1.73 m2), and severe (CrCL
<30 ml/min/1.73 m2) renal impairment, respectively, compared to subjects with normal renal function (CrCL >80 ml/min/1.73 m2), and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Following a single 250 mg/250 mg intravenous dose of TIENAM given
24 hours after haemodialysis, AUCs for imipenem and cilastatin were 3.7-fold and 16.4-fold higher, respectively, as compared to subjects with normal renal function. Urinary recovery, renal clearance
and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of TIENAM. Dose adjustment is necessary for patients with impaired renal function (see section 4.2).
Hepatic insufficiency
The pharmacokinetics of imipenem in patients with hepatic insufficiency have not been established. Due to the limited extent of hepatic metabolism of imipenem, its pharmacokinetics are not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment (see section 4.2).
Paediatric population
The average clearance (CL) and volume of distribution (Vdss) for imipenem were approximately 45% higher in paediatric patients (3 months to 14 years) as compared to adults. The AUC for imipenem following administration of 15/15 mg/kg per body weight of imipenem/cilastatin to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the exposure following administration of 25/25 mg/kg imipenem/cilastatin to children was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg dose.
Elderly
In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of TIENAM 500 mg/500 mg administered intravenously over
20 minutes were consistent with those expected in subjects with slight renal impairment for which no dose alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin were 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity studies.
Animal studies showed that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Co-administration of cilastatin with imipenem in a 1:1 ratio prevented the nephrotoxic effects of imipenem in rabbits and monkeys. Available evidence suggests that cilastatin prevents the nephrotoxicity by preventing entry of imipenem into the tubular cells.
A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40/40 mg/kg/day (bolus intravenous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhoea, abortion, and death in some cases. When doses of imipenem-cilastatin sodium (approximately 100/100 mg/kg/day or approximately 3 times the usual recommended daily human intravenous dose) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups (see section 4.6).
Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin.
Sodium bicarbonate
This medicinal product is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate. However, it can be administered into an I.V. system through which a lactate solution is being infused.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Do not store above 25 °C.
Do not freeze the reconstituted solution.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
20 ml Type I glass vials.
The medicinal product is supplied in packs of 1 vial, 10 vials and 25 vials. Not all pack sizes may be marketed.
Each vial is for single use only. Reconstitution:
Contents of each vial must be transferred to 100 ml of an appropriate infusion solution (see sections
6.2 and 6.3): 0.9% sodium chloride. In exceptional circumstances where 0.9% sodium chloride cannot be used for clinical reasons 5% glucose may be used instead.
A suggested procedure is to add approximately 10 ml of the appropriate infusion solution to the vial. Shake well and transfer the resulting mixture to the infusion solution container.
CAUTION: THE MIXTURE IS NOT FOR DIRECT INFUSION.
Repeat with an additional 10 ml of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear.
The concentration of the reconstituted solution following the above procedure is approximately 5 mg/ml for both imipenem and cilastatin.
Variations of colour, from colourless to yellow, do not affect the potency of the product.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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