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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Properties
Tinzaparin sodium is a low molecular weight heparin
produced by enzymatic depolymerization of
conventional heparin.
The molecular mass is between 1,000 and 14,000 dalton,
with a peak maximum molecular mass of approx. 4,500
dalton. Tinzaparin sodium is an anti-thrombotic agent.
innohep® has a bioavailability of about 90% following
subcutaneous injection. The absorption half-life is 200
minutes, peak plasma activity being observed after
4–6 hours.
The elimination half-life is about 80 minutes. Tinzaparin
sodium is eliminated, primarily with the urine, as
unchanged drug.
The pharmacokinetics/pharmacodynamics of innohep®
are monitored by anti-Xa activity. There is a linear doseresponse
relationship between plasma activity and the
dose administered.
The biological activity of innohep® is expressed in
international units anti-Xa.
Indications
Treatment of deep-vein thrombosis and pulmonary
embolism.
Prevention of postoperative deep-vein thrombosis in
patients undergoing general and orthopaedic surgery.
Prevention of clotting in in-dwelling intravenous lines
for extracorporeal circulation and haemodialysis.


Contraindications
Known hypersensitivity to any of the constituents.
The 20,000 IU anti-Xa/ml formulation of innohep®
contains sodium metabisulphite, which may cause
allergic reactions, including anaphylaxis in predisposed
patients. In the remaining formulations without sulphite,
this risk does not exist.
Other contraindications are generalized or local
haemorrhagic tendency. Uncontrolled severe
hypertension. Acute cerebral insults. Septic
endocarditis.
For vials only:
innohep® vials contain 10 mg/ml of the preservative
benzyl alcohol. These formulations must not be given to
premature babies and neonates due to the risk of
gasping syndrome.
Special precautions
innohep® should be given with caution to patients with
hepatic insufficiency. Precaution is recommended in
the treatment of patients with severe renal impairment
(creatinine clearance < 30 ml/min).
Precaution is recommended in the treatment of elderly
patients with renal impairment. Renal function should
be assessed and in patients with severe renal
impairment (creatinine clearance < 30 ml/min),
monitoring of anti-factor Xa activity should be
considered.
innohep® should not be administered by intramuscular
injection due to risk of local haematoma formation.
Patients receiving innohep® concurrently with spinal or
epidural anaesthesia should be closely monitored for
signs or symptoms of neurological injury.
Interactions
Concomitant administration of other drugs affecting
haemostasis, e.g. vitamin K antagonists and dextran,
may enhance the anticoagulant effect of innohep®.
Use during Pregnancy and Lactation
Data on a number (637) of exposed pregnancies
indicate no additional risk of tinzaparin on pregnancy or
on the health of the foetus / new-born child. No
transplacental passage was demonstrated in two (2)
clinical studies. Data from sequential pharmacokinetic
monitoring in 55 pregnancies suggest that
pharmacokinetic properties of tinzaparin do not differ
from the non-pregnant state.
Tinzaparin is not recommended for use in pregnant
women with prosthetic heart valves.
Caution should be exercised when prescribing tinzaparin to
pregnant women.
There are no data available concerning lactation.
For vials only:
Cases of "Gasping Syndrome" have occurred in
premature infants when large amounts of benzyl alcohol
have been administered (99-404 mg/Kg/day). Despite the
low content of benzyl alcohol in the vials (10 mg per ml),
as it may cross the placenta the use of innohep®
formulations containing benzyl alcohol is not
recommended during pregnancy.
Incompatibilities
innohep® is compatible with isotonic sodium chloride
(9 mg/ml) or isotonic glucose (50 mg/ml). It should not be
admixed with other infusion fluids.


Dosage
Treatment of DVT and PE:
The recommended dose is 175 IU anti-Xa/kg bodyweight
s.c. once daily.
Thromboprophylaxis in patients with moderate risk of
thrombosis (general surgery):
On the day of operation 3,500 IU anti-Xa s.c. 2 hours
before surgery and postoperatively once daily 3,500 IU
anti-Xa for 7–10 days.
Thromboprophylaxis in patients with high risk of
thrombosis (e.g. total hip replacement):
On the day of operation 4,500 IU anti-Xa s.c. 12 hours
before surgery or 50 IU anti-Xa/kg body-weight s.c.
2 hours before surgery and then once daily until the
patient has been mobilized.
For short-term haemodialysis (less than 4 hours):
A bolus dose of 2,000–2,500 IU anti-Xa into the arterial
side of the dialyser (or intravenously) at the beginning of
dialysis.
Long-term haemodialysis (more than 4 hours):
A bolus dose of 2,500 IU anti-Xa into the arterial side of
the dialyser (or intravenously) at the beginning of
dialysis, followed by an infusion of 750 IU anti-Xa /hour.
Dose adjustment: Increase or decrease of the bolus
dose, if required, can be made in steps of 250–500 IU
anti-Xa until a satisfactory response is obtained.
Elderly:
Renal function should be assessed with e.g. the
Cockcroft-Gault formula to estimate creatinine
clearance levels.
No dose reduction is needed in elderly patients with
normal renal function. (See Special precautions).
Renal impairment:
No dose reduction is needed in patients having
creatinine clearance levels down to 20 ml/min.
However, precaution is recommended when treating
patients with severe renal impairment (creatinine
clearance < 30 ml/min). (See Special precautions).

Overdose
An overdose of innohep® may be complicated by
haemorrhage. At recommended doses there should be
no need for an antidote, but in the event of accidental
administration of an overdose, the effect of innohep®
can be reversed by intravenous administration of 1%
protamine sulphate solution.
The dose of protamine sulphate required per
neutralization should be accurately determined by
titrating with the plasma of the patient. As a rule, 1 mg
of protamine sulphate neutralizes the effect of 100 IU
anti-Xa of tinzaparin.

Instructions for use of the innohep® syringes:
Wash your hands before you inject the medicine.
Wipe clean the skin around the injection site with spirit
and let it dry – do not rub.
Subcutaneous injection of innohep® should be carried
out according to the following steps:

1. Open the tube bending the
coloured lid all the way back
and remove the syringe.
Inspect the content of the
syringe before you use it. If
you observe cloudiness or
precipitate in the medicine, do
not use it but take another
syringe. The medicine may
turn yellow during storage but
can still be used if the solution
is clear.
2. Bend the safety device down
away from the cap on the
needle.
3. Remove the protective needle
cap without bending the
needle. Adjust the syringe to
the dose prescribed by your
doctor. Remove the remaining
solution by pressing the
plunger in vertical position.
Do not pull back the plunger
and do not press out the air
bubble. If the air bubble is not
placed right by the plunger,
then tap lightly on the syringe
until the air bubble is in place.
4. Hold a skin fold loosely
between thumb and index
finger of one hand and with
the other hand insert the
needle vertically at the skin
fold, at a right angle to the
skin.
5. Slowly inject the required
dose into the fatty tissue of
e.g. the abdominal skin, the
extensor sides of the thigh,
lower back or upper arm.
Wait a few seconds to give
the solution time to distribute
before you remove the needle
and release the skin fold.
6. Wipe off any blood with a tissue. Choose a different
injection site next time (for instance, move from the
left to the right of the abdomen).
7. Bend the safety device back
to its original position so it is
now underneath the needle.
Then with the safety device
flat against a hard surface,
push downwards until the
needle locks into the device.
8. You can either place the used
syringe in the tube with the
needle downwards or you can
put the used syringe into a
sharps container. The syringe
is now secured, and the tube
or sharps container can be
handed over for destruction at
the hospital or by the pharmacist.

 


Adverse effects
innohep® is safe with regard to bleeding risks, when
applied at the doses recommended, provided that
patients with increased bleeding potential (bleeding
disorders, severe thrombocytopenia) are excluded or
treated with special care.
Priapism and skin necrosis have been reported in only
a few cases.


Storage condition
Do not store above 30°C.


10 Vials of 2 ml
Tinzaparin sodium 10,000 IU anti-Xa/ml, preserved with
benzyl alcohol (10 mg/ml).
Tinzaparin sodium 20,000 IU anti-Xa/ml, preserved with
benzyl alcohol (10 mg/ml), stabilized with sodium
metabisulphite.
10 Pre-filled syringes with needle safety device of
0.25ml, 0.35ml or 0.45ml
Tinzaparin sodium 10,000 IU anti-Xa/ml.
2 Pre-filled syringes with needle safety device of 0.5ml,
0.7ml or 0.9ml
Tinzaparin sodium 20,000 IU anti-Xa/ml, stabilized with
sodium metabisulphite.


10 Vials of 2 ml Tinzaparin sodium 10,000 IU anti-Xa/ml, preserved with benzyl alcohol (10 mg/ml). Tinzaparin sodium 20,000 IU anti-Xa/ml, preserved with benzyl alcohol (10 mg/ml), stabilized with sodium metabisulphite. 10 Pre-filled syringes with needle safety device of 0.25ml, 0.35ml or 0.45ml Tinzaparin sodium 10,000 IU anti-Xa/ml. 2 Pre-filled syringes with needle safety device of 0.5ml, 0.7ml or 0.9ml Tinzaparin sodium 20,000 IU anti-Xa/ml, stabilized with sodium metabisulphite.

Marketing Authorization Holder: LEO Pharma A/S, Denmark


This leaflet was last revised in October 2015
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

الخصائص:

تينزابارين الصوديوم هو هيبارين منخفض الوزن الجزيئي، تنتجه إزالة البلمرة الإنزيمية للهيبارين التقليدي.

الكتلة الجزيئية تتراوح ما بين 1000 و 14000 دالتون، مع كتلة جزيئية بذروة قصوى تبلغ 4500 دالتون تقريباً. تينزابارين الصوديوم هو عامل مضاد للجلطات.

لإنّوهيب® التوافر البيولوجي بحوالي 90% بعد الحقن تحت الجلد. امتصاص نصف العمر هو 200 دقيقة. وقد لوحظ ذروة نشاط البلازما بعد 4-6 ساعات.

نصف عمر التخلص هو حوالي 80 دقيقة. يتم التخلص من تينزابارين الصوديوم، في المقام الأول مع البول، كعقار غير متغير.

لقد تم رصد حرية ومبحث تأثير الدواء لدى إنّوهيب® بواسطة أنشطة مضاد – إكس إيه. ووجد أن هنالك علاقة استجابية خطية للدواء بين نشاط البلازما والجرعة المعطاة.

يُعرب عن نشاط البيولوجي لإنّوهيب® في الوحدات الدولية لمضاد – إكس إيه.

دواعي الاستعمال:

علاج تجلط الأوردة العميقة والانسداد الرئوي:

الوقاية من جلطة الأوردة العميقة ما بعد الجراحة لدى المرضى الذين أجروا الجراحة العامة وجراحة العظام.

منع تجلط الدم داخل الخطوط المسارية الوريدية خارج الجسم وعملية غسيل الكلى.

موانع الاستعمال

يحظر من تعاطي الدواء في حال الحساسية المفرطة لأي من مكونات الدواء.

إن 20000 وحدة دولية مضاد – إكس إيه / مل المصاغ من إنّوهيب® يحتوي على ميتا ثاني كبريتيت الصوديوم، الذي قد يسبب الحساسية، بما في ذلك الحساسية المفرطة لدى المرضى الميّالين لذلك. في التركيبات المتبقية، دون الكبريتيت، لا وجود للخطورة. الموانع الأخرى هي موانع عامة أو موضعية وجود ميل بؤري للنزيف. ارتفاع ضغط الدم الشديد غير المتحكم فيه. الإصابة الدماغية الحادة. تقيح الشغاف (التهابات بطانة القلب).

لقوارير فقط:

تحتوي قارورة إنّوهيب® على 10 ملجم / مل من المادة الحافظة كحول البنزيل. يجب مراعاة عدم إعطاء هذه الصيغ للرضيع الخديج وحديثي الولادة ويعود ذلك لخطر ظهور أعراض متلازمة اللهث.

الاحتياطات الخاصة

ينبغي إعطاء إنّوهيب® بحذر لمرضى القصور الكبدي.

ينصح بالتحوط في علاج مرضى الفشل الكلوي الحاد (تصفية الكرياتينين < 30 مل / دقيقة).

ينصح بالحذر في علاج المرضى المسنين الذين يعانون من القصور الكلوي. يجب تقييم وظائف الكلى لدى مرضى القصور الكلوي الحاد (تصفية الكرياتينين < 30 مل / دقيقة)، وينبغي رصد العوامل المضادة لنشاط إكس إيه.

يجب مراقبة المرضى الذين يتعاطون إنّوهيب® عن كثب تزامناً مع التخدير النخاعي أو التخدير فوق الجافية لأي علامات أو أعراض للإصابات العصبية.

التفاعلات

تعاطي الدواء مع أدوية أخرى ذات تأثير على إيقاف النزيف الدموي، مثل مضادات فيتامين ك وديكستران، قد تعزز من فعالية تأثير مضاد التجلد لإنّوهيب®.

الاستعمال أثناء الحمل والرضاعة

لا تشير بيانات كم عدد (637) من حالات الحمل عن أي مخاطر إضافية من جراء تناول تينزابارين على الحمل أو على صحة الجنين / المولود الجديد. وقد ثبت عدم المرور والوصول إلى خلايا المشيمة من خلال دراستين (2) سريريتين تحليليتين. وقد أوحت البيانات المستمدة من رصد الحركة الدوائية في 55 حالة متتابعة لنساء حوامل تشير إلى خواص الحركة الدوائية في تينزابارين لا تختلف عن تلك الخواص لدى النساء غير الحوامل.

لا ينصح بتناول تينزابارين لدى النساء الحوامل اللواتي لهن صمامات قلب اصطناعية.

ينبغي توخي الحذر عند وصف تينزابارين للنساء الحوامل. لا توجد بيانات متاحة تتعلق بالرضاعة.

للقوارير فقط

وقعت حالات "متلازمة اللهث" لدى الخدج عند تناول كميات كبيرة من كحول البنزيل (66-404 مجم / كجم / يومياً). على الرغم من المحتوى المنخفض لكحول البنزيل في قارورة (10 ملجم لكل مل)، وذلك لاحتمال عبوره المشيمة، لهذا لا ينصح باستعمال مستحضرات إنّوهيب® التي تحتوي على كحول البنزيل أثناء الحمل.

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الجرعة

علاج تجلط الأوردة العميقة والانسداد الرئوي:

الجرعة الموصى بها هي 175 وحدة دولية مضاد – إكس إيه / مل / كجم من وزن الجسم مضاد – إكس إيه بالحقن تحت الجلد، مرة واحدة يومياً.

الجرعات العلاجية الوقائية للتجلط لدى المرضى الذين يعانون من مخاطر معتدلة للتجلط (جراحة عامة):

تُعطى جرعة مقدارها 3500 وحدة دولية مضاد – إكس إيه / مل بالحقن تحت الجلد، قبل ساعتين من إجراء العملية الجراحية، و 3500 وحدة دولية مضاد – إكس إيه / مل بعد العملية مرة واحدة يومياً لمدة 7 - 10 أيام.

الجرعات العلاجية الوقائية للتجلد لدى المرضى الذين يعانون من مخاطر عالية للتجلد (مثل الاستبدال الكلي للورك):

تُعطى في يوم العملية جرعة مقدارها 4.500 وحدة دولية مضاد – إكس إيه / مل بالحقن تحت الجلد قبل 12 ساعة من الجراحة، أو 50 وحدة دولية مضاد – إكس إيه / كجم من وزن الجسم بالحقن تحت الجلد قبل ساعتين من إجراء العملية الجراحية، ومن ثم مرة يومياً إلى أن يتسنى للمريض التحرك ومغادرة الفراش.

غسيل الكلى على المدى القصير (أقل من 4 ساعات):

تُعطى جرعة كاملة مقدارها 2000 – 2500 وحدة دولية مضاد – إكس إيه داخل الجانب الشرياني من جهاز الاستفزاز) dialyser (أو عن طريق الوريد) عند بداية غسيل الكلى.

غسيل الكلى على المدى الطويل (أكثر من 4 ساعات):

تُعطى جرعة كاملة مقدارها 2000 – 2500 وحدة دولية مضاد – إكس إيه / مل داخل الجانب الشرياني من جهاز الاستفزاز) dialyser (أو عن طريق الوريد) عند بداية غسيل الكلى، يليها تسريب 750 و. د/ ساعة مضاد – إكس إيه.

تضبيط الجرعة: إذا لزم الأمر زيادة أو نقصان في الجرعات الكاملة، فذلك يمكن عمله بإعطاء جرعات من 250 – 500 وحدة دولية مضاد – إكس إيه حتى يتم الحصول على استجابة مرضية.

كبار السن:

ينبغي تقييم وظائف الكلى مع، على سبيل المثال، صيغة كوكروفت – غولت لتقدير مستويات تصفية الكرياتينين.

لا حاجة لخفض الجرعة لدى المرضى المسنين ذوي تقييم وظائف الكلى الطبيعية (انظر الاحتياطات الخاصة).

الاختلال الكلوي:

لا حاجة لخفض الجرعة لدى المرضى الذين يعانون من مستويات تصفية الكرياتينين وصولاً إلى 20 مل / دقيقة، ومع ذلك، يتوخى الحذر عند علاج المرضى الذين يعانون من القصور الكلوي الشديد (تصفية الكرياتينين < 30 مل / دقيقة). (انظر الاحتياطات الخاصة).

الإفراط في الجرعة

قد يؤدي تجاوز الجرعة العلاجية من إنّوهيب® إلى نزيف دموي. لا حاجة لإعطاء الترياق حين تعاطي الجرعة الموصى بها. إلا أنه عند تجاوز الجرعة وفي الحالات الطارئة، يمكن عكس تأثر لإنّوهيب® بواسطة تسريب 1% من محلول كريبتات البروتامين داخل الوريد. ينبغي أن تكون جرعات كبريتات البروتامين يعادل 100 وحدة دولية مضاد – إكس إيه من تينزابارين.

 

غسيل اليدين قبل القيام بحقن الدواء. مسح وتنظيف ما حول موضع الحقن بمحلول كحولي وارتكه ليجف. يجب مراعاة – عدم التدليك (الدعك).

يجب مواصلة عملية حقن إنّوهيب® تحت الجلد وفقاً للخطوات التالية:

1- فتح الأنبوبة برفع الغطاء الملون للأنبوبة وثنيه للخلف تماماً وإزالة

الحقنة (الإبرة).

تفقد جيداً محتوى الحقنة قبل الاستعمال.

إذا تمت ملاحظة غيوم أو وجود ترسبات في الدواء يجب عدم استعماله، واستعمال حقنة أخرى.

قد يتغير لون الدواء للون أصفر أثناء التخزين، إلا أنه يمكن استعمال الدواء إذا كان المحلول صافياً.

 
 

 

 

 

2- ابعد نظام الأمان بثنيه عن خطاء رأس الحقنة (الإبرة الواقي.

 

3- إزالة الغطاء الواقي لإبرة الحقن بدون ثني الإبرة. تعديل وضبط

الجرعة وفقاً لما وصفه الطبيب. إزالة بقايا المحلول بالضغط عمودياً

على الغطاس (المكسب) يجب مراعاة عدم سحب الغطاس (المكبس)،

ولا تضغط فقاقات الهواء للخارج. إذا لم تكن فقاقات الهواء في مكانها الصحيح بواسطة الغطاس (المكسب)، فهنا يتم النقر خفيفاً ويرفق على الحقنة حتى تأخذ الفقاقات مكانها.

4- ثني طية جلدية بين الإبهام والسبابة بيد وباليد الأخرى إدخال

إبرة الحقن عمودياً في طية (ثنية) الجلد، وفي الزاوية الصحيحة.

 

5- حقن الجرعة المطلوبة ببطء إلى داخل الأنسجة الدهنية

وعلى سبيل المثال الجلد البطني، العضلة الباسطة من جانبي الفخذ،

أسفل الظهر أو أعلى الذراع، انتظر بضعة ثواني لإعطاء المحلول

وقتاً للتوزيع قبل إزالة إبرة الحقن وعودة ثنية الجلد لطبيعتها.

6- مسح وإزالة أي دم بمنديل / منشفة. يجب مراعاة اختيار موضع آخر للحقن في المرة القادمة (على سبيل المثال الانتقال من اليسار لليمين من البطن).

7- طي (ثني) جهاز الأمن وإعادته لموضعه الطبيعي تحت إبرة الحقن.

وبالاستناد إلى سطح صلد، على طول إبرة الحقن. ثم الضغط لأسفل

حتى يتم وضع الإبرة في داخل الجهاز.

- يمكن إعادة وضع إبرة الحقن المستعملة في الأنبوبة بتوجيه رأس

الإبرة نحو أسفل، ويمكن أيضاً رمي إبرة الحقن في مستودع جمع إبر

الحقن المستعملة. وبهذه الطريقة تكون الأنبوبة أو إبر الحقن المستعملة

في مكان آمن في مستودع جمع إبر الحقن المستعملة، حيث يمكن تسليمها للمستشفى أو للصيدلي

الآثار الجانبية

وكما هو الحال في كل الأدوية، يمكن أن يؤدي مرهم الفيوسيدين® لحدوث آثار جانبية، إلا أن هذا لا يشمل جميع الناس. الآثار الجانبية الهامة والتي يجب ملاحظتها جيداً: يجب الحصول على مساعدة طبيبة عاجلة وبوجه السرعة إذا كنت تعاني أي من الأعراض التالية. فقد تعاني من ارتكاس أرجي (تحسسي):

- صعوبة في التنفس.

- انتفاخ وتضخم في الوجه والحلق.

- تطور وظهور طفح جلدي حاد.

التأثيرات الجانبية الأخرى التي يمكن حدوثها:

- تأثيرات جانبية غير مألوفة (قد تؤثر على أقل من شخص واحد من بين 100 شخص).

- تهيجات في مواقع استعمال ودهن الكريم (تشمل آلام، تحرق (شعور بحرق)، شعور بلدغ (لسع) واحمرار جلدي).

- حكة.

- طفح جلدي.

إذا أصبحت أي من التأثيرات الجانبية خطيرة، أو لاحظتم حدوث أي تأثيرات جانبية غير واردة في هذه النشرة الطبية، الرجاء إبلاغ الطبيب أو الصيدلي.

شروط التخزين

يجب ألا يُخزن بدرجة حرارة تتجاوز الـ 30 درجة مئوية.

قوارير تحتوي كل منها على 2 مل

تينزابارين الصوديوم 10000 وحدة دولية مضاد – إكس آيه/ مل محفوظة بكحول البنزيل (10 ملجم/ مل).

تينزابارين الصوديوم 20000 وحدة دولية مضاد – إكس آيه/ مل محفوظة بكحول البنزيل (10 ملجم/ مل)، مثبتة بميتا ثاني كبريتيت الصوديوم.

10 حقن بتعبئة مسبقة مع جهاز أمان إبرة الحقن، تحتوي على 0,25 مل، 0,35 مل أو 0,45 مل.

تينزابارين الصوديوم 10000 وحدة دولية مضاد – إكس آيه/ مل

حقنتين (2 حقنة) بتعبئة مسبقة مع جهاز أمان إبرة الحقن، تحتوي على 0,5 مل، 0,7 مل أو 0,9 مل.

تينزابارين الصوديوم 20000 وحدة دولية مضاد – إكس آيه/ مل، مثبتة بميتا ثاني كبريتيت الصوديوم.

قوارير تحتوي كل منها على 2 مل

تينزابارين الصوديوم 10000 وحدة دولية مضاد – إكس آيه/ مل محفوظة بكحول البنزيل (10 ملجم/ مل).

تينزابارين الصوديوم 20000 وحدة دولية مضاد – إكس آيه/ مل محفوظة بكحول البنزيل (10 ملجم/ مل)، مثبتة بميتا ثاني كبريتيت الصوديوم.

10 حقن بتعبئة مسبقة مع جهاز أمان إبرة الحقن، تحتوي على 0,25 مل، 0,35 مل أو 0,45 مل.

تينزابارين الصوديوم 10000 وحدة دولية مضاد – إكس آيه/ مل

حقنتين (2 حقنة) بتعبئة مسبقة مع جهاز أمان إبرة الحقن، تحتوي على 0,5 مل، 0,7 مل أو 0,9 مل.

تينزابارين الصوديوم 20000 وحدة دولية مضاد – إكس آيه/ مل، مثبتة بميتا ثاني كبريتيت الصوديوم.

مالك حق التسويق: LEO Pharma A/S, Denmark

تاريخ آخر مراجعة للنشرة أكتوبر 2015
 Read this leaflet carefully before you start using this product as it contains important information for you

Innohep

One pre-filled syringe contains 20,000 anti-Xa IU/ml tinzaparin sodium and is available as: 8,000 anti-Xa IU/0.4 ml tinzaparin sodium 10,000 anti-Xa IU/0.5 ml tinzaparin sodium 12,000 anti-Xa IU/0.6 ml tinzaparin sodium 14,000 anti-Xa IU/0.7 ml tinzaparin sodium 16,000 anti-Xa IU/0.8 ml tinzaparin sodium 18,000 anti-Xa IU/0.9 ml tinzaparin sodium Excipients with known effect: Sodium metabisulfite (1.83 mg/mL) and sodium (up to 40 mg/mL). For the full list of excipients, see section 6.1.

Solution for injection, pre-filled syringes 1 ml syringe holding a colourless or straw-coloured liquid, free from turbidity and from precipitated particles.

Treatment of venous thrombosis and thromboembolic disease including deep vein thrombosis and pulmonary embolus in adults.

 

Extended treatment of venous thromboembolism and prevention of recurrences in adult patients with active cancer.

Some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alterna- tive treatment, such as surgery or thrombolysis, may be indicated.


Posology

Adults

175 anti-Xa IU/kg body weight given subcutaneously once daily for at least 6 days and until ade- quate oral anticoagulation is established.

 

Extended treatment in cancer patients

175 IU anti-Xa/kg dose given subcutaneously once daily. The recommended treatment duration is 6 months. Anticoagulant treatment beyond 6 months should be evaluated.

 

Neuraxial anaesthesia

Treatment doses of Innohep (175 IU/kg) are contraindicated in patients who receive neuraxial an- aesthesia, see section 4.3. If neuraxial anaesthesia is planned, Innohep should be discontinued at least 24 hours before the procedure is performed. Innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed.

 

Interchangeability

For interchangeability with other low molecular weight heparins, see section 4.4.

 

Paediatric population

The safety and efficacy of Innohep in children below 18 years have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

 

Renal impairment

If renal impairment is suspected, renal function should be assessed using a formula based on serum creatinine to estimate creatinine clearance level. Use in patients with a creatinine clearance level < 30 mL/minute is not recommended, as dosage in this population has not been established. Availa- ble evidence demonstrates no accumulation in patients with creatinine clearance levels down to 20 mL/min. When required in these patients, Innohep treatment can be initiated with anti-Xa monitor- ing, if the benefit outweighs the risk (see section 4.4: Renal impairment). In this situation, the dose of Innohep should be adjusted, if necessary, based on anti-factor Xa activity. If the anti-factor Xa level is below or above the desired range, the dose of Innohep should be increased or reduced re- spectively, and the anti-factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-factor Xa level is achieved. For guidance: mean levels between 4 and 6 hours after administration in healthy volunteers and patients without severe renal insufficiency have been between 0.5 and 1.5 IU/anti-factor Xa IU/ml. Anti-factor Xa activity determinations were by a chromogenic assay.

 

 

Elderly

Innohep should be used in the elderly in standard doses. Precaution is recommended in the treat- ment of elderly patients with renal impairment. If renal impairment is suspected, see section 4.2: Renal impairment and section 4.4: Renal impairment.

 

Method of administration

Parenteral products should be inspected visually prior to administration. Do not use if cloudiness or precipitate is observed. The liquid may turn yellow by storage but is still suitable.

Administration is by subcutaneous injection. This can be done in abdominal skin, the outer side of the thigh, lower back, upper leg or upper arm. Do not inject in the area around the navel, near scars

 

or in wounds. For abdominal injections, the patient should be in supine position, alternating the in- jections between left and right side. The air-bubble within the syringe should not be removed. Dur- ing the injection, the skin should be held in a fold.

 

Doses are administered in 1,000 IU increments facilitated by theInnohep 0.05 mL graduations on the syringes. The calculated dose, based on the patient’s body weight, should therefore be rounded up or down as appropriate. If necessary, any excess volume should be expelled, to achieve the ap- propriate dosage before subcutaneous injection.

 

Guide to appropriate dosages for different body weights - 175 IU/kg body weight subcuta- neously once daily

 

 

Kg*

International units (IU)

Injection volume (ml)

 

 

 

 

 

20,000

IU/ml in graduated syringes

32-37

6,000

0.30

38-42

7,000

0.35

43-48

8,000

0.40

49-54

9,000

0.45

55-59

10,000

0.50

60-65

11,000

0.55

66-71

12,000

0.60

72-77

13,000

0.65

78-82

14,000

0.70

83-88

15,000

0.75

89-94

16,000

0.80

95-99

17,000

0.85

100-105

18,000

0.90

*For patients weighing <32 kg or >105 kg, the same calculation as above should be used to estab- lish the appropriate dose/volume


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Current or history of immune-mediated heparin-induced thrombocytopenia (type II) (see section 4.4). Active major haemorrhage or conditions predisposing to major haemorrhage. Major haemorrhage is defined as fulfilling any one of these three criteria: a) occurs in a critical area or organ (e.g. intracranial, intraspinal, intraocular, retroperitoneal, itra- articular or pericardial, intra-uterine or intramuscular with compartment syndrome), b) causes a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or c) leads to transfusion of two or more units of whole blood or red blood cells. Septic endocarditis. Treatment doses of Innohep (175 IU/kg) are contraindicated in patients who receive neuraxial an- aesthesia. If neuraxial anaesthesia is planned, Innohep should be discontinued at least 24 hours be- fore the procedure is performed. Innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed. Patients should be closely moni- tored for signs and symptoms of neurological injury.

Haemorrhage

Caution is advised when administering Innohep to patients at risk of haemorrhage. For patients at risk of major haemorrhage see section 4.3. The combination with medicinal products affecting platelet function or the coagulation system should be avoided or carefully monitored (see section 4.5).

 

Intramuscular injections

Innohep should not be administered by intramuscular injection due to the risk of haematoma. Due to the risk of haematoma, concomitant intramuscular injections should also be avoided.

 

Heparin-induced thrombocytopenia

Platelet count should be measured before the start of treatment and periodically thereafter, because of the risk of immune-mediated heparin-induced thrombocytopenia (type II). Innohep must be dis- continued in patients who develop immune-mediated heparin-induced thrombocytopenia (type II) (see section 4.3 and 4.8). Platelet counts will usually normalise within 2 to 4 weeks after with- drawal.

Regular monitoring of platelet count also applies to extended treatment for cancer associated thrombosis, especially during the first month, considering that cancer and its treatments such as chemotherapy may also cause thrombocytopenia.

 

Hyperkalaemia

Heparin products can suppress adrenal secretion of aldosterone, leading to hyperkalaemia. Risk factors include diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium at pre-treatment, concomitant therapy with drugs that may elevate plasma potas- sium, and long-term use of Innohep. In patients at risk, potassium levels should be measured before starting Innohep and monitored regularly thereafter. Heparin-related hyperkalaemia is usually re- versible upon treatment discontinuation, though other approaches may need to be considered if Innohep treatment is considered lifesaving (e.g. decreasing potassium intake, discontinuing other drugs that may affect potassium balance).

 

Prosthetic heart valves

Therapeutic failures have been reported in patients with prosthetic heart valves on full anti-coagu- lant doses of Innohep and other low molecular weight heparins. Innohep is not recommended for use in this population.

 

Renal impairment

Use in patients with a creatinine clearance level < 30 mL/minute is not recommended, as dosage in this population has not been established. Available evidence demonstrates no accumulation in pa- tients with creatinine clearance levels down to 20 mL/minute. When required in these patients, Innohep treatment can be used cautiously with anti-Xa monitoring, if the benefit outweighs the risk (see section 4.2). Although anti-Xa monitoring remains a poor predictor of haemorrhage risk, it is the most appropriate measure of the pharmacodynamic effects of Innohep.

 

Elderly

Elderly are more likely to have reduced renal function (see section 4.4: Renal impairment); there- fore caution should be exercised when prescribing Innohep to the elderly.

 

Interchangeability

Low molecular weight heparins should not be used interchangeably because of differences in pharmacokinetics and biological activities. Switching to an alternative low molecular weight heparin, especially during extended use, must be exercised with particular caution and specific dosing instructions for each proprietary product must be followed.

 

Excipients warnings

Innohep 20,000 anti-Xa IU/mL contains sodium metabisulfite. Metabisulfites may rarely cause se- vere hypersensitivity reactions and bronchospasm. Innohep formulations containing sodium meta- bisulfite must be used with caution in patients with asthma.

 

This medicinal product contains up to 40 mg sodium per mL. The amount 40 mg is equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.


The anticoagulant effect of Innohep may be enhanced by other drugs affecting the coagulation sys- tem, such as those inhibiting platelet function (e.g. acetylsalicylic acid and other non-steroidal anti- inflammatory drugs), thrombolytic agents, vitamin K antagonists, activated protein C, direct factor Xa and IIa inhibitors. Such combinations should be avoided or carefully monitored (see section 4.4).

Pregnancy and lactation

 

Fertility

There are no clinical studies with Innohep regarding fertility.

 

Pregnancy

Anticoagulant treatment of pregnant women requires specialist involvement.

 

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive tox- icity (see section 5.3).

 

A large amount of data on pregnant women (more than 2,200 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of tinzaparin. Tinzaparin does not cross the placenta. Innohep can be used during all trimesters of pregnancy if clinically needed.

 

Epidural anaesthesia:

Due to the risk of spinal haematoma, treatment doses of Innohep (175 IU/kg) are contraindicated in patients who receive neuraxial anaesthesia. Therefore, epidural anaesthesia in pregnant women should always be delayed until at least 24 hours after administration of the last treatment dose of Innohep. Prophylactic doses may be used as long as a minimum delay of 12 hours is allowed be- tween the last administration of Innohep and the needle or catheter placement.

 

Pregnant women with prosthetic heart valves:

Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full an- ticoagulant doses of Innohep and other low molecular weight heparins. Innohep cannot be recom- mended for use in this population.

 

Breast-feeding

Animal data indicate that Innohep excretion into breast milk is minimal.

 

It is unknown whether tinzaparin is excreted into human milk. Although oral absorption of low mo- lecular weight heparins is unlikely, a risk to newborns/infants cannot be excluded. In patients at risk, the incidence of venous thromboembolism is particularly high during the first six weeks after child birth. A decision must be made whether to discontinue breast-feeding or to discontinue/ab- stain from Innohep therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.


innohep® has no or negligible influence on the ability to drive and use machines.


innohep® has no or negligible influence on the ability to drive and use machines.


The most frequently reported undesirable effects are haemorrhage events, anaemia secondary to haemorrhage and injection site reactions.

 

Haemorrhage may present in any organ and have different degrees of severity. Complications may occur particularly when high doses are administered. Although major haemorrhages are uncom- mon, death or permanent disability has been reported in some cases.

 

Immune-mediated heparin-induced thrombocytopenia (type II) largely manifests within 5 to 14 days of receiving the first dose. Furthermore, a rapid-onset form has been described in patients pre- viously exposed to heparin. Immune-mediated heparin-induced thrombocytopenia (type II) may be associated with arterial and venous thrombosis. Innohep must be discontinued in all cases of im- mune-mediated heparin-induced thrombocytopenia (see section 4.4).

 

In rare cases, Innohep may cause hyperkalaemia due to hypoaldosteronism. Patients at risk include those with diabetes mellitus or renal impairment (see section 4.4).

 

Serious allergic reactions may sometimes occur. These include rare cases of skin necrosis, toxic skin eruption (e.g. Stevens-Johnson syndrome), angioedema and anaphylaxis. Treatment should be promptly discontinued at the slightest suspicion of such severe reactions.

 

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical studies and from spontaneous reporting.

 

Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

 

Very common (≥1/10) Common ≥1/100 and (<1/10)

Uncommon (≥1/1,000 and <1/100) Rare (≥1/10,000 and <1/1,000)

Very rare (<1/10,000), unknown (could not be estimated from currently available data)

 

Blood and lymphatic system disorders

Common ≥1/100 and <1/10

Anaemia (incl. haemoglobin decreased)

Uncommon ≥1/1,000 and <1/100

Thrombocytopenia (type I) (incl. platelet count de- creased)

Rare ≥1/10,000 and <1/1,000

Heparin-induced thrombocytopenia (type II) Thrombocytosis

Immune system disorders

Uncommon ≥1/1,000 and <1/100

Hypersensitivity

Rare ≥1/10,000 and <1/1,000

Anaphylactic reaction

Metabolism and nutrition disorders

Rare ≥1/10,000 and <1/1,000

Hyperkalaemia

Vascular disorders

Common ≥1/100 and <1/10

Haemorrhage Haematoma

Uncommon ≥1/1,000 and <1/100

Bruising, ecchymosis and purpura

Hepatobiliary disorders

Uncommon ≥1/1,000 and <1/100

Hepatic enzyme increased (incl. increased trans- aminases, ALT, AST and GGT)

Skin and subcutaneous tissue disorders

Uncommon ≥1/1,000 and <1/100

Dermatitis (incl. dermatitis allergic and bullous)

 

 

 

Rash Pruritus

Rare ≥1/10,000 and <1/1,000

Toxic skin eruption (including Stevens-Johnson syndrome)

Skin necrosis Angioedema

Urticaria

Musculoskeletal and connective tissue disorders

Rare ≥1/10,000 and <1/1,000

Osteoporosis (in connection with long-term treat- ment)

Reproductive system and breast disorders

Rare ≥1/10,000 and <1/1,000

Priapism

General disorders and administration site conditions

Common ≥1/100 and <1/10

Injection site reaction (incl. injection site haema- toma, haemorrhage, pain, pruritus, nodule, ery- thema and extravasation)

 

Patients with cancer on extended treatment

In a trial of patients with cancer on extended (6 months) treatment with Innohep, the overall fre- quency of adverse reactions was comparable to that seen in other patients treated with Innohep. Pa- tients with cancer generally have an increased risk of haemorrhage, which is further influenced by older age, comorbidities, surgical interventions and concomitant medications. Thus, as expected, the incidence of haemorrhagic events was higher than previously observed in short-term use, and similar to the rates seen with extended use of anticoagulants in patients with cancer.

 

Paediatric population

Limited information derived from one study and post-marketing data indicates that the pattern of adverse reactions in children and adolescents is comparable to that in 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:

 

Danish Medicines Agency Axel Heides Gade 1

DK-2300 Copenhagen S

Homepage: www.meldenbivirkning.dk


Haemorrhage is the main complication of overdose. Due to the relatively short half-life of Innohep (see section 5.2), minor haemorrhages can be managed conservatively following treatment discon- tinuation. Serious haemorrhage may require the administration of the antidote protamine sulphate. Patients should be carefully monitored.


Tinzaparin sodium is a low molecular weight heparin of porcine origin with an anti-Xa/anti-IIa ra- tio between 1.5 and 2.5. Tinzaparin sodium is produced by enzymatic depolymerisation of conven- tional unfractionated heparin. Like conventional heparin, tinzaparin sodium acts as an anticoagu- lant by potentiating antithrombin III's inhibition of activated coagulation factors, primarily factor Xa.

 

The biological activity of tinzaparin sodium is standardised against the current "International stand- ards for low molecular weight heparins", and expressed in anti-Xa international units (IU).

 

The anti-Xa activity of tinzaparin sodium is not less than 70 and not more than 120 IU/mg. The anti-IIa activity of tinzaparin sodium is approximately 55 IU/mg. The characteristic value of the mass-average molecular mass of tinzaparin sodium is about 6,500. The mass percentage of chains lower than 2,000 is not more than 10.0 %. The mass percentage of chains between 2,000 and 8,000 ranges between 60.0 and 72.0 % (typical 66%). The mass percentage of chains above 8,000 ranges between 22.0 and 36.0 %.


The absolute bioavailability based on anti-Xa activity after subcutaneous administration is approximately 90% and time to reach maximal activity is 4-6 hours. The terminal elimination half-life is approximately 3.7 hours. Due to the long half-life of the pharmacological effect for Innohep, once daily administration is sufficient.

 

Tinzaparin sodium undergoes minor metabolisation in the liver through a depolymerisation and is excreted via the kidneys as an unchanged or almost unchanged form.

 

The pharmacokinetic activity of Innohep has been studied in pregnant women. Data from sequen- tial pharmacokinetic monitoring of 55 pregnant women indicate that the pharmacokinetic proper- ties do not differ from the pharmacokinetic properties in non-pregnant women. There was a slight, but non-statistically significant drop in anti-Xa levels as the pregnancy progressed. Some monitor- ing of peak anti-Xa levels 4 hours after administration of tinzaparin sodium is recommended in the first weeks of treatment as well as later in the pregnancy.

 

Paediatric population

Preliminary data on the use of tinzaparin suggest that younger children including neonates and infants clear tinzaparin faster and therefore might require higher doses than older children.

However, data are not sufficient to allow for dosing recommendations, see section 4.2.


Heparins and low molecular weight heparins (LMWH) are generally only slightly toxic, and this applies for tinzaparin sodium as well. The most important effect observed in studies of acute, sub- acute and chronic toxicity, reproduction toxicity and mutagenicity is haemorrhaging caused by the very high doses administered.

 

After intramuscular administration of LMWH in animals necrotising haematoma was observed. Osteoporotic effects were revealed in a 12 months study in rats. Animal studies in rats and rabbits did not show a teratogenic potential of LMWH in doses up to 25 mg/kg body weight. Fetuses which were prenatally exposed to 10 mg/kg body weight were found to have lower body weights than controls.


Sodium metabisulfite (E223)

Sodium hydroxide

 

Water for injections


This medicinal product must not be mixed with other medicinal products.


3 years

This medicinal product does not require any special storage conditions.


Pre-filled syringe (graduated), with protective cap, plunger and needle safety device Pack sizes: 2, 6, 10, 30, 50 and 100 injection syringes.

Not all pack sizes may be marketed.

 


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


LEO Pharma A/S Industriparken 55 DK-2750 Ballerup Denmark

13. February 2020
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