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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)

Calciumfolinat “Ebewe” is a solution containing the active ingredient Calcium folinate, which is one of a group of medicines called detoxifying agents.

 

Calciumfolinat “Ebewe” is used to reduce the side effects of certain anticancer drugs or if too much has been given in adults and children. Calciumfolinat “Ebewe” works by acting against drugs that work against folic acid such as methotrexate. This is called "Calcium Folinate Rescue".

 

Calciumfolinat “Ebewe” may also be used in combination with 5-fluorouracil (another anticancer drug).

 

Calcium Folinate Injection is also used to reduce the side effects of other medicines (a group of medicines called folic acid antagonists). Examples of folic acid antagonists are:

·    trimetrexate (an antibiotic and anti-cancer medicine)

·    trimethoprim (an antibiotic)

·    pyrimethamine (a medicine often used to treat malaria) It may also be used to treat an overdose of these medicines.


You should not be given Calciumfolinat “Ebewe” if you:

-     are allergic to calcium folinate or any of the other ingredients of this medicine (listed in section 6)

-     have a decrease in the amount of red blood cells (anaemia)

 

You should not be given Calciumfolinat “Ebewe” together with certain anticancer drugs if you are pregnant or breastfeeding (your doctor will know which these are).

 

Calciumfolinat “Ebewe” should only be given by intramuscular or intravenous injection and must not be administered directly in your spine or brain (intrathecally).

 

Warnings and precautions

Talk to your doctor before you are given Calciumfolinat “Ebewe” if you have

 

-     epilepsy

-     a kidney disorder

 

Tell your doctor if you develop any of the following conditions during treatment:

-     diarrhoea

-     inflammation of the mouth

 

Other medicines and Calciumfolinat “Ebewe”

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

 

For example

-     treatments for epilepsy

-     5-fluorouracil (an anticancer drug)

-     co-trimoxazole (an antibiotic)

-     pyrimethamine (a treatment for malaria)

 

Pregnancy, breast-feeding and fertility

You should not be given [Calciumfolinat “Ebewe”] together with 5-fluorouracil while pregnant or breast-feeding as it might harm the baby.

 

You will only be given Calciumfolinat “Ebewe” together with methotrexate when pregnant or breast-feeding if your doctor thinks it is necessary.

 

Driving and using machines

There is no evidence that Calciumfolinat “Ebewe” affects driving or using machines.

 

Calciumfolinat “Ebewe” contains sodium.

Doses  below    7ml  (70mg):

This medicinal product contains less than 1mmol sodium (23mg), i.e. essentially sodium-free.

This medicinal product contains 3.3 mg (0.14mmol) sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

 


Calciumfolinat “Ebewe” will only be given by a doctor or nurse under the supervision of a doctor who has experience in the use of chemotherapy. Calciumfolinat “Ebewe” may be given by injection or infusion into a vein, or as an injection into a muscle.

 

The dose depends on your body surface area, the type of anticancer treatment used, and any other treatment you may be receiving.

 

If you have any further questions on the use of this product, ask your doctor or pharmacist.


Like all medicines, Calciumfolinat “Ebewe” can cause side effects, although not everybody gets them.

 

Tell your doctor immediately

·    if you have a severe allergic reaction - you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint. This is a serious side effect. Contact a doctor immediately.

 

This side effect is very rare (may affect up to 1 in 10,000 people).

 

Other side effects:

 

The following additional side effects have been reported:

 

Uncommon (may affect up to 1 in 100 people)

·    fever

 

Rare (may affect up to 1 in 1,000 people)

·    difficulty sleeping (insomnia)

·    agitation

·    depression

·    problems with the digestive system

·    an increase in convulsions (fits) in patients with epilepsy

 

If you receive Calciumfolinat “Ebewe” in combination with an anticancer medicine containing fluoropyrimidines, it is more likely that you experience the following side effects of this other medicine:

 

Very common: may affect more than 1 in 10 people

·    nausea

·    vomiting

·    severe diarrhoea

·    drying out which may be due to diarrhea

·    inflammation of the lining of the intestine and mouth (life-threatening conditions have occurred)

·    reduction in the number of blood cells (including life-threatening conditions)

 

Common

·    redness and swelling of the palms of the hands or the soles of the feet which may cause the skin to peel (hand-foot syndrome)

 

Not known: frequency cannot be estimated from the available data

·    elevated ammonia level in the blood


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

 

Do not use this medicine after the expiry date which is stated on the label and the carton after

EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C - 8°C).

Information about storage and the time to use Calciumfolinat “Ebewe”, after it has been diluted for infusion, are described in the information for healthcare professionals, at the end of this leaflet.

 

Do not use this medicine if you notice cloudy appearance or particles in the solution.

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.


−  The active substance is calcium folinate.

One ml of solution for injection/infusion contains 10 mg of folinic acid as calcium folinate hydrate.

−  The  other  ingredients  are  water  for  injections and nitrogen.


Calciumfolinat “Ebewe” is a clear, yellowish solution. Amber vials of hydrolytic type I glass, packed in a carton. Vials are closed with a rubber stopper with an aluminium crimp cap with flip-off. 1 vial containing 10ml equivalent to 100mg of folinic acid. 1 vial containing 20ml equivalent to 200mg of folinic acid. 1 vial containing 30ml equivalent to 300mg of folinic acid. 1 vial containing 35ml equivalent to 350mg of folinic acid. 1 vial containing 80ml equivalent to 800mg of folinic acid. Not all package sizes may be marketed.

EBEWE Pharma Ges.m.b.H. Nfg.KG

A-4866 Unterach, AUSTRIA

 


07/2020
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

عقار كالسيوم فولينات "إيبيفيه" عبارة عن محلول يحتوي على المادة الفعالة فولينات الكالسيوم، وهو واحد من مجموعة من الأدوية تُسمى أدوية إزالة السموم.

 

يُستخدم عقار كالسيوم فولينات "إيبيفيه" للحد من الآثار الجانبية لبعض الأدوية المضادة لمرض السرطان أو إذا تم إعطاء كمية كبيرة منها للبالغين والأطفال. يعمل عقار كالسيوم فولينات "إيبيفيه" عن طريق مقاومة العقاقير التي تعمل ضد حمض الفوليك مثل ميثوتريكسات. يطلق على ذلك "الوقاية بفولينات الكالسيوم".

 

قد يُستخدم أيضًا عقار كالسيوم فولينات "إيبيفيه" بمصاحبة 5-فلورويوراسيل (دواء آخر مضاد لمرض السرطان).

 

تُستخدم حقن فولينات الكالسيوم أيضًا؛ للحدِّ من الآثار الجانبية للأدوية الأخرى (مجموعة من الأدوية تُسمى مناهضات حمض الفوليك). ومن أمثلة مناهضات حمض الفوليك ما يلي:

·         ترايميتريكسات (عبارة عن مضاد حيوي ودواء مضاد للسرطان)

·         ترايميثوبريم (مضاد حيوي)

·         بيريميثامين (دواء يُستخدم غالبًا لعلاج الملاريا). قد يُستخدم أيضًا لعلاج الجرعة الزَّائدة من هذه الأدوية.

يجب عدم إعطائك عقار كالسيوم فولينات "إيبيفيه" في الحالات الآتية:

-     إذا كانت لديك حساسية تجاه فولينات الكالسيوم أو أي مكونات أخرى موجودة بهذا الدَّواء (المدرجة في قسم: 6)

-     إذا كان لديك انخفاض في تعداد خلايا الدَّم الحمراء (فقر الدَّم).

 

يجب ألا يتم إعطاؤكِ عقار كالسيوم فولينات "إيبيفيه" بمصاحبة بعض الأدوية المضادة لمرض السرطان إذا كنتِ حاملًا أو مرضعًا (سيعرف طبيبكِ ما هي تلك الأدوية).

 

يجب ألا يتم إعطاء عقار كالسيوم فولينات "إيبيفيه" إلا عن طريق الحقن العضلي أو عن طريق الحقن الوريدي، ويجب عدم إعطائه في العمود الفقري أو المخ لديك مباشرة (داخل القراب).

 

تحذيرات واحتياطات

تحدَّث إلى طبيبك قبل أن يتم إعطاؤك عقار كالسيوم فولينات "إيبيفيه" إذا كنت تعاني من الآتي:

 

-     الصرع.

-     إحدى الاضطرابات بالكُلى.

 

أخبر طبيبك إذا أصبت بأيٍّ من الحالات الآتية أثناء العلاج:

-     إِسْهال.

-     التهاب الفم.

 

استخدام أدوية أخرى مع عقار كالسيوم فولينات "إيبيفيه"

يُرجى إخبار طبيبك أو الصيدلي الخاص بك إذا كنت تتناول أو تناولت مؤخرًا أو قد تتناول أيَّة أدوية أخرى.

 

على سبيل المثال:

-     الأدوية المعالجة للصَّرع.

-     5-فلورويوراسيل (دواء مضاد لمرض السرطان).

-     كوتريموكسازول (مضاد حيوي).

-     بيريميثامين (علاج للملاريا).

 

الحمل والرَّضاعة الطبيعية والخصوبة

يجب ألا يتم إعطاؤكِ عقار [كالسيوم فولينات "إيبيفيه"] بمصاحبة 5-فلورويوراسيل أثناء الحمل أو الرضاعة الطبيعيَّة؛ إذ قد يضر بالجنين.

 

لن يتم إعطاؤكِ عقار كالسيوم فولينات "إيبيفيه" بمصاحبة ميثوتريكسات عند الحمل أو الرضاعة الطبيعيَّة إلا إذا كان طبيبكِ يعتقد أن ذلك ضروريًّا.

 

ممارسة القيادة واستخدام الآلات

لا يوجد دليل على أنَّ عقار كالسيوم فولينات "إيبيفيه" يُؤثر على ممارسة القيادة أو استخدام الآلات.

 

يحتوي عقار كالسيوم فولينات "إيبيفيه" على الصوديوم.

الجرعات الأقل من 7 مللي لتر (70 مجم):

يحتوي هذا المنتج الدَّوائي على أقل من 1 مللي مول صوديوم (23 مجم)، أي أنه خالٍ من الصوديوم بشكل أساسي.

 

يحتوي هذا المنتج الدَّوائي على 3.3 مجم (0.14 مللي مول) صوديوم لكل مللي لتر. يجب أخذ ذلك في عين الاعتبار من قبل المرضى الذين يتبعون نظامًا غذائيًّا متحكَّم الصوديوم.

 

https://localhost:44358/Dashboard

لن يتم إعطاؤك عقار كالسيوم فولينات "إيبيفيه" إلا عن طريق طبيب أو ممرض(ة) تحت إشراف طبيب من ذوي الخبرة في استخدام العلاج الكيميائي. قد يتم إعطاء عقار كالسيوم فولينات "إيبيفيه" عن طريق الحقن أو التَّسريب الوريدي، أو في هيئة حقن داخل العضل.

 

تعتمد الجرعة على مساحة سطح الجسم لديك، ونوع العلاج المُستخدم المضاد لمرض السرطان، وأي علاج آخر قد تتلقاه.

 

إذا كانت لديك أية أسئلة إضافية حول استخدام هذا المنتج، فاستشر طبيبك أو الصيدلي الخاص بك.

مثل كافة الأدوية، قد يُسبب عقار كالسيوم فولينات "إيبيفيه" آثارًا جانبية، على الرَّغم من عدم حدوثها لدى الجميع.

 

أخبر طبيبك على الفور في الحالات الآتية:

·      إذا كنت تعاني من إحدى تفاعلات الحساسية الشديدة -قد تصاب فجأة بطفح جلدي مصحوب بحكة (شرى "أرتكاريا")، تورم اليدين، القدمين، الكاحلين، الوجه، الشفتين، الفم أو الحلق (مما قد يُسبب صعوبة في البلع أو التنفس)، وقد تشعر بأنك على وشك الإغماء. يُعد هذا أثرًا جانبيًّا خطيرًا. اتصل بالطبيب فورًا.

 

هذا الأثر الجانبي نادر جدًّا (قد يُؤثر على ما يصل إلى شخص واحد من بين كل 10000 شخص).

 

آثار جانبية أخرى:

 

تم الإبلاغ عن الآثار الجانبية الإضافية التَّالية:

 

غير شائعة (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 100 شخص)

·      حمى.

 

نادرة (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 1000 شخص)

·         صعوبة في النوم (أرق).

·         هِياج.

·         اكتئاب.

·         مشاكل بالجهاز الهضمي.

·         زيادة في حدوث التشنجات (النوبات التشنجية) في المرضى الذين يعانون من الصرع.

 

إذا تلقيت عقار كالسيوم فولينات "إيبيفيه" بمصاحبة أحد الأدوية المضادة لمرض السرطان التي تحتوي على فلوروبيريميدين، فمن المرجح أن تعاني من الآثار الجانبية الآتية لهذا الدَّواء الآخر:

 

شائعة جدًّا: قد تُؤثر على أكثر من شخص واحد من بين كل 10 أشخاص

 

·         غثيان.

·         قيء.

·         إِسْهال شديد.

·         الجفاف الذي قد يكون ناجمًا عن الإسهال.

·         التهاب بطانة الأمعاء والفم (حدثت إصابة بحالات مهددة للحياة).

·         انخفاض عدد خلايا الدَّم (بما في ذلك، الإصابة بحالات مهددة للحياة).

 

شائعة

·         احمرار وتورم براحتي اليدين أو باطن القدمين مما قد يُؤدي إلى تقشر الجلد (متلازمة اليد والقدم).

 

غير معروفة: لا يمكن تقدير معدل التكرار من واقع البيانات المتاحة

·         ارتفاع مستوى الأمونيا في الدَّم.

يُحفظ هذا الدَّواء بعيدًا عن رؤية ومُتناوَل الأطفال.

 

لا تستخدم هذا الدَّواء بعد تاريخ انتهاء الصلاحية المدون على الملصق والعبوة الكرتونية بعد كلمة "EXP"

 يُشير تاريخ انتهاء الصَّلاحية إلى اليوم الأخير من ذلك الشهر. يحفظ في الثلاجة (عند 2—8 درجة مئوية).

يتم وصف المعلومات حول تخزين ووقت استخدام عقار كالسيوم فولينات "إيبيفيه" بعد تخفيفه لإعداده للتسريب؛ في المعلومات الخاصة بأخصائيي الرعاية الصحية في نهاية هذه النَّشرة.

 

لا تستخدم هذا الدَّواء إذا لاحظت مظهرًا غائمًا أو جسيمات في المحلول.

 

لا تتخلص من الأدوية عن طريق إلقائها في مياه الصرف أو مع المخلفات المنزلية. استشر الصيدلي الخاص بك عن كيفية التَّخلص من الأدوية التي لم تَعُد تستخدمها. سوف تُساعد هذه الإجراءات في الحفاظ على البيئة.

-           المادة الفعالة هي فولينات الكالسيوم.

يحتوي كل مللي لتر واحد من المحلول المُعَد للحَقن/ التَّسريب على 10 مجم من حمض الفولينيك في هيئة هيدرات فولينات الكالسيوم.

-           المكونات الأخرى هي ماء للحقن و نيتروجين

 

عقار كالسيوم فولينات "إيبيفيه" عبارة عن محلول صافٍ يميل إلى اللون الأصفر.

 

    زجاجات كهرمانية اللون مصنوعة من الزجاج المقاوم للتحلل المائي من النوع 1 ومُعبأة في عبوة كرتونية.

    تكون الزجاجات مغلقة بسدادة مطاطية ذات غطاء ضاغط مصنوع من الألومنيوم وقابل للنزع.

  

     زجاجة واحدة تحتوي على 10 مللي لتر أي ما يعادل 100 مجم من حمض الفولينيك.

    زجاجة واحدة تحتوي على 20 مللي لتر أي ما يعادل 200 مجم من حمض الفولينيك.

    زجاجة واحدة تحتوي على 30 مللي لتر أي ما يعادل 300 مجم من حمض الفولينيك.

    زجاجة واحدة تحتوي على 35 مللي لتر أي ما يعادل 350 مجم من حمض الفولينيك.

    زجاجة واحدة تحتوي على 80 مللي لتر أي ما يعادل 800 مجم من حمض الفولينيك.

 

    قد لا يتم تسويق جميع أحجام العبوات.

 

    شركة إيبيفيه فارما المحدودة Nfg.KG

    أ-4866 أونتراخ، النمسا

07/2020
 Read this leaflet carefully before you start using this product as it contains important information for you

Calciumfolinat "Ebewe"10 mg/ml solution for injection/infusion

One ml of solution for injection/infusion contains 10 mg of folinic acid provided as calcium folinate hydrate. For the full list of excipients, see section 6.1.

Solution for injection/infusion Clear, yellowish solution, practically free from turbidity and foreign matter with pH of 7.0 - 8.6 and osmolarity of 275 mOsm.

Calcium folinate is indicated

 

·      to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as "Calcium Folinate Rescue"

 

·      in combination with 5-fluorouracil in cytotoxic therapy.


Posology

 

 

  Calcium   Folinate          Rescue in methotrexate therapy:

Refer to the applied intermediate- or high-dose methotrexate protocol for posology and method of administration of calcium folinate.  The methotrexate protocol will dictate the dosage regimen of Calcium Folinate Rescue because it depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration.

 

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

 

 

 

 

 

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

 

Calcium Folinate Rescue is necessary when methotrexate is given at doses exceeding 500 mg/m2 body surface and has to be considered with doses of 100 mg – 500 mg/m2 body surface.

 

Dosage and duration of use of Calcium folinate primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of Calcium folinate is 15 mg (6-12 mg/m²) to be given 12-

24 hours (24 hours at the latest) after the beginning of the methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

 

In addition to calcium folinate administration, measures to ensure the rapid excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the Calcium Folinate Rescue treatment. Renal function should be monitored by measuring serum creatinine levels daily.

 

The residual methotrexate-level, in the blood, should be measured, forty-eight hours after the start of the  methotrexate-infusion.  If the  residual  methotrexate-level  is  >  0.5 µmol/l, then the dosage of calcium folinate dosages should be adapted according to the following table:

 

Residual methotrexate level in the blood 48 hours

after the start of the methotrexate administration

Additional Calcium folinate to be administered

every  6 hours  for  48 hours  or  until  levels  of methotrexate are lower than 0.05µmol/l

> 0.5 µmol/l

15 mg/m²

> 1.0 µmol/l

100 mg/m²

> 2.0 µmol/l

200 mg/m²

 

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, however, no optimal dosage or regimen have been determined.

The following regimens have been used in adults and the elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of calcium folinate in combination with 5-fluorouracil  in children:

 

Bimonthly regimen:

Calcium folinate 200mg/m² by intravenous infusion over two hours, followed by an intravenous bolus of 400 mg/m² of 5-Fluorouracil and a 22-hour intravenous infusion of 5-Fluorouracil (600 mg/m²) for

2 consecutive days, every 2 weeks on days 1 and 2.

 

Weekly regimen:

Calcium folinate 20mg/m² by intravenous bolus. injection or 200 to 500 mg/m² intravenous. infusion over a period of 2 hours, plus 500 mg/m² 5-fluorouracil as an intravenous bolus injection in the middle, or at the end, of the calcium folinate infusion.

 

 

 

 

 

Monthly regimen:

Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of

2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as an intravenous bolus injection over five consecutive days.

 

For the use of calcium folinate in combination with 5-fluorouracil, modification of the 5-fluorouacil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

 

The number of repeat cycles used is at the discretion of the clinician.

Antidote to the folic acid antagonists trimetrexate, trimethoprime, and pyrimethamine: Trimetrexate toxicity:

·    Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

·    Over dosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate

40 mg/m2 IV every 6 hours for 3 days.

 

Trimethoprime toxicity:

·    After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

·    In cases of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate

5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

 

Method of administration:

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally.

 

Death has been reported when folinic acid has been administered intrathecally, following intrathecal overdose of methotrexate.

 

In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

 

For intravenous infusion, calcium folinate may be diluted with 0.9 % sodium chloride solution or 5 % glucose solution before use. For instructions on dilution of the product before administration, see section 6.6.


• Hypersensitivity to calcium folinate, or to any of the excipients listed in section 6.1 • Pernicious anaemia or other anaemias due to vitamin B12 deficiency For the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6 and the Summaries of Product Characteristics for methotrexate- and 5-fluorouracil- containing medicinal products.

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally.

 

Death has been reported when folinic acid has been administered intrathecally, following intrathecal overdose of methotrexate.

 

General:

Calcium folinate should be used with methotrexate or 5-fluorouracil only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

 

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin

B12 deficiency.

Many   cytotoxic   medicinal   products   (direct   or   indirect   DNA   synthesis   inhibitors   such   as

hydroxycarbamide, cytarabine, mecaptopurine, thioguanine) lead to macrocytosis. Such macrocytosis should not be treated with folinic acid.

 

In epileptic patients treated with phenobarbital, phenytoine, primidone, and succinimides there is a risk of increased frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possible monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during and after calcium folinate administration is recommended (see also section 4.5).

 

Calcium folinate / 5-fluorouracil

Calcium folinate may enhance the toxicity of 5-fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea which may be dose limiting. In cases of toxicity when calcium folinate and 5-fluorouracil are used in combination, the 5-fluorouracil dosage should be reduced more than in cases of toxicity when 5- fluorouracil is used alone.

Combined 5-fluorouracil/calcium folinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.

 

Because diarrhoea may be a sign of gastrointestinal toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and / or stomatitits occur, it is advisable to reduce the dose of 5-FU until symptoms have fully disappeared. The elderly and patients with a low

 

 

 

 

 

physical performance due to their illness are especially prone to these toxicities. Therefore, particular care should be taken when treating these patients.

 

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-fluorouracil.

 

Calcium folinate must generally not be mixed with 5-fluorouracil in the same intravenous injection or infusion. For more information, please refer to section 6.2.

 

Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate treatment and calcium supplementation should be provided if calcium levels are low.

 

Calcium folinate / methotrexate

For  specific  details  on  reduction  of  methotrexate  toxicity  refer  to  the  Summary  of  Product

Characteristics for methotrexate.

 

Calcium folinate has no effect on the non–haematological toxicities of methotrexate, such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and other toxicities associated with methotrexate (please refer to the Summary of Product Characteristics for methotrexate). The presence of pre-existing- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses, or more prolonged use, of calcium folinate.

 

Excessive calcium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

 

Resistance to methotrexate as a result of decreased membrane transport also implies resistance to folinic acid rescue as both medicinal products share the same transport system.

 

An accidental overdose with a folinate antagonist, such as methotrexate, should be treated as a medicinal emergency. As the time interval between methotrexate administration and Calcium Folinate Rescue increases, the effectiveness of calcium folinate to counteract the toxicity decreases.

 

The possibility that the patient is taking other medications that interact with methotrexate (eg. medication which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

 

Excipients with known effect

Doses below 7ml (70mg):

This medicinal product contains less than 1mmol sodium (23mg), i.e. essentially sodium-free.

 

This medicinal product contains 3.3 mg (0.14mmol) sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

 


When calcium folinate is given in conjunction with a folic acid antagonist (e.g. co-trimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

 

Calcium folinate may diminish the effect of the anti-epileptic substances: phenobarbital, primidone and phenytoine, succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also sections 4.4 and 4.8).

 

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance both the efficacy and toxicity of 5-fluorouracil (see section 4.5, 4.4 and 4.8).


Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There is no indication that folinic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folinate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

 

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breast- feeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

 

Please  refer  also  to  the  Summaries  of  Product  Characteristics  for  methotrexate-,  other  folate antagonists and 5-fluorouracil containing medicinal products.

 

Breastfeeding

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.


There is no evidence that calcium folinate has an effect on the ability to drive or use machines.


The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories:

very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥1/1000, < 1/100), rare (≥ 1/10000,

< 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

 

Both therapeutic indications:

 

Immune system disorders

Very rare: allergic reactions, including anaphylactoid/anaphylactic reactions and urticaria.

 

Psychiatric disorders

Rare: insomnia, agitation and depression after following high doses.

 

Nervous system disorders

Rare: increase in the frequency of attacks in epileptics (see also section 4.5)

 

Gastrointestinal disorders

Rare: gastrointestinal disorders after high doses.

 

General disorders and administration site conditions

Uncommon: fever has been observed after administration of calcium folinate as solution for injection.

 

Combination therapy with 5-fluorouracil:

 

Generally, the safety profile depends on the applied regimen of 5-fluorouracil, due to enhancement of the 5-fluorouracil induced toxicities.

 

Metabolism and Nutritional Disorder: Not known: Hyperammonaemia

 

Blood and lymphatic system disorders:

Very common: bone marrow failure, including fatal cases

 

General disorders and administration site conditions

Very common: mucositis, including stomatitis and chelitis. Fatalities have occurred as a result of mucositis

 

Skin and subcutaneous tissue disorders: Common: Palmar-Plantar Erythrodysaesthesia

 

Monthly regimen:

 

Gastrointestinal disorders

Very common: vomiting and nausea

 

No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).

 

Weekly regimen:

 

Gastrointestinal disorders

Very  common:  diarrhoea  with  higher grades  of  toxicity,  and  dehydration,  resulting  in  hospital admission for treatment and even death.

 


There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

 

Should over-dosage of the combination of 5-fluorouracil and calcium folinate occur, the over-dosage instructions for 5-FU should be followed.


Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC-Code: V03A F03

 

Mechanism of action

Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

 

Calcium  folinate  is  frequently  used  to  diminish the  toxicity  and  counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. Calcium folinate also protects cells from the effects of folate antagonists by repletion of the reduced folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme form as of folic acid.

 

Calcium folinate is also frequently used in the biochemical modulation of fluoropyridine (5- fluorouracil) to enhance its cytotoxic activity. 5-fluorouracil inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosyntheses, and calcium folinate enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5-fluorouracil-TS complex and increasing activity.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the oral administration of folic acid. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.


Absorption

Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

 

Distribution

The distribution volume of folinic acid is not known.

 

Peak serum levels of the parent substance (D/L-formyl-tetrahydrofolic acid, folinic acid) are reached

10 minutes after intravenous administration.

 

The AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±11 mg.min/l, respectively, after a dose of 25mg. The inactive D-isomer is present in higher concentration than L-5- formyl-tetrahydrofolate.

 

Biotransformation

Calcium folinate is a racemate where the L-form (L-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer.

 

The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

 

Elimination

The elimination half-life is32 – 35 minutes for the active L-form and 352 – 485 minutes for the inactive D-form, respectively.

 

The total half-life of the active metabolites is about 6 hours (after both intravenous and intramuscular administration).

 

80-90 % is excreted in the urine as the inactive metabolites, 5- and 10-formyl-tetrahydrofolate, 5-8 %

is excreted in the faeces.


There are no preclinical data considered relevant to clinical safety beyond data included in other sections of this Summary of Product Characteristics.


Water for injections

 


Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.

 

Droperidol

1.  Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml; immediate precipitation was observed after direct admixture in a syringe for 5 minutes at 25°C followed by 8 minutes of centrifugation.

 

2.  Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml; immediate precipitation was observed when the drugs were injected sequentially into a Y-connector without flushing the Y- side arm between injections.

 

Fluorouracil

Generally, calcium folinate must not be mixed in the same infusion as fluorouracil because a precipitate  may  form.  Fluorouracil  50  mg/ml  with  calcium  folinate  20  mg/ml,  with  or  without dextrose 5 % in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32°C in polyvinyl chloride containers.

 

However, a 1:1 mixed solution of calcium folinate solution (10 mg/ml) and fluorouracil solution (50 mg/ml) has been shown to be compatible and stable over a period of 48 hours stored at maximum

32°C protected from light.

 

Foscarnet

The formation of a cloudy yellow solution has been reported when foscarnet 24 mg/ml is mixed with calcium folinate 20 mg/ml.

 


Unopened 2 years ​​​​​​​After dilution for infusion Chemical and physical in-use stability has been demonstrated for 28 days at 2°C to 8°C after dilution with sodium chloride 0.9 % to concentrations of 0.2 mg/ml and 4.0 mg/ml. Chemical and physical in-use stability has been demonstrated for 4 days at 2°C to 8°C after dilution with glucose 5 % to a concentration of 0.2 mg/ml and for 28 days at 2°C to 8°C after dilution to a concentration of 4.0 mg/ml. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2-8°C).

 

For storage conditions after dilution of the medicinal product, see section 6.3.

 


Amber vials of hydrolytic type I glass, packed in a carton.

Vials are closed with a rubber stopper with an aluminium crimp cap with flip-off.

 

1 vial containing 10ml equivalent to 100mg of folinic acid.

1 vial containing 20ml equivalent to 200mg of folinic acid.

1 vial containing 30ml equivalent to 300mg of folinic acid.

1 vial containing 35ml equivalent to 350mg of folinic acid.

1 vial containing 80ml equivalent to 800mg of folinic acid.

 

Not all package sizes may be marketed.


Prior to administration, calcium folinate should be inspected visually. The solution for injection/infusion should be a clear yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded.

 

Dilution for infusion

Based on the required dose for the patient expressed in mg, the corresponding amount of solution for injection/infusion containing 10 mg/ml calcium folinate is aseptically withdrawn from the vial(s) and then diluted with 0.9 % sodium chloride solution or 5 % glucose solution.

 

For single use only. Discard any unused solution immediately after initial use.

 

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


EBEWE Pharma Ges.m.b.H. Nfg.KG A-4866 Unterach, AUSTRIA

07/2020
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