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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)

The active substance of Galvus, vildagliptin, belongs to a group of medicines called “oral antidiabetics”.

 

Galvus is used to treat adult patients with type 2 diabetes. It is used when diabetes cannot be controlled by diet and exercise alone. It helps to control the level of sugar in the blood. Your doctor will prescribe Galvus either alone or together with certain other antidiabetic medicines which you will already be taking, if these have not proved sufficiently effective to control diabetes.

 

Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body makes does not work as well as it should. It can also develop if the body produces too much glucagon.

 

Insulin is a substance which helps to lower the level of sugar in the blood, especially after meals. Glucagon is a substance which triggers the production of sugar by the liver, causing the blood sugar level to rise. The pancreas makes both of these substances.

 

How Galvus works

Galvus works by making the pancreas produce more insulin and less glucagon. This helps to control the blood sugar level. This medicine has been shown to reduce blood sugar, which may help to prevent complications from your diabetes. Even though you are now starting a medicine for your diabetes, it is important that you continue to follow the diet and/or exercise which has been recommended for you.


Do not take Galvus:

·                if you are allergic to vildagliptin or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic to vildagliptin or any of the other ingredients of Galvus, do not take this medicine and talk to your doctor.

 

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Galvus

·                if you have type 1 diabetes (i.e. your body does not produce insulin) or if you have a condition called diabetic ketoacidosis.

·                if you are taking an anti-diabetic medicine known as a sulphonylurea (your doctor may want to reduce your dose of the sulphonylurea when you take it together with Galvus in order to avoid low blood glucose [hypoglycaemia]).

·                if you have moderate or severe kidney disease (you will need to take a lower dose of Galvus).

·                if you are on dialysis.

·                if you have liver disease.

·                if you suffer from heart failure.

·                if you have or have had a disease of the pancreas.

·                If you have previously taken vildagliptin but had to stop taking it because of liver disease, you should not take this medicine.

 

Diabetic skin lesions are a common complication of diabetes. You are advised to follow the recommendations for skin and foot care that you are given by your doctor or nurse. You are also advised to pay particular attention to new onset of blisters or ulcers while taking Galvus. Should these occur, you should promptly consult your doctor.

 

A test to determine your liver function will be performed before the start of Galvus treatment, at three-month intervals for the first year and periodically thereafter. This is so that signs of increased liver enzymes can be detected as early as possible.

 

Children and adolescents

The use of Galvus in children and adolescents up to 18 years of age is not recommended.

 

Other medicines and Galvus

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

 

Your doctor may wish to alter your dose of Galvus if you are taking other medicines such as:

-       thiazides or other diuretics (also called water tablets)

-       corticosteroids (generally used to treat inflammation)

-       thyroid medicines

-       certain medicines affecting the nervous system.

 

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

 

You should not use Galvus during pregnancy. It is not known if Galvus passes into breast milk. You should not use Galvus if you are breast-feeding or plan to breast-feed.

 

Driving and using machines

If you feel dizzy while taking Galvus, do not drive or use machines.

 

Galvus contains lactose

Galvus contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

 

Galvus contains sodium

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


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

 

How much to take and when

The amount of Galvus people have to take varies depending on their condition. Your doctor will tell you exactly how many tablets of Galvus to take. The maximum daily dose is 100 mg.

 

The usual dose of Galvus is either:

·         50 mg daily taken as one dose in the morning if you are taking Galvus with another medicine called a sulphonylurea.

 

·         100 mg daily taken as 50 mg in the morning and 50 mg in the evening if you are taking Galvus alone, with another medicine called metformin or a glitazone, with a combination of metformin and a sulphonylurea, or with insulin.

 

·         50 mg daily in the morning if you have moderate or severe kidney disease or if you are on dialysis.

 

How to take Galvus

·         Swallow the tablets whole with some water.

 

How long to take Galvus

·         Take Galvus every day for as long as your doctor tells you. You may have to take this treatment over a long period of time.

·         Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

 

If you take more Galvus than you should

If you take too many Galvus tablets, or if someone else has taken your medicine, talk to your doctor straight away. Medical attention may be needed. If you need to see a doctor or go to the hospital, take the pack with you.

 

If you forget to take Galvus

If you forget to take a dose of this medicine, take it as soon as you remember. Then take your next dose at the usual time. If it is almost time for your next dose, skip the dose you missed. Do not take a double dose to make up for a forgotten tablet.

 

If you stop taking Galvus

Do not stop taking Galvus unless your doctor tells you to. If you have questions about how long to take this medicine, talk to your doctor.


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

 

Some symptoms need immediate medical attention:

You should stop taking Galvus and see your doctor immediately if you experience the following side effects:

·         Angioedema (rare: may affect up to 1 in 1 000 people): Symptoms include swollen face, tongue or throat, difficulty swallowing, difficulties breathing, sudden onset rash or hives, which may indicate a reaction called “angioedema”.

·         Liver disease (hepatitis) (frequency not known): Symptoms include yellow skin and eyes, nausea, loss of appetite or dark-coloured urine, which may indicate liver disease (hepatitis).

·         Inflammation of the pancreas (pancreatitis) (rare: may affect up to 1 in 1 000 people): Symptoms include severe and persistent pain in the abdomen (stomach area), which might reach through to your back, as well as nausea and vomiting.

 

Other side effects

 

Some patients have had the following side effects while taking Galvus:

·         Very common (may affect more than 1 in 10 people): sore throat, runny nose, fever.

·         Common (may affect up to 1 in 10 people): itchy rash, trembling, headache, dizziness, muscle pain, joint pain, constipation, swollen hands, ankles or feet (oedema), excessive sweating, vomiting, pain in and around the stomach (abdominal pain), diarrhoea, heartburn, nausea (feeling sick), blurred vision.

·         Uncommon (may affect up to 1 in 100 people): weight increase, chills, weakness, sexual dysfunction, low blood glucose, flatulence.

·         Rare (may affect up to 1 in 1 000 people): inflammation of the pancreas.

 

Since this product has been marketed, the following side effects have also been reported:

·                Frequency not known (cannot be estimated from the available data): localised peeling of skin or blisters, blood vessel inflammation (vasculitis) which may result in skin rash or pointed, flat, red, round spots under the skin's surface or bruising.

 

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.


·         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 blister and the carton after “EXP”. The expiry date refers to the last day of that month.

·         Store in the original package in order to protect from moisture.

·         Do not use any Galvus pack that is damaged or shows signs of tampering.

·         Do not store above 30⁰ C.


·                The active substance is vildagliptin.

Each tablet contains 50 mg vildagliptin.

·                The other ingredients are lactose anhydrous, microcrystalline cellulose, sodium starch glycolate (type A) and magnesium stearate.


Galvus 50 mg tablets are round, white to light yellowish and flat, with “NVR” on one side and “FB” on the other. Galvus 50 mg tablets are available in packs containing 28 or 56 tablets.

The Marketing Authorization Holder for this Product is Novartis Pharma AG.

www.Novartis.com


This leaflet was last approved / revised by EMA on July 2022 e. To report any side effect(s): • Saudi Arabia The National Pharmacovigilance Centre (NPC): o Fax: +966-11-205-7662 o SFDA call center: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: https://ade.sfda.gov.sa Patient Safety Department Novartis Consulting AG - Saudi Arabia: o Toll Free Number: 8001240078 o Phone: +966112658100 o Fax: +966112658107 o Email: adverse.events@novartis.com • Other GCC States: - Please contact the relevant competent authority.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

تنتمي المادة الفعالة في عقار جالفس، فيلداجليبتن، إلى مجموعة من الأدوية تسمى " الأدوية المضادة لمرض السكري الفموية".

 

يُستخدم عقار جالفس لعلاج المرضى البالغين المصابين بمرض السكري من النوع 2. ويُستخدم عندما لا يمكن السيطرة على مرض السكري من خلال اتباع نظام غذائي وممارسة التمارين الرياضية فقط. فهو يساعد على التحكم في مستوى السكر في الدم. سيصف لك الطبيب عقار جالفس لتتناوله إما بمفرده أو مع أدوية أخرى معينة مضادة للسكري والتي ستتناولها بالفعل، إذا لم تثبت فعالية هذه الأدوية بشكل كافٍ للسيطرة على مرض السكري.

 

يظهر مرض السكري من النوع 2 إذا كان الجسم لا ينتج ما يكفي من الأنسولين أو إذا كان الأنسولين الذي ينتجه الجسم لا يعمل كما ينبغي. ويمكن أن يظهر أيضًا إذا كان الجسم ينتج الكثير من الجلوكاجون.

 

الأنسولين هو مادة تساعد على خفض مستوى السكر في الدم، خاصةً بعد الوجبات. الجلوكاجون هو مادة تحفز إنتاج الكبد للسكر، مما يتسبب في ارتفاع مستوى السكر في الدم. ويصنع البنكرياس هاتين المادتين.

 

كيف يعمل عقار جالفس

يعمل عقار جالفس عن طريق جعل البنكرياس ينتج ينتج كمية أكبر من الأنسولين وكمية أقل من الجلوكاجون. يساعد هذا على التحكم في مستوى السكر في الدم. ثبت أن هذا العقار يُخفض من مستوى السكر في الدم، مما قد يساعد في منع المضاعفات الناجمة عن مرض السكري. على الرغم من أنك بدأت الآن في تناول عقار لمرض السكري الذي تعاني منه، إلا أنه من المهم أن تستمر في اتباع نظام غذائي و/أو ممارسة الرياضة المُوصى بها لك.

لا تتناول عقار جالفس:

·                إذا كانت لديك حساسية ضد فيلداجليبتن أو أي من المكونات الأخرى لهذا العقار (المُدرجة في القسم 6). إذا كنت تعتقد أنك قد تعاني من حساسية ضد فيلداجليبتن أو أي من مكونات عقار جالفس الأخرى، فلا تتناول هذا العقار وتحدث إلى الطبيب.

 

تحذيرات واحتياطات

تحدث إلى الطبيب المتابع لك، أو الصيدلي أو الممرضة قبل أن تتناول عقار جالفس في الحالات الآتية:

·                • إذا كنت مصابًا بمرض السُّكَّرِيّ من النوع 1 (أي أن جسمك لا يُنتج الأنسولين) أو إذا كنت تعاني من حالة تُسمى الحماض الكيتوني السُّكَّرِي.

·                إذا كنت تتناول عقار مضادًا للسكري يُعرف باسم السلفونيل يوريا (قد يرغب طبيبك في تقليل جرعتك من السلفونيل يوريا عند تناوله مع عقار جالفس لتجنب انخفاض الجلوكوز في الدم [نقص سكر الدم]).

·                إذا كنت تعاني من مرض متوسط أو شديد في الكلي (سيتعين عليك تناول جرعة أقل من عقار جالفس).

·                إذا كنت تخضع للغسيل الكُلوي.

·                إذا كنت مصاباً بمرض في الكبد.

·                إذا كنت تعاني من قصور في القلب.

·                إذا كنت مصاباً أو سبق لك أن كنت مصاباً بمرض في البنكرياس.

 

إذا كنت قد تناولت فيلداجليبتن من قبل ولكنك اضطررت إلى التوقف عن تناوله بسبب مرض في الكبد، فيجب ألا تتناول هذا العقار.

 

تُعد الآفات الجلدية في مرضى السكري إحدى المضاعفات الشَّائعة لمرض السُّكَّرِي. يُنصَح باتباع التَّوصيات الخاصَّة بالعناية بالجلد والقدمين التي يُعطيها لك الطبيب أو الممرضة. يُنصح أيضًا بإيلاء اهتمام خاص في حالة ظهور بثور أو قرح جديدة أثناء تناول عقار جالفس. في حالة حدوث ذلك، يجب عليك استشارة الطبيب على الفور.

 

سيُجرى اختبار لمعرفة وظائف الكبد لديك قبل بدء العلاج بعقار جالفس، على فترات زمنية تبلغ ثلاثة أشهر خلال العام الأول و بصفة دورية بعد ذلك. وذلك حتى يمكن اكتشاف علامات زيادة إنزيمات الكبد في أقرب وقت ممكن.

 

الأطفال والمراهقون

لا يوصى باستخدام عقار جالفس في الأطفال والمراهقين حتى سن 18 عامًا.

 

الأدوية الأخرى وعقار جالفس

أخبر الطبيب أو الصيدلي إذا كنت تتناول، أو إذا تناولت مؤخرًا، أو قد تتناول أية أدوية أخرى.

 

قد يرغب الطبيب في تغيير جرعتك من عقار جالفس إذا كنت تتناول أدوية أخرى مثل:

-          ثيازيد أو مدرات البول الأخرى (تسمى أيضًا أقراص الماء)

-          الكورتيكوستيرويدات (تُستخدم عمومًا لعلاج الالتهابات)

-          أدوية الغدة الدرقية

-          بعض الأدوية التي تُؤثر على الجهاز العصبي.

 

الحمل والرضاعة الطبيعية

إذا كنتِ حاملاً أو ترضعين طبيعيًا، أو تعتقدين أنكِ حامل أو تخططين لإنجاب طفل، فاطلبي نصيحة الطبيب المتابع لكِ أو الصيدلي قبل تناول هذا العقار.

 

يجب ألا تستخدمي عقار جالفس أثناء الحمل. من غير المعروف إذا كان عقار جالفس يمر في حليب الثدي. يجب ألا تستخدمي عقار جالفس إذا كنتِ تُرضعين رضاعة طبيعية أو تخططين للإرضاع رضاعة طبيعية.

 

قيادة السيارة واستخدام الآلات

إذا شعرت بالدوار أثناء تناول عقار جالفس، فلا تقوم بقيادة السيارة أو استخدام الآلات.

 

يحتوي عقار جالفس على اللاكتوز

يحتوي عقار جالفس على اللاكتوز (سكر الحليب). إذا أخبرك الطبيب بأنك لا تتحمل بعض السكريات، فاتصل به قبل تناول هذا العقار.

 

يحتوي عقار جالفس على الصوديوم

يحتوي هذا العقار على أقل من 1 مليمول من الصوديوم (23 ملغ) لكل قرص، أي أنه "خالٍ من الصوديوم" بشكل أساسي.

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يتعين عليك تناول هذا العقار دومًا بحسب توجيهات الطبيب تمامًا. يجب استشارة الطبيب أو الصيدلي إذا كنت غير متأكد.

 

ما هي الكمية التي يجب أن تتناولها؟ ومتى؟

تختلف كمية عقار جالفس التي يجب على الأشخاص تناولها حسب حالتهم. سوف يخبرك الطبيب بعدد أقراص عقار جالفس بالضبط التي يجب أن تتناولها. أقصى جرعة يومية هي 100 ملغ.

 

الجرعة المعتادة من عقار جالفس تكون إما:

·         50 ملغ يوميًا كجرعة واحدة تؤخذ في الصباح إذا كنت تتناول عقار جالفس مع عقار آخر يُسمى السلفونيل يوريا.

 

·         100 ملغ يوميًا تُؤخذ 50 ملغ صباحًا و50 ملغ مساءً إذا كنت تتناول عقار جالفس بمفرده، مع عقار آخر يُسمى ميتفورمين أو جليتازون ، مع توليفة من ميتفورمين والسلفونيل يوريا، أو مع الأنسولين.

 

·         50 مجم يوميًّا في الصباح إذا كنت مُصابًا بمرض متوسط أو شديد بالكُلى أو إذا كنت تخضع للغسيل الكُلوي.

 

كيف تتناول عقار جالفس

·         ابتلع الأقراص كاملة مع القليل من الماء.

 

كم من الوقت يجب تناول عقار جالفس

·         تناول عقار جالفس كل يوم طالما أخبرك الطبيب بذلك. وقد تضطر إلى تناول هذا العلاج على مدى فترة زمنية طويلة.

·         سيتابع الطبيب حالتك بانتظام للتحقق من أن العلاج يحقق المفعول المرغوب.

 

إذا تناولت أكثر مما ينبغي من عقار جالفس

إذا تناولت الكثير من أقراص جالفس، أو إذا تناول شخص آخر دوائك، فتحدث إلى الطبيب على الفور. حيثُ قد تكون هناك حاجة إلى الرعاية الطبية. إذا كنت بحاجة إلى زيارة طبيب أو الذهاب إلى المستشفى، فخذ العبوة معك.

 

إذا نسيت تناول عقار جالفس

إذا نسيت تناول جرعة من هذا العقار، فتناولها بمجرد أن تتذكر. ثم تناول جرعتك التالية في الوقت المعتاد. إذا كان وقت جرعتك التالية قريباً، فيمكنك تجاوز الجرعة التي فاتتك. لا تأخذ جرعة مزدوجة لتعويض قرص منسي.

 

إذا توقفت عن تناول عقار جالفس

لا تتوقف عن تناول عقار جالفس إلا إذا طلب منك الطبيب ذلك. إذا كانت لديك أسئلة حول مدة تناول هذا العقار، فتحدث إلى الطبيب.

مثل كل الأدوية، قد يسبب هذا العقار آثارًا جانبية، ولكن هذه الآثار لا تصيب كل من يتناوله.

 

تحتاج بعض الأعراض إلى رعاية طبية فورية:

ينبغي عليك التوقف عن تناول عقار جالفس وزيارة الطبيب على الفور إذا تعرضت لأيٍ من الآثار الجانبية التالية:

·         الوذمة الوعائية (نادرة: قد تُصيب ما يصل إلى شخص واحد (1) من كل 1000 شخص): تشمل الأعراض تورّم الوجه، أو اللسان أو الحلق، وصعوبة في البلع، وصعوبة في التنفس، وظهور طفح جلدي مفاجئ أو شرى، مما قد يشير إلى رد فعل يُسمى "الوذمة الوعائية".

·         مرض الكبد (التهاب كبدي وبائي) (معدل تكراره غير معروف): تشمل الأعراض اصفرار الجلد والعينين، والغثيان، وفقدان الشهية أو البول الداكن، مما قد يشير إلى مرض الكبد (التهاب كبدي وبائي).

·         التهاب البنكرياس (نادر: قد يُصيب ما يصل إلى شخص واحد (1) من بين كل 1000 شخص): تشمل الأعراض ألمًا شديدًا ومستمرًا في البطن (منطقة المعدة)، والذي قد يمتد إلى الظهر، بالإضافة إلى الغثيان والقيء.

 

الآثار الجانبية الأخرى

 

عانى بعض المرضى من الآثار الجانبية التالية أثناء تناول عقار جالفس:

·         شائعة جدًا (قد تصيب أكثر من شخص واحد (1) من كل 10 أشخاص): التهاب الحلق، سيلان الأنف، الحمى.

·         شائعة (قد تؤثر على ما يصل إلى شخص واحد (1) من كل 10 أشخاص): طفح جلدي مصحوب بحكة، ارتعاش، صداع، دوخة، ألم في العضلات، ألم في المفاصل، إمساك، تورم اليدين، أو الكاحلين أو القدمين (وذمة)، فرط التعرّق، قيء، ألم في المعدة وحولها (ألم في البطن)، إسهال، حرقة في المعدة، غثيان (الشعور بالمرض)، تشوش الرؤية.

·         غير شائعة (قد تُصيب ما يصل إلى شخص واحد (1) من كل 100 شخص): زيادة الوزن، قشعريرة، ضعف، اختلال الوظيفة الجنسية، انخفاض الجلوكوز في الدم، انتفاخ البطن.

·         نادرة (قد تُصيب ما يصل إلى شخص واحد (1) من بين كل 1000 شخص): التهاب البنكرياس.

 

منذ تسويق هذا المنتج، تم الإبلاغ أيضًا عن الآثار الجانبية التالية:

·                معدل التكرار غير معروف (لا يمكن تقديره من البيانات المتاحة): تقشر موضعي للجلد أو بثور، التهاب الأوعية الدموية (التهاب وعائي) الذي قد يؤدي إلى طفح جلدي أو بقع مدببة، أو مسطحة، أو حمراء، أو مستديرة تحت سطح الجلد أو كدمات.

 

الإبلاغ عن الآثار الجانبية

إذا أًصبتَ بأيّة آثار جانبية، فتحدث إلى الطبيب المتابع لك أو الصيدلي أو الممرضة. يشمل هذا أيّة آثار جانبية محتملة غير مذكورة في هذه النشرة.

·         احفظ هذا العقار بعيدًا عن رؤية ومتناول الأطفال.

·         لا تستعمل هذا الدَّواء بعد انتهاء تاريخ الصلاحية المدون على العبوة والشريط بعد كلمة "EXP". يُشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

·         احفظها في العبوة الأصلية للحماية من الرطوبة.

·         لا تستخدم أي عبوة لعقار جالفس تالفة أو تظهر عليها علامات العبث بها.

·         لا تخزنه في درجة حرارة أعلى من 30 درجة مئوية.

·                المادة الفعالة هي فيلداجليبتن.

يحتوي كل قرص على 50 ملغ من فيلداجليبتن.

·                المكونات الأخرى هي اللاكتوز اللامائي، وسليلوز دقيق التبلور، وجليكُولات نشا الصوديوم (النوع أ) وستيرات المغنيسيوم.

عقار جالفس 50 مجم أقراص هو عبارة عن أقراص دائرية الشكل، ذات لون أبيض مائل إلى الأصفر الفاتح ومسطحة، يظهر على أحد وجهيها "NVR" وعلى الوجه الآخر "FB".

 

عقار جالفس 50 مجم أقراص متوفر في عبوات تحتوي على 28 أو 56 قرصًا.

مالك حق التسويق لهذا المنتج هي شركة نوفارتس فارما إيه جي.

www.Novartis.com

‌تم اعتماد هذه النَّشرة من قبل منظمة الأدوية الأوروبية في يوليو 2022 ج. للإبلاغ عن الأعراض الجانبية : • المملكة العربية السعودية - المركز الوطني للتيقظ والسلامة الدوائية (NPC) • الفاكس: +966-11-205-7662 • مركز اتصال الهيئة السعودية للغذاء والدواء: 19999 • البريد الالكتروني: npc.drug@sfda.gov.sa • الموقع الالكتروني: https://ade.sfda.gov.sa - شركة نوفارتس - السعودية - قسم سلامة المرضى: • الهاتف المجاني: 8001240078 • الهاتف: +966112658100 • الفاكس: +966112658107 • البريد الالكتروني: adverse.events@novartis.com • دول مجلس التَّعاون الخليجي الأخرى: - يُرجى الاتصال بسلطات الاختصاص المعنية
 Read this leaflet carefully before you start using this product as it contains important information for you

Galvus 50 mg tablets

Each tablet contains 50 mg of vildagliptin. Excipient with known effect: Each tablet contains 47.82 mg lactose (anhydrous). For the full list of excipients, see section 6.1.

Tablet. White to light yellowish, round (8 mm diameter), flat-faced, bevelled-edge tablet. One side is debossed with “NVR”, and the other side with “FB”.

Vildagliptin is indicated in the treatment of type 2 diabetes mellitus in adults:

As monotherapy

-        in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

As dual oral therapy in combination with

-        metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin,

-        a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of a sulphonylurea and for whom metformin is inappropriate due to contraindications or intolerance,

-        a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a thiazolidinedione is appropriate.

As triple oral therapy in combination with

-        a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.

Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when diet

and exercise plus a stable dose of insulin do not provide adequate glycaemic control.


Posology

 

Adults

When used as monotherapy, in combination with metformin, in combination with thiazolidinedione, in combination with metformin and a sulphonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.

 

When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily.

 

When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

 

Doses higher than 100 mg are not recommended.

 

If a dose of Galvus is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

 

The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a thiazolidinedione have not been established.

 

Additional information on special populations

Elderly (≥ 65 years)

No dose adjustments are necessary in elderly patients (see also sections 5.1 and 5.2).

 

Renal impairment

No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥ 50 ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of Galvus is 50 mg once daily (see also sections 4.4, 5.1 and 5.2).

 

Hepatic impairment

Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN) (see also sections 4.4 and 5.2).

 

Paediatric population

Galvus is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of Galvus in children and adolescents (< 18 years) have not been established. No data are available (see also section 5.1).

 

Method of administration

 

Oral use

Galvus can be administered with or without a meal (see also section 5.2).


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

General

 

Galvus is not a substitute for insulin in insulin-requiring patients. Galvus should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

 

Renal impairment

 

There is limited experience in patients with ESRD on haemodialysis. Therefore Galvus should be used with caution in these patients (see also sections 4.2, 5.1 and 5.2).

 

Hepatic impairment

 

Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment ALT or AST > 3x ULN (see also sections 4.2 and 5.2).

 

Liver enzyme monitoring

 

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function test results returned to normal after discontinuation of treatment. Liver function tests should be performed prior to the initiation of treatment with Galvus in order to know the patient’s baseline value. Liver function should be monitored during treatment with Galvus at three-month intervals during the first year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT of 3x ULN or greater persist, withdrawal of Galvus therapy is recommended.

 

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Galvus.

 

Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should not be reinitiated.

 

Cardiac failure

 

A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional class I‑III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive (see section 5.1).

 

There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.

 

Skin disorders

 

Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.

 

Acute pancreatitis

 

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis.

 

If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

 

Hypoglycaemia

 

Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.

 

Excipients

 

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

 

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


Vildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.

 

Combination with pioglitazone, metformin and glyburide

 

Results from studies conducted with these oral antidiabetics have shown no clinically relevant pharmacokinetic interactions.

 

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)

 

Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.

 

Combination with amlodipine, ramipril, valsartan or simvastatin

 

Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin.

 

Combination with ACE-inhibitors

 

There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors.(see section 4.8).

 

As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.


Pregnancy

 

There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Galvus should not be used during pregnancy.

 

Breast-feeding

 

It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of vildagliptin in milk. Galvus should not be used during breast-feeding.

 

Fertility

 

No studies on the effect on human fertility have been conducted for Galvus (see section 5.3).


No studies on the effects on the ability to drive and use machines have been performed. Patients who experience dizziness as an adverse reaction should avoid driving vehicles or using machines.


Summary of the safety profile

 

Safety data were obtained from a total of 5 451 patients exposed to vildagliptin at a daily dose of 100 mg (50 mg twice daily) in randomised double‑blind placebo‑controlled trials of at least 12 weeks duration. Of these patients, 4 622 patients received vildagliptin as monotherapy and 829 patients received placebo.

 

The majority of adverse reactions in these trials were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose. Hypoglycaemia has been reported in patients receiving vildagliptin concomitantly with sulphonylurea and insulin. The risk of acute pancreatitis has been reported with the use of vildagliptin (see section 4.4).

 

Tabulated list of adverse reactions

 

Adverse reactions reported in patients who received Galvus in double-blind studies as monotherapy and add-on therapies are listed below for each indication by system organ class and absolute frequency. Frequencies are defined as 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 1       Adverse reactions reported in patients who received vildagliptin as monotherapy or as add‑on therapy in controlled clinical studies and in post‑marketing experience

 

System organ class - adverse reaction

Frequency

Infections and infestations

Nasopharyngitis

Very common

Upper respiratory tract infection

Common

Metabolism and nutrition disorders

Hypoglycaemia

Uncommon

Nervous system disorders

Dizziness

Common

Headache

Common

Tremor

Common

Eye disorders

 

Vision blurred

Common

Gastrointestinal disorders

Constipation

Common

Nausea

Common

Gastro-oesophageal reflux disease

Common

Diarrhoea

Common

Abdominal pain, including upper

Common

Vomiting

Common

Flatulence

Uncommon

Pancreatitis

Rare

Hepatobiliary disorders

Hepatitis

Not known*

Skin and subcutaneous tissue disorders

Hyperhidrosis

Common

Rash

Common

Pruritis

Common

Dermatitis

Common

Urticaria

Uncommon

Exfoliative and bullous skin lesions, including bullous pemphigoid

Not known*

Cutaneous vasculitis

Not known*

Musculoskeletal and connective tissue disorders

Arthralgia

Common

Myalgia

Common

Reproductive system and breast disorders

Erectile dysfunction

Uncommon

General disorders and administration site conditions

Asthenia

Common

Oedema peripheral

Common

Fatigue

Uncommon

Chills

Uncommon

Investigations

Abnormal liver function tests

Uncommon

Weight increase

Uncommon

*        Based on post-marketing experience.

 

Description of selected adverse reactions

 

Hepatic impairment

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations ³ 3x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

 

Angioedema

Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an angiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.

 

Hypoglycaemia

Hypoglycaemia was uncommon when vildagliptin (0.4%) was used as monotherapy in comparative controlled monotherapy studies with an active comparator or placebo (0.2%). No severe or serious events of hypoglycaemia were reported. When used as add-on to metformin, hypoglycaemia occurred in 1% of vildagliptin‑treated patients and in 0.4% of placebo‑treated patients. When pioglitazone was added, hypoglycaemia occurred in 0.6% of vildagliptin‑treated patients and in 1.9% of placebo‑treated patients. When sulphonylurea was added, hypoglycaemia occurred in 1.2% of vildagliptin treated patients and in 0.6% of placebo‑treated patients. When sulphonylurea and metformin were added, hypoglycaemia occurred in 5.1% of vildagliptin treated patients and in 1.9% of placebo treated patients. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemia was 14% for vildagliptin and 16% for placebo.

 

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.

 

To report any side effect(s):

·         Saudi Arabia

 

-          The National Pharmacovigilance Centre (NPC):

 

o Fax: +966-11-205-7662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

 

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

 

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

 

•    Other GCC States:

-  Please contact the relevant competent authority.


Information regarding overdose with vildagliptin is limited.

 

Symptoms

 

Information on the likely symptoms of overdose was taken from a rising dose tolerability study in healthy subjects given Galvus for 10 days. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.

 

Management

 

In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed by haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed by haemodialysis.


Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH02

 

Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.

 

Mechanism of action

 

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

 

Pharmacodynamic effects

 

By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin 50‑100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-b (Homeostasis Model Assessment–b), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

 

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.

 

The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.

 

The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment.

 

Clinical efficacy and safety

 

More than 15 000 patients with type 2 diabetes participated in double-blind placebo- or active-controlled clinical trials of up to more than 2 years’ treatment duration. In these studies, vildagliptin was administered to more than 9 000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5 000 male and more than 4 000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1 900 patients receiving vildagliptin 50 mg once daily or 100 mg daily were ≥ 65 years. In these trials, vildagliptin was administered as monotherapy in drug-naïve patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products.

 

Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in combination with metformin, a sulphonylurea, and a thiazolidinedione, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2).

 

In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients with higher baseline HbA1c.

 

In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline HbA1c by ‑1% compared to ‑1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was not achieved. Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse reactions versus those treated with metformin.

 

In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared to rosiglitazone (8 mg once daily). Mean reductions were ‑1.20% with vildagliptin and ‑1.48% with rosiglitazone in patients with mean baseline HbA1c of 8.7%. Patients receiving rosiglitazone experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced no weight gain (‑0.3 kg). The incidence of peripheral oedema was lower in the vildagliptin group than in the rosiglitazone group (2.1% vs. 4.1% respectively).

 

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day). After two years, mean reduction in HbA1c was ‑0.5% for vildagliptin and ‑0.6% for gliclazide, from a mean baseline HBA1c of 8.6%. Statistical non-inferiority was not achieved. Vildagliptin was associated with fewer hypoglycaemic events (0.7%) than gliclazide (1.7%).

 

In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions from baseline HbA1c of 8.4% were ‑0.9% with vildagliptin added to metformin and ‑1.0% with pioglitazone added to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.

 

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg/day – mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily dose: 1894 mg). After 1 year mean reductions in HbA1c were ‑0.4% with vildagliptin added to metformin and ‑0.5% with glimepiride added to metformin, from a mean baseline HbA1c of 7.3%. Body weight change with vildagliptin was ‑0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycaemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycaemia differences were maintained.

 

In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose: 229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline 1928 mg/day). After 1 year, mean reductions in HbA1c were ‑0.81% with vildagliptin added to metformin (mean baseline HbA1c 8.4%) and ‑0.85% with gliclazide added to metformin (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI ‑0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.

 

In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1c by ‑1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by ‑1.61%, metformin 1000 mg twice daily by ‑1.36% and vildagliptin 50 mg twice daily by ‑1.09% from a mean baseline HbA1c of 8.6%. The decrease in HbA1c observed in patients with a baseline ≥10.0% was greater.

 

A 24-week, multi-centre, randomised, double-blind, placebo-controlled trial was conducted to evaluate the treatment effect of vildagliptin 50 mg once daily compared to placebo in 515 patients with type 2 diabetes and moderate renal impairment (N=294) or severe renal impairment (N=221). 68.8% and 80.5% of the patients with moderate and severe renal impairment respectively were treated with insulin (mean daily dose of 56 units and 51.6 units respectively) at baseline. In patients with moderate renal impairment vildagliptin significantly decreased HbA1c compared with placebo (difference of ‑0.53%) from a mean baseline of 7.9%. In patients with severe renal impairment, vildagliptin significantly decreased HbA1c compared with placebo (difference of ‑0.56%) from a mean baseline of 7.7%.

 

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo.The placebo-adjusted mean reduction from a mean baseline HbA1c of 8.8% was ‑0.76%.

 

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 units), with concomitant use of metformin (N=276) or without concomitant metformin (N=173). Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo. In the overall population, the placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was ‑0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in HbA1c was ‑0.63% and ‑0.84%, respectively. The incidence of hypoglycaemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin experienced no weight gain (+0.2 kg) while those receiving placebo experienced weight reduction (‑0.7 kg).

 

In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled on insulin (short and longer acting, average insulin dose 80 IU/day), the mean reduction in HbA1c when vildagliptin (50 mg twice daily) was added to insulin was statistically significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycaemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).

 

A 52-week multi-centre, randomised, double-blind trial was conducted in patients with type 2 diabetes and congestive heart failure (NYHA functional class I‑III) to evaluate the effect of vildagliptin 50 mg twice daily (N=128) compared to placebo (N=126) on left-ventricular ejection fraction (LVEF). Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing CHF. Adjudicated cardiovascular events were balanced overall. There were more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However, there were imbalances in baseline cardiovascular risk favouring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8% at week 16. In the subgroup with NYHA class III, the decrease in HbA1c compared to placebo was lower (difference 0.3%) but this conclusion is limited by the small number of patients (n=44). The incidence of hypoglycaemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.

 

A five-year multi-centre, randomised, double-blind study (VERIFY) was conducted in patients with type 2 diabetes to evaluate the effect of an early combination therapy with vildagliptin and metformin (N = 998) against standard-of-care initial metformin monotherapy followed by combination with vildagliptin (sequential treatment group) (N = 1 003) in newly diagnosed patients with type 2 diabetes. The combination regimen of vildagliptin 50 mg twice daily plus metformin resulted in a statistically and clinically significant relative reduction in hazard for “time to confirmed initial treatment failure” (HbA1c value ≥7%) vs metformin monotherapy in treatment-naïve patients with type 2 diabetes over the 5-year study duration (HR [95%CI]: 0.51 [0.45, 0.58]; p<0.001). The incidence of initial treatment failure (HbA1c value ≥7%) was 429 (43.6%) patients in the combination treatment group and 614 (62.1%) patients in the sequential treatment group.

 

Cardiovascular risk

A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV monotherapy and combination therapy clinical studies of up to more than 2 years duration (mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) was performed and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk versus comparators. The composite endpoint of adjudicated major adverse cardiovascular events (MACE) including acute myocardial infarction, stroke or cardiovascular death was similar for vildagliptin versus combined active and placebo comparators [Mantel–Haenszel risk ratio (M-H RR) 0.82 (95% CI 0.61‑1.11)]. A MACE occurred in 83 out of 9 599 (0.86%) vildagliptin-treated patients and in 85 out of 7 102 (1.20%) comparator-treated patients. Assessment of each individual MACE component showed no increased risk (similar M-H RR). Confirmed heart failure (HF) events defined as HF requiring hospitalisation or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients with M-H RR 1.08 (95% CI 0.68‑1.70).

 

Table 2 Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and in add-on combination therapy trials (primary efficacy ITT population)

 

Monotherapy placebo controlled studies

Mean baseline HbA1c (%)

Mean change from baseline in HbA1c (%) at week 24

Placebo-corrected mean change in HbA1c (%) at week 24 (95% CI)

Study 2301: Vildagliptin 50 mg twice daily (N=90)

8.6

‑0.8

‑0.5* (‑0.8, ‑0.1)

Study 2384: Vildagliptin 50 mg twice daily (N=79)

8.4

‑0.7

‑0.7* (‑1.1, ‑0.4)

 

 

* p< 0.05 for comparison versus placebo

Add-on / Combination studies

 

 

 

Vildagliptin 50 mg twice daily + metformin (N=143)

8.4

‑0.9

‑1.1* (‑1.4, ‑0.8)

Vildagliptin 50 mg daily + glimepiride (N=132)

8.5

‑0.6

‑0.6* (‑0.9, ‑0.4)

Vildagliptin 50 mg twice daily + pioglitazone (N=136)

8.7

‑1.0

‑0.7* (‑0.9, ‑0.4)

Vildagliptin 50 mg twice daily + metformin + glimepiride (N=152)

8.8

‑1.0

‑0.8* (‑1.0, ‑0.5)

 

 

* p< 0.05 for comparison versus placebo + comparator

 

Paediatric population

 

The European Medicines Agency has waived the obligation to submit the results of studies with vildagliptin in all subsets of the paediatric population with type 2 diabetes mellitus (see section 4.2 for information on paediatric use).


Absorption

 

Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%). However, the magnitude of change is not clinically significant, so that Galvus can be given with or without food. The absolute bioavailability is 85%.

 

Distribution

 

The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

 

Biotransformation

 

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Accordingly, the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.

 

Elimination

 

Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

 

Linearity/non-linearity

 

The Cmax for vildagliptin and the area under the plasma concentrations versus time curves (AUC) increased in an approximately dose proportional manner over the therapeutic dose range.

 

Characteristics in specific groups of patients

 

Gender

No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected by gender.

 

Elderly

In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily) was increased by 32%, with an 18% increase in peak plasma concentration as compared to young healthy subjects (18‑40 years). These changes are, however, not considered to be clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age.

 

Hepatic impairment

The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison with healthy subjects. The exposure to vildagliptin after a single dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for patients with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of the hepatic disease and changes in the exposure to vildagliptin.

 

Renal impairment

A multiple-dose, open-label trial was conducted to evaluate the pharmacokinetics of the lower therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment defined by creatinine clearance (mild: 50 to <80 ml/min, moderate: 30 to <50 ml/min and severe: <30 ml/min) compared to normal healthy control subjects.

 

Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. AUC of the metabolites LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with mild, moderate and severe renal impairment, respectively. Limited data from patients with end stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations were approximately 2‑3-fold higher than in patients with severe renal impairment.

 

Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3‑4 hour haemodialysis session starting 4 hours post dose).

 

Ethnic group

Limited data suggest that race does not have any major influence on vildagliptin pharmacokinetics.


Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg (7-fold human exposure based on Cmax).

 

Accumulation of foamy alveolar macrophages in the lung was observed in rats and mice. The no-effect dose in rats was 25 mg/kg (5-fold human exposure based on AUC) and in mice 750 mg/kg (142-fold human exposure).

 

Gastrointestinal symptoms, particularly soft faeces, mucoid faeces, diarrhoea and, at higher doses, faecal blood were observed in dogs. A no-effect level was not established.

 

Vildagliptin was not mutagenic in conventional in vitro and in vivo tests for genotoxicity.

 

A fertility and early embryonic development study in rats revealed no evidence of impaired fertility, reproductive performance or early embryonic development due to vildagliptin. Embryo-foetal toxicity was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in association with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-fold human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a transient decrease in body weight and reduced motor activity in the F1 generation.

 

A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 200 times human exposure at the maximum recommended dose). No increases in tumour incidence attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg. An increased incidence of mammary adenocarcinomas and haemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and 100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice is considered not to represent a significant risk to humans based on the lack of genotoxicity of vildagliptin and its principal metabolite, the occurrence of tumours only in one species and the high systemic exposure ratios at which tumours were observed.

 

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters were observed. They were reversible despite continued treatment and were not associated with histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.


Lactose, anhydrous

Cellulose, microcrystalline

Sodium starch glycolate (type A)

Magnesium stearate


Not applicable.


36 months

Do not store above 30ºC

Store in the original package in order to protect from moisture.


Aluminium/Aluminium (PA/Al/PVC//Al) blister

Available in packs containing 28 or 56 tablets.


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


The Marketing Authorization Holder for this Product is Novartis Pharma AG. www.Novartis.com

07/2022 By EMA
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