EUCREAS - PACKAGE LEAFLET - LEAFLETS

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Eucreas - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Metformin, Vildagliptin

Eucreas 50 mg / 850 mg film-coated tablets

Eucreas package inserts are available for pack sizes:

Eucreas 50 mg / 850 mg film-coated tablets
Eucreas 50 mg / 1000 mg film-coated tablets

Indications Why is Eucreas used? What is it for?

The active substances in Eucreas, vildagliptin and metformin, belong to a group of medicines called 'oral antidiabetics'.

Eucreas is used to treat adult patients with type 2 diabetes. This type of diabetes is also known as non-insulin dependent diabetes mellitus.

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

Both insulin and glucagon are produced in the pancreas. Insulin helps lower blood sugar levels, especially after meals. Glucagon stimulates the liver to produce sugar, causing blood sugar levels to rise.

How Eucreas works

Both active substances, vildagliptin and metformin, help control blood sugar levels. The substance vildagliptin works by causing the pancreas to produce more insulin and less glucagon. The substance metformin works by helping the body to make better use of insulin.

This medicine has been shown to reduce blood sugar. This can help prevent complications from your diabetes.

Contraindications When Eucreas is not to be used

Do not take Eucreas

if you are allergic to vildagliptin, metformin or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic to any of these substances, talk to your doctor before taking Eucreas.
if you have or have suffered from severe complications of diabetes, such as diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea and / or vomiting) or diabetic coma.
if you have recently had a heart attack or if you have heart failure or severe circulatory problems or difficulty in breathing which may be a sign of heart problems.
if you have kidney problems.
if you have a severe infection or are severely dehydrated (your body has lost a lot of water).
if you are to undergo an X-ray examination with a contrast agent (a particular type of X-ray that involves the use of a dye for injection). In this regard, see also the information given in the paragraph "Warnings and precautions".
if you have liver problems.
if you drink too much alcohol (whether you do so on a daily basis or only occasionally).
if you are breast-feeding (see also "Pregnancy and breast-feeding").

Precautions for use What you need to know before taking Eucreas

Stop taking this medicine and tell your doctor if you develop one or more of the following symptoms, which may be linked to a condition called 'lactic acidosis':

feeling cold or unwell
muscular pain
severe nausea or vomiting
pain in the stomach or surrounding areas (abdominal pain)
sleepiness or dizziness
rapid breathing

Eucreas is not a substitute for insulin. Therefore, Eucreas should not be prescribed to you for the treatment of type 1 diabetes.

Talk to your doctor, pharmacist or nurse with diabetes experience before taking Eucreas if you have or have ever had pancreatic disease.

Talk to your doctor, pharmacist or diabetes nurse before taking Eucreas if you are taking an anti-diabetic medicine known as a sulphonylurea. If you take it together with Eucreas, your doctor may want to reduce your dose of sulphonylurea, to avoid low blood glucose (hypoglycemia).

If you have previously taken vildagliptin but had to stop due to liver disease, you should not take this medicine.

Skin lesions are a common complication of diabetes. You are advised to follow the recommendations for skin and foot care given to you by your doctor or nurse. You are also advised to pay particular attention to the formation of new blisters or ulcers when taking Eucreas. If this happens you should contact immediately to the doctor.

If you have stopped using Eucreas for surgery (you must stop at least 48 hours before a scheduled surgery under general anesthesia and after the surgery you must not start again until at least 48 hours have passed) or for an x-ray that requires the use of an injectable dye, talk to your doctor before resuming treatment with Eucreas.

Before starting treatment with Eucreas, an examination will be carried out to evaluate the functioning of the liver, which will be repeated every three months during the first year of treatment and periodically thereafter. This is to detect signs of increased liver enzymes as soon as possible.

At least once a year, your doctor will check your kidneys are working properly. Your doctor will regularly check your blood and urine sugar content.

Elderly patients taking Eucreas should have their kidney function checked regularly. Check-ups should be more frequent in patients with kidney problems.

Children and adolescents

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

Interactions Which drugs or foods can change the effect of Eucreas

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is especially important if you are already taking other medicines used to treat heart disease or problems related to blood sugar, kidney or blood pressure problems, such as medicines containing:

glucocorticoids, generally used to treat inflammation
beta-2 agonists, generally used to treat respiratory disorders
other medicines used to treat diabetes
diuretics
ACE inhibitors, generally used to treat high blood pressure
certain medicines that affect the thyroid
certain medicines that affect the nervous system

Eucreas with alcohol

Avoid alcohol while taking Eucreas as alcohol can increase the risk of lactic acidosis (see also section "Possible side effects").

Warnings It is important to know that:

Pregnancy and breastfeeding

Tell your doctor if you are pregnant, if you think you may be pregnant or if you are planning to become pregnant. Your doctor will discuss with you the potential risks of taking Eucreas during pregnancy.
Do not use Eucreas if you are pregnant or breastfeeding (see also "Do not take Eucreas"). Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

If you feel dizzy when taking Eucreas, do not drive or use machines.

Dose, Method and Time of Administration How to use Eucreas: Posology

The amount of Eucreas that must be taken varies according to individual conditions. Your doctor will tell you exactly the dose to take.

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is one 50 mg / 850 mg or 50 mg / 1000 mg film-coated tablet taken twice daily.

If you have kidney problems, your doctor may prescribe a lower dose for you. Your doctor may prescribe a lower dose even if you are taking an antidiabetic known as a sulphonylurea.

Your doctor may prescribe this medicine alone or with some medicines that lower your blood sugar level.

When and how to take Eucreas

Take the tablets whole with a glass of water.
Take one tablet in the morning and the other in the evening, with food or immediately after eating. Taking the tablet immediately after eating will reduce the risk of stomach upset.

Continue to follow any dietary advice your doctor has given you, particularly if you are following a diabetes weight control diet, you should continue this while taking Eucreas.

If you forget to take Eucreas

If you forget to take a tablet, take it with your next meal, unless you are due to take one anyway. Do not take a double dose (two tablets together) to make up for a forgotten tablet.

If you stop taking Eucreas

Keep taking this medicine for as long as your doctor prescribes it so that you can continue to monitor your blood sugar. Do not stop taking Eucreas unless your doctor tells you to. If you have any questions about how long to take this medicine, ask your doctor.

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

Overdose What to do if you have taken too much Eucreas

If you take too many Eucreas tablets, or if someone else takes your tablets, talk to your doctor or pharmacist immediately.Medical attention may be required. If you need to go to a doctor or hospital, take the pack and this leaflet with you.

Side Effects What are the side effects of Eucreas

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

Some symptoms require immediate medical attention

You must stop taking Eucreas and contact your doctor immediately if any of the following side effects occur:

Angiedema (rare: may affect up to 1 in 1,000 people): symptoms include swelling of the face, tongue or throat, difficulty swallowing, difficulty breathing, sudden rash or hives, which may indicate a reaction called " angioedema ".
Liver disease (hepatitis) (rare): Symptoms include yellow skin and eyes, nausea, loss of appetite, or dark colored urine, which may indicate liver disease (hepatitis).
Inflammation of the pancreas (pancreatitis) (frequency not known). Symptoms include severe and persistent pain in the abdomen (stomach area) which may extend to the back, as well as nausea and vomiting.

Other side effects

Some patients have experienced the following side effects while taking Eucreas:

Very common (may affect more than 1 in 10 people): nausea, vomiting, diarrhea, pain in or around the stomach (abdominal pain), loss of appetite.
Common (may affect up to 1 in 10 people): dizziness, headache, hesitation that cannot be controlled, metallic taste, low blood glucose levels.
Uncommon (may affect up to 1 in 100 people): joint pain, tiredness, constipation, swelling of the hands, ankles or feet (edema).
Very rare (may affect up to 1 in 10,000 people): sore throat, runny nose, fever; signs of a high level of lactic acid in the blood (known as lactic acidosis) such as sleepiness or dizziness, severe nausea or vomiting, abdominal pain, irregular heartbeat or rapid and deep breathing; redness of the skin, itching; reduced levels of vitamin B12 (paleness, tiredness, mental symptoms such as confusion or memory problems).

Some patients have experienced the following side effects while taking Eucreas and a sulphonylurea:

Common: dizziness, tremor, weakness, low blood glucose, excessive sweating.

Some patients have experienced the following side effects while taking Eucreas and insulin:

Common: headache, chills, nausea (feeling sick), low blood glucose levels, heartburn.
Uncommon: diarrhea, flatulence.

The following side effects have also been reported during the marketing of this medicine.

Frequency not known (cannot be estimated from the available data): itchy rash, inflammation of the pancreas, localized peeling of the skin or blisters, muscle pain.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or diabetes nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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 carton after "EXP" / "EXP". The expiry date refers to the last day of the month.
Do not store above 30 ° C.
Store in the original package (blister) to protect the medicine from moisture.

Deadline "> Other information

What Eucreas contains

The active substances are vildagliptin and metformin hydrochloride.
Each Eucreas 50 mg / 850 mg film-coated tablet contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride (equivalent to 660 mg of metformin).
Each Eucreas 50 mg / 1000 mg film-coated tablet contains 50 mg of vildagliptin and 1000 mg of metformin hydrochloride (equivalent to 780 mg of metformin).
The other ingredients are: hydroxypropylcellulose, magnesium stearate, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), macrogol 4000 and talc.

What Eucreas looks like and contents of the pack

Eucreas 50 mg / 850 mg film-coated tablets are yellow, oval, with "NVR" on one side and "SEH" on the other.

Eucreas 50 mg / 1000 mg film-coated tablets are dark yellow, oval, with "NVR" on one side and "FLO" on the other.

Eucreas is available in packs containing 10, 30, 60, 120, 180 or 360 film-coated tablets and in multipacks containing 120 (2x60), 180 (3x60) or 360 (6x60) film-coated tablets.

Not all pack sizes may be marketed in your country.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Eucreas can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

EUCREAS 50 MG / 850 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each film-coated tablet contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride (corresponding to 660 mg of metformin).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablet.

Oval, yellow, film-coated, bevelled edge tablet debossed with the letters "NVR" on one side and "SEH" on the other.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Eucreas is indicated for the treatment of type 2 diabetes mellitus:

- Eucreas is indicated for the treatment of adult patients who are unable to achieve sufficient glycemic control with the maximum tolerated dose of oral metformin alone or who are already on a combination of vildagliptin and metformin given as separate tablets.

- Eucreas is indicated in combination with a sulphonylurea (triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled with metformin and a sulphonylurea.

- Eucreas is indicated for triple combination therapy with insulin as an adjunct to diet and exercise to improve glycemic control in adult patients for whom stable-dose insulin and metformin alone do not provide adequate glycemic control.

04.2 Posology and method of administration -

Dosage

Adults with normal renal function (GFR ≥ 90 mL / min)

The dose of antihyperglycemic therapy with Eucreas should be individualized based on the patient's current regimen, efficacy and tolerability without exceeding the maximum recommended daily dose of 100 mg vildagliptin. Eucreas can be started with either the 50 mg / 850 mg tablet or the 50 mg / 1000 mg tablet twice a day, one tablet in the morning and the other in the evening.

- For patients inadequately controlled on the maximum tolerated dose of metformin monotherapy:

The starting dose of Eucreas should provide 50 mg of vildagliptin twice daily (100 mg total daily dose) plus the dose of metformin already in use.

- For patients switching from co-administration of vildagliptin and metformin as separate tablets:

Eucreas should be started with the dose of vildagliptin and metformin already being used.

- For patients inadequately controlled with the dual combination of metformin and a sulphonylurea:

Eucreas doses should provide vildagliptin 50 mg twice daily (100 mg total daily dose) and the dose of metformin similar to the dose already in use. When Eucreas is used in combination with a sulphonylurea, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.

- For patients inadequately controlled on dual combination therapy with insulin and maximum tolerated dose of metformin:

The Eucreas dose should provide vildagliptin 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already in use.

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

Special populations

Elderly (≥ 65 years old)

Since metformin is excreted via the kidney and elderly patients have a tendency to have decreased renal function (Glomerular Filtration Rate, GFR), the renal function of elderly patients taking Eucreas should be monitored regularly (see sections 4.4 and 5.2).

Renal impairment

GFR should be assessed prior to initiating treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be evaluated more frequently. eg every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin treatment in patients with GFR

If an adequate strength of Eucreas is not available, the individual monocomponents should be used instead of the fixed dose combination.

GFR ml / min Metformin Vildagliptin 60-89 The maximum daily dose is 3,000 mg. A dose reduction may be considered in the event of worsening of renal function. No dose adjustment 45-59 The maximum daily dose is 2,000 mg. The starting dose should not exceed half of the maximum dose. The maximum total daily dose is 50 mg 30-44 The maximum daily dose is 1,000 mg. The starting dose should not exceed half of the maximum dose. Metformin is contraindicated.

Impaired liver function

Eucreas should not be used in patients with hepatic impairment, including patients who have alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 3x upper limit of normal (ULN) before treatment (see sections 4.3, 4.4 and 4.8).

Pediatric population

The use of Eucreas is not recommended in children and adolescents (

Method of administration

Oral use.

Taking Eucreas with food, or immediately after a meal, may reduce the gastrointestinal symptoms associated with metformin (see also section 5.2).

04.3 Contraindications -

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

• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

• Diabetic pre-coma

• Severe renal insufficiency (GFR

• Acute conditions potentially capable of altering renal function, such as

• dehydration,

• severe infection,

• shock,

• intravascular administration of iodinated contrast agents (see section 4.4).

• Acute or chronic conditions that can cause tissue hypoxia, such as

• heart or respiratory failure,

• recent myocardial infarction,

• shock.

• Hepatic impairment (see sections 4.2, 4.4 and 4.8).

• Acute alcoholic intoxication, alcoholism.

• Breastfeeding (see section 4.6).

04.4 Special warnings and appropriate precautions for use -

General

Eucreas is not a substitute for insulin in insulin dependent patients and should not be used in patients with type 1 diabetes.

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, occurs more frequently due to acute worsening of kidney function or cardiorespiratory disease or sepsis. Accumulation of metformin occurs with acute worsening of kidney function and increases the risk of lactic acidosis.

In the event of dehydration (severe diarrhea or vomiting, fever or reduced fluid intake), administration of metformin should be temporarily interrupted and the patient should be advised to consult a healthcare professional.

Caution should be exercised in initiating treatment with medicinal products that may acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) in patients treated with metformin. Other risk factors for lactic acidosis are excessive alcohol consumption, hepatic impairment, poorly controlled diabetes, ketosis, prolonged fasting and any other conditions associated with hypoxia, as well as concomitant use of medicinal products that can cause lactic acidosis (see sections 4.3 and 4.5).

Patients and / or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. If symptoms are suspected, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (plasma lactate (> 5 mmol / L) and increased anion gap and lactate / pyruvate ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents can lead to contrast-induced nephropathy. This causes accumulation of metformin and increases the risk of lactic acidosis. Metformin administration should be discontinued before or at the time of imaging and should not be resumed until at least 48 hours have elapsed after the examination. , provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5.)

Kidney function

GFR should be assessed prior to initiation of treatment and at regular intervals thereafter (see section 4.2). Metformin is contraindicated in patients with GFR

Impaired liver function

Patients with hepatic impairment, including patients with pre-treatment ALT or AST> 3x ULN, should not be treated with Eucreas (see sections 4.2, 4.4 and 4.8).

Control of liver enzymes

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, patients were generally asymptomatic with no clinical consequences and liver function tests returned to normal after discontinuation of treatment. Liver function tests should be performed before starting treatment with Eucreas in order to know the patient's baseline value. During treatment with Eucreas, liver function should be checked every three months during the first year of treatment and periodically thereafter. Patients who develop elevated transaminase levels should be checked with a second liver function assessment to confirm the results and then followed up with frequent liver function tests until the abnormality (s) returns to normal. . If the elevation in AST or ALT persists at 3 times the ULN or above, it is recommended that Eucreas be discontinued. Patients who develop jaundice or other signs suggesting hepatic dysfunction should discontinue Eucreas treatment. .

After discontinuation of Eucreas treatment and normalization of liver function parameters, Eucreas treatment should not be restarted.

Skin disorders

In non-clinical toxicology studies, skin lesions, including vesicles and ulcerations, on the extremities of monkeys have been reported with vildagliptin (see section 5.3). Although an "increased incidence of skin lesions" was not observed in clinical trials, there was limited experience in patients with diabetic skin complications. In addition, there have been post-marketing reports of bullous and exfoliative skin lesions.In accordance with the routine care of the diabetic patient, monitoring of any skin diseases, such as blisters and ulcerations, is therefore recommended.

Acute pancreatitis

The 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.

Hypoglycemia

Sulfonylureas are known to cause hypoglycemia. 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.

Surgical interventions

Metformin should be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy can be resumed no earlier than 48 hours following surgery or restarting oral nutrition, provided that renal function has been re-evaluated and found to be stable.

04.5 Interactions with other medicinal products and other forms of interaction -

No formal interaction studies have been performed for Eucreas. The following reflects the information available on the individual active substances.

Vildagliptin

Vildagliptin has a low potential for interaction when combined with other medicinal products. Since vildagliptin is not a substrate of the cytochrome P (CYP) 450 enzyme and does not inhibit or induce CYP 450 enzymes, interaction with active substances that are substrates, inhibitors or inducers of these enzymes is not likely.

The results of clinical studies performed with the oral antidiabetic agents pioglitazone, metformin and glibenclamide in combination with vildagliptin revealed no clinically relevant pharmacokinetic interactions in the reference population.

Drug interaction studies performed with digoxin (p-glycoprotein substrate) and warfarin (CYP2C9 substrate) in healthy subjects revealed no clinically relevant pharmacokinetic interactions following co-administration with vildagliptin.

Drug interaction studies have been performed with amlodipine, ramipril, valsartan and simvastatin in healthy subjects. In these studies, no clinically relevant pharmacokinetic interactions were observed following co-administration with vildagliptin. However, this evidence was not confirmed in the reference population.

Combination with ACE inhibitors

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

As with other oral antidiabetics, the hypoglycaemic effect of vildagliptin may be reduced by some active substances, including thiazides, corticosteroids, thyroid medicines and sympathomimetics.

Metformin

Concomitant use not recommended

Alcohol

Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Iodized contrast agents

Metformin administration should be discontinued prior to or at the time of imaging and should not be resumed until at least 48 hours have elapsed after examination, provided renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).

Cationic active ingredients

The cationic active substances eliminated by renal tubular secretion (eg cimetidine) can interact with metformin because they compete with the same renal tubular transport systems and thus reduce the elimination of metformin, increasing the risk of lactic acidosis. A study conducted. in healthy volunteers it has been shown that cimetidine, given at a dose of 400 mg twice daily, increases the systemic exposure (AUC) to metformin by 50%. Therefore, careful monitoring of glycemic control, dose adjustment within the recommended posology and changes in diabetes therapy should be considered when co-administering cationic medicinal products that are eliminated by renal tubular secretion (see section 4.4. ).

Associations requiring precautions for use

Some medicines can adversely affect kidney function, thereby increasing the risk of lactic acidosis, eg. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, particularly loop diuretics. When these medicinal products are used in combination with metformin, close monitoring of renal function is required.

Glucocorticoids, beta-2-agonists and diuretics possess intrinsic hyperglycemic activity. The patient should be informed and blood glucose monitoring should be performed more frequently, particularly at the start of treatment. If necessary, the dosage of Eucreas can be adjusted during concomitant therapy and at the time of its discontinuation.

Angiotensin converting enzyme inhibitors (ACE inhibitors) can decrease blood glucose levels. If necessary, the dosage of the hypoglycemic drug should be adjusted during therapy with the other drug taken concomitantly and at the time of its discontinuation.

04.6 Pregnancy and breastfeeding -

Pregnancy

There are no adequate data from the use of Eucreas in pregnant women. Studies with vildagliptin in animals have shown reproductive toxicity at high doses. Studies with metformin in animals have not shown reproductive toxicity. Studies with vildagliptin and metformin effected in animals showed no teratogenicity but foetotoxic effects at doses toxic to the mother (see section 5.3) The potential risk for humans is unknown Eucreas should not be used during pregnancy.

Feeding time

Animal studies have shown that both vildagliptin and metformin are excreted in milk. It is not known whether vildagliptin is excreted in human milk, but metformin is excreted in human milk in small amounts. Eucreas should not be used during lactation, either due to the potential risk of hypoglycaemia in the neonate due to metformin, or due to the lack of human data with vildagliptin (see section 4.3).

Fertility

Studies on the effect of Eucreas on human fertility have not been conducted (see section 5.3).

04.7 Effects on ability to drive and use machines -

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

04.8 Undesirable effects -

No therapeutic clinical studies have been performed with Eucreas. However, the bioequivalence of Eucreas with co-administered vildagliptin and metformin has been demonstrated (see section 5.2). The data presented here refer to the co-administration of vildagliptin and metformin, where vildagliptin was added to metformin. No studies have been performed in which metformin was added to vildagliptin.

Summary of the safety profile

Most adverse reactions were mild and transient in nature and did not require discontinuation of therapy. There was no association between adverse reactions and age, ethnicity, duration of exposure or daily dose. .

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, patients were generally asymptomatic with no clinical consequences and liver function returned to normal after discontinuation of treatment. From data from controlled monotherapy or add-on therapy studies of up to 24 weeks duration, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal (classified as present in at least 2 consecutive controls or at final visit during treatment) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. These transaminase elevations were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

Rare cases of angioedema have been reported with vildagliptin, with an incidence similar to the control group. The majority of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. Most events were of moderate severity and resolved during treatment with vildagliptin.

Table of adverse reactions

Adverse reactions reported in patients who received vildagliptin in double-blind studies as monotherapy and add-ons are listed below by system organ class and absolute frequency. The adverse reactions listed in Table 5 are based on information from the Summary of Product Characteristics of metformin available at European (EU) level. Frequencies are defined as very common (≥1 / 10), common (≥1 / 100, ≤1 / 10), uncommon (≥1 / 1,000,

Table 1 Adverse reactions reported in patients who received vildagliptin 100 mg daily in add-on with metformin compared to placebo plus metformin in double-blind studies (N = 208)

Metabolism and nutrition disorders common Hypoglycemia Nervous system disorders common Tremor common Headache common Dizziness Uncommon Fatigue Gastrointestinal disorders common Nausea

Description of selected adverse reactions

In controlled clinical trials with the combination of vildagliptin 100 mg daily plus metformin, no withdrawals due to adverse reactions were reported in either the vildagliptin 100 mg daily plus metformin group or the placebo plus metformin group.

In clinical studies, the incidence of hypoglycaemia was common in patients who received vildagliptin in combination with metformin (1%) and uncommon in patients who received placebo + metformin (0.4%). No serious events were reported. hypoglycaemics in the vildagliptin arms.

In clinical studies, weight did not change from baseline when vildagliptin 100 mg per day was combined with metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).

Clinical studies of up to more than 2 years duration have shown no additional safety signals or unanticipated risks when vildagliptin was combined with metformin.

Combination with a sulphonylurea

Table 2 Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with metformin and a sulphonylurea (N = 157)

Metabolism and nutrition disorders common Hypoglycemia Nervous system disorders common Dizziness, tremor Skin and subcutaneous tissue disorders common Hyperhidrosis General disorders and administration site conditions common Asthenia

Description of selected adverse reactions

There were no withdrawals due to adverse reactions reported in the vildagliptin + metformin + glimepiride treatment group compared to 0.6% in the placebo + metformin + glimepiride treatment group.

The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group). One event was reported in the vildagliptin group. of severe hypoglycemia.

At the end of the study, the effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

Association with insulin

Table 3 Adverse reactions reported in patients who received vildagliptin 100 mg daily in combination with insulin (with or without metformin) in double-blind studies (N = 371)

Metabolism and nutrition disorders common Decrease in blood glucose Nervous system disorders common Headache, chills Gastrointestinal disorders common Nausea, gastroesophageal reflux disease Uncommon Diarrhea, flatulence

Description of selected adverse reactions

In controlled clinical trials with the combination of vildagliptin 50 mg twice daily plus insulin, with or without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was 0.3% in the vildagliptin treatment group. and there were no withdrawals in the placebo group.

The incidence of hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin group versus 16.4% in the placebo group). Two patients in the vildagliptin group and 6 patients in the placebo group experienced serious hypoglycaemic events.

At the end of the study, the effect on mean body weight was neutral (+0.6 kg from baseline in the vildagliptin group and no weight change in the placebo group).

Further information on the individual active ingredients of the fixed combination

Vildagliptin

Table 4 Adverse reactions reported in patients who received vildagliptin 100 mg daily as monotherapy in double-blind studies (N = 1855)

Infections and infestations Very rare Upper respiratory tract infection Very rare Nasopharyngitis Metabolism and nutrition disorders Uncommon Hypoglycemia Nervous system disorders common Dizziness Uncommon Headache Vascular pathologies Uncommon Peripheral edema Gastrointestinal disorders Uncommon Constipation Musculoskeletal and connective tissue disorders Uncommon Arthralgia

Description of selected adverse reactions

The overall incidence of withdrawals from controlled monotherapy studies due to adverse reactions was not higher in patients treated with vildagliptin at doses of 100 mg daily (0.3%) compared to those treated with placebo (0.6%) or comparator medicines (0.5%).

In comparative controlled monotherapy studies, hypoglycaemia was uncommon and reported in 0.4% (7 of 1,855) of patients treated with vildagliptin at a dose of 100 mg daily compared with 0.2% (2 of 1,082) of patients. patients in the comparator or placebo groups, with no serious or severe events reported.

In clinical studies, weight did not change from baseline when vildagliptin 100 mg daily was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively).

Clinical studies of up to 2 years duration have shown no additional safety signals or unexpected risks when vildagliptin was combined with metformin.

Metformin

Table 5 Adverse reactions related to the metformin component

Metabolism and nutrition disorders Very rare Reduced absorption of vitamin B12 and lactic acidosis * Nervous system disorders common Metallic flavor Gastrointestinal disorders Very common Nausea, vomiting, diarrhea, abdominal pain and loss of appetite Hepatobiliary disorders Very rare Abnormal liver function tests or hepatitis ** Skin and subcutaneous tissue disorders Very rare Skin reactions such as erythema, itching and hives

* Reduced absorption of vitamin B12 with decreased serum levels has been observed very rarely in patients treated with metformin for long periods. If the patient has megaloblastic anemia, it is recommended that this etiology be considered.

** There have been isolated reports of liver function test abnormalities or hepatitis which resolved after discontinuation of metformin.

Gastrointestinal adverse reactions occur more frequently upon initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 daily doses, with or after meals. Even a slow increase in dose may improve. gastrointestinal tolerability.

Post-marketing experience

Table 6 Post-marketing adverse reactions

Gastrointestinal disorders Not known Pancreatitis Hepatobiliary disorders Not known Hepatitis (reversible after stopping the medicine) Abnormal liver function tests (reversible after stopping the medicine) Musculoskeletal and connective tissue disorders Not known Myalgia Skin and subcutaneous tissue disorders Not known Urticaria Bullous and exfoliative skin lesions

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.

04.9 Overdose -

There are no data on overdose with Eucreas.

Vildagliptin

Information on overdose with vildagliptin is limited.

Symptoms

Information on likely symptoms of overdose with vildagliptin was derived from a dose-escalation tolerability study in healthy subjects treated with vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain and individual cases of mild and transient paraesthesia, fever, edema and a transient increase in lipase levels. At 600 mg, one subject developed edema in the feet and hands and increased levels of creatine phosphokinase (CPK), AST, C-reactive protein (CRP), and myoglobin. Three other subjects developed foot edema, with paresthesia in two cases.All symptoms and laboratory abnormalities resolved without treatment after discontinuation of study drug.

Metformin

Severe metformin overdose (or the coexisting risk of lactic acidosis) can lead to lactic acidosis, which is an emergency medical condition and must be treated in hospital.

Treatment

The most effective method of removing metformin is hemodialysis. However, Vildagliptin cannot be eliminated by hemodialysis, although the major hydrolysis-derived metabolite may be (LAY 151). Supportive treatment is recommended.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: drugs used in diabetes, combinations of oral hypoglycemic drugs.

ATC code: A10BD08.

Mechanism of action

Eucreas combines two hypoglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the class of pancreatic islet modulators, and metformin hydrochloride, a member of the biguanide class.

Vildagliptin belongs to the class of pancreatic islet modulators and is a potent and selective inhibitor of dipeptidyl-peptidase-4 (DPP-4). Metformin works mainly by decreasing the endogenous production of glucose by the liver.

Pharmacodynamic effects

Vildagliptin

Vildagliptin works primarily by inhibiting DPP-4, the enzyme responsible for the degradation of the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide).

Administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity, resulting in increased endogenous fasting and postprandial levels of incretin GLP-1 and GIP.

By increasing endogenous levels of incretins, vildagliptin increases the sensitivity of beta cells to glucose, resulting in an improvement in glucose-dependent insulin secretion. Treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved i marker of beta cell function, including HOMA-β (Homeostasis Model Assessment -β), the ratio of proinsulin to insulin and the measures of responsiveness of the beta cells in the tolerance test for meals with frequent sampling. In non-diabetic subjects (normal blood glucose), vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous levels of GLP-1, vildagliptin also increases the sensitivity of alpha cells to glucose, resulting in more adequate glucagon secretion for glucose amounts.

The increase in the insulin / glucagon ratio in hyperglycemia caused by an increase in incretin levels causes a reduction in fasting and postprandial hepatic glucose production, resulting in a reduction in blood glucose.

The known effect of increased GLP-1 levels that slow gastric emptying is not observed in vildagliptin treatment.

Metformin

Metformin is a biguanide with hypoglycemic effects, which decreases both basal and postprandial plasma glucose. It does not stimulate insulin secretion so it does not produce hypoglycemia or weight gain.

Metformin can decrease the glucose level by three mechanisms:

- reducing the production of hepatic glucose by inhibiting gluconeogenesis and glycogenolysis;

- in the muscle, moderately increasing the sensitivity to insulin, improving theuptake and peripheral use of glucose;

- delaying intestinal absorption of glucose.

Metformin stimulates the intracellular synthesis of glycogen by acting on glycogen synthetase and increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, regardless of its action on blood glucose, metformin has favorable effects on lipid metabolism. This has been demonstrated at therapeutic doses in medium- or long-term controlled clinical trials: metformin reduces serum levels of total cholesterol, LDL cholesterol and triglycerides.

The UK Prospective Diabetes Study (UKPDS) randomized prospective study established the long-term benefit of intensive blood glucose control in type 2 diabetes. :

- a significant reduction in the absolute risk of any diabetes-related complications in the metformin group (29.8 events / 1,000 patient-years) versus the diet-only group (43.3 events / 1,000 patient-years), p = 0, 0023, and versus the combination of the sulfonylurea and insulin monotherapy groups (40.1 events / 1,000 patient-years), p = 0.0034;

- a significant reduction in the absolute risk of diabetes-related mortality: metformin 7.5 events / 1,000 patient-years, diet alone 12.7 events / 1,000 patient-years, p = 0.017;

- a significant reduction in the absolute risk of overall mortality: metformin 13.5 events / 1,000 patient-years versus diet alone 20.6 events / 1,000 patient-years (p = 0.011) and the combination of the sulfonylurea monotherapy and insulin 18.9 events / 1,000 patient-years (p = 0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events / 1,000 patient-years, diet alone 18 events / 1,000 patient-years (p = 0.01).

Clinical efficacy and safety

Vildagliptin, given to patients whose glycemic control was unsatisfactory despite metformin monotherapy treatment, after 6 months of treatment produced additional statistically significant mean reductions in HbA1c compared to placebo (differences between groups from -0.7% to -1.1% for vildagliptin 50 mg and 100 mg) The proportion of patients achieving ≥ 0.7% reduction in HbA1c from baseline was statistically significantly higher in both vildagliptin plus metformin groups (46 % and 60%, respectively) compared to the metformin plus placebo group (20%).

In a 24-week clinical study, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled on metformin (mean daily dose: 2020 mg). Compared with baseline HbA1c of 8.4%, the mean reductions were -0.9% with vildagliptin in combination with metformin and -1.0% with pioglitazone in combination with metformin. In patients receiving pioglitazone in combination with metformin it is A mean weight gain of +1.9 kg was observed compared to +0.3 kg observed in those receiving vildagliptin in combination with metformin.

In a study of up to more than 2 years duration, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg / day - 2-year mean dose: 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 in combination with metformin and -0.5% with glimepiride in combination with metformin, compared with a mean baseline HbA1c of 7.3%. The change in body weight was -0.2 kg with vildagliptin compared to +1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At the study endpoint (2 years), in both treatment groups, HbA1c was found to be similar to baseline values and body weight changes and differences in hypoglycemia were maintained.

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

The efficacy of the fixed combination of vildagliptin and metformin (titrated gradually to a dose of 50 mg / 500 mg twice daily or 50 mg / 1000 mg twice daily) as therapy was evaluated in a 24-week study. in previously untreated (de-novo) patients. HbA1c was reduced by -1.82% with vildagliptin / metformin 50 mg / 1000 mg twice daily, by -1.61% with vildagliptin / metformin 50 mg / 500 mg twice daily, -1.36% with metformin 1000 mg twice daily and -1.09% with vildagliptin 50 mg twice daily starting from a mean baseline HbA1c of 8.6 %. The reduction in HbA1c observed in patients with a baseline ≥10.0% was more prominent.

A 24-week, randomized, double-blind, placebo-controlled study 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 to placebo The placebo-adjusted mean reduction in HbA1c from a mean baseline of 8.8% was -0 , 76%.

A 24-week, randomized, double-blind, placebo-controlled study 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 to placebo. In the general population, the placebo-adjusted mean reduction in HbA1c from a mean baseline HbA1c of 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin, the mean placebo-adjusted reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycaemia in the general 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 patients receiving placebo had manifested 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, mean insulin dose of 80 IU / day) the mean reduction in HbA1c when vildagliptin ( 50 mg twice daily) was added to insulin was statistically and significantly greater than with placebo + insulin (0.5% vs. 0.2%). The incidence of hypoglycemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).

Cardiovascular risk

A meta-analysis of 25 Phase III clinical trials of greater than 2 years duration of independently and prospectively awarded cardiovascular events was performed. This analysis showed that vildagliptin treatment was not associated with an increased cardiovascular risk compared to comparisons. The composite endpoint of proven cardiovascular and cerebrovascular (CCV) events [acute coronary syndrome (ACS), transient ischemic attack (with evidence of heart attack on imaging), stroke or CCV death], was similar for vildagliptin compared to the combination of comparison of active and placebo [Mantel-Haenszel risk ratio 0.84 (95% confidence interval 0.63-1.12)]. A total of 99 out of 8,956 patients in the vildagliptin group reported an event versus 91 out of 6,061 patients in the comparator group.

Pediatric population

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

05.2 "Pharmacokinetic properties -

Eucreas

Absorption

Bioequivalence has been demonstrated between three strengths of Eucreas (50 mg / 500 mg, 50 mg / 850 mg and 50 mg / 1000 mg) and the free combination of vildagliptin and metformin hydrochloride tablets at the corresponding doses.

Food does not influence the degree and rate of absorption of vildagliptin by Eucreas. The rate and extent of absorption of metformin from Eucreas 50 mg / 1000 mg decreased when administered with food, as indicated by the 26% reduction in Cmax, 7% reduction in AUC and slowed Tmax (from 2, 0 to 4.0 hours).

The information below reflects the pharmacokinetic properties of the individual active substances in Eucreas.

Vildagliptin

Absorption

Following oral administration in the fasted state, vildagliptin is rapidly absorbed, with peak plasma concentrations occurring at 1.7 hours. Food slightly delays (2.5 hours) the time to reach peak plasma concentration, but does not alter the overall exposure (AUC). Administration of vildagliptin with food results in a reduced Cmax (19%) compared to However, the extent of the change is not clinically significant, so that vildagliptin can be taken regardless of food. The absolute bioavailability is 85%.

Distribution

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

Biotransformation

In humans, metabolism is the major route of elimination for vildagliptin and accounts for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano group and accounts for 57% of the dose, followed by from the hydrolysis product of amide (4% of the dose). DPP-4 partially contributes to vildagliptin hydrolysis according to one study in vivo conducted using DPP-4-free rats. Vildagliptin is not metabolised to a quantifiable extent by CYP 450 enzymes and, consequently, the metabolic clearance of vildagliptin is not expected to be affected by concomitant administration of CYP 450 inhibitor and / or inducer medicinal products. Studies in vitro demonstrated that vildagliptin does not inhibit / induce CYP 450 enzymes. Therefore vildagliptin is not likely to affect the metabolic clearance of medicinal products metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4 / 5 , when administered simultaneously.

Elimination

Following oral administration of [14C] vildagliptin, approximately 85% of the dose is excreted in the urine and 15% of the dose is recovered in the faeces. After oral administration, the renal excretion of unchanged vildagliptin amounts to 23% of the dose. In healthy subjects, following intravenous administration, the total plasma and renal clearances of vildagliptin are 41 and 13 L / hour, respectively. After administration by route intravenous, the mean elimination half-life is approximately 2 hours. After oral administration, the elimination half-life is approximately 3 hours.

Linearity / non-linearity

Within the therapeutic dose range, vildagliptin Cmax and area under the plasma concentration-time curve (AUC) increase approximately dose proportionally.

Special patient groups

Gender: No clinically relevant differences in vildagliptin pharmacokinetics were observed between healthy male and female subjects over a "wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin does not is influenced by sex.

Age: In elderly healthy subjects (≥ 70 years), overall vildagliptin exposure (100 mg once daily) increased by 32%, with an 18% increase in peak plasma concentration, compared to healthy young subjects. (18-40 years). However, these changes are not considered clinically relevant. Inhibition of DPP-4 by vildagliptin is not affected by age.

Hepatic impairment: There were no clinically significant changes in vildagliptin exposure (maximum ≥30%) in subjects with mild, moderate or severe (Child-Pugh A-C) hepatic impairment.

Renal impairment: In subjects with mild, moderate or severe renal impairment, systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) and total body clearance was reduced compared to subjects with normal kidney function.

Ethnic groups: Limited data suggest that ethnicity does not have a major influence on the pharmacokinetics of vildagliptin.

Metformin

Absorption

After an oral dose of metformin, the maximum plasma concentration (Cmax) is achieved after approximately 2.5 hours. The absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose the unabsorbed fraction found in the faeces is 20-30%.

After oral administration, the absorption of metformin is saturable and incomplete. It is assumed that the absorption kinetics of metformin are non-linear. At doses and according to the normal posology of metformin, steady-state plasma concentrations are achieved within 24-48. hours and are generally less than 1 μg / mL In controlled clinical trials, maximum plasma metformin levels (Cmax) did not exceed 4 μg / mL, even at maximum doses.

Food slightly delays and decreases the extent of absorption of metformin. Following administration of the 850 mg dose, the peak plasma concentration was 40% lower, the AUC decreased by 25%, and the time to peak plasma concentration was prolonged by 35 minutes. Clinical relevance of this decrease is unknown.

Distribution

Plasma protein binding is negligible. Metformin distributes into erythrocytes. The mean volume of distribution (Vd) ranged from 63 to 276 liters.

Metabolism

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Metformin is eliminated by renal excretion. Renal clearance of metformin is> 400 mL / min indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged. resulting in increased plasma metformin levels.

05.3 Preclinical safety data -

Animal studies of up to 13 weeks duration have been performed with the associated substances in Eucreas. No new combination-related toxicities were identified. The following data are the results of individual studies with vildagliptin or metformin.

Vildagliptin

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

An accumulation of foamy alveolar macrophages in the lungs was observed in rats and mice. The no effect dose was 25 mg / kg (5 times the human exposure based on AUC) in rats and 750 mg / kg (142 times the human exposure) in mice.

Gastrointestinal symptoms, particularly soft stools, mucoid stools, diarrhea and, at higher doses, blood in the stool have been observed in dogs. A no-effect level has not been established.

In conventional genotoxicity studies in vitro And in vivo vildagliptin was not mutagenic.

In rats, a fertility and early embryonic development study did not show that vildagliptin causes impairment of fertility, reproductive capacity or early embryonic development. Embryo-fetal toxicity was evaluated in rats and rabbits. In rats, an increased incidence of floating ribs was observed in association with a decrease in maternal body weight parameters, with a no effect dose of 75 mg / kg (10 times the human exposure). In rabbits, decreased fetal weight and skeletal changes, indicative of developmental delay, were observed only in the presence of severe maternal toxicity, with a no-effect dose of 50 mg / kg (9 times the human exposure). A study on pre- and postnatal development was performed in rats Effects were observed only in association with maternal toxicity with ≥ 150 mg / kg and including a transient reduction in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study in rats was performed with oral doses up to 900 mg / kg (approximately 200 times the human exposure at the maximum recommended dose). No increase in the incidence of tumors attributable to vildagliptin was observed. Another two-year carcinogenicity study was conducted in mice with oral doses up to 1000 mg / kg. An increase in the incidence of mammary and breast adenocarcinomas was observed. hemangiosarcomas, with no effect doses of 500 mg / kg (59 times the human exposure) and 100 mg / kg (16 times the human exposure), respectively. The increased incidence of these tumors in mice was not considered to represent a significant risk to humans based on the lack of genotoxicity of vildagliptin and its major metabolite, the development of tumors in one species and all. high systemic exposure ratio at which tumors were observed.

In a 13-week toxicology study in monkeys cynomolgus skin lesions have been reported at doses ≥ 5 mg / kg / day. The lesions were consistently localized to the extremities (hands, feet, ears and tail). At a dose of 5 mg / kg / day (approximately equivalent to the human AUC after exposure to the 100 mg dose) only vesicles were observed. These regressed despite continuing treatment and were not associated with histopathological abnormalities. At doses ≥ 20 mg / kg / day (approximately 3 times the AUC in humans after exposure to the 100 mg dose), peeling and peeling of the skin, scabs and tail sores, with related histopathological changes, were noted. Necrotic lesions of the tail were observed at doses ≥ 80 mg / kg / day. Over a 4-week recovery period, skin lesions did not regress in monkeys treated with 160 mg / kg / day.

Metformin

Non-clinical data on metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Tablet core:

Hydroxypropylcellulose

Magnesium stearate

Coating film:

Hypromellose

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Macrogol 4000

Talc

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

PA / Alu / PVC / Alu 2 years

PCTFE / PVC / Alu 18 months

06.4 Special precautions for storage -

Do not store above 30 ° C.

Store in the original package (blister) to protect the medicine from moisture.

06.5 Nature of the immediate packaging and contents of the package -

Aluminum / aluminum blister (PA / Alu / PVC / Alu)

Available in packs containing 10, 30, 60, 120, 180 or 360 film-coated tablets and in multipacks containing 120 (2 packs of 60), 180 (3 packs of 60) or 360 (6 packs of 60) coated tablets. movie.

Polychlorotrifluoroethylene (PCTFE) / PVC / Alu blisters

Available in packs containing 10, 30, 60, 120, 180 or 360 film-coated tablets and in multipacks containing 120 (2 packs of 60), 180 (3 packs of 60) or 360 (6 packs of 60) coated tablets. movie.

Not all pack sizes and strengths may be marketed.