2017 ‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר על ידו בפברואר‬

1. NAME OF THE MEDICINAL PRODUCT

Eucreas® 50 mg/500 mg
Eucreas® 50 mg/850 mg
Eucreas® 50 mg/1000 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of vildagliptin and 500, 850 or 1000 mg of metformin
hydrochloride.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Eucreas 50 mg/500 mg: light yellow, ovaloid film-coated tablet, beveled edge, imprinted with
"NVR" on one side and "LLO" on the other side.
Eucreas 50 mg/850 mg: yellow, ovaloid film-coated tablet, beveled edges, imprinted with
“NVR” on one side and “SEH” on the other side.
Eucreas 50 mg/1000 mg: dark yellow, ovaloid film coated tablet, beveled edges, imprinted with
"NVR" on one side and "FLO" on the other side.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Eucreas is indicated in the treatment of type 2 diabetes mellitus:
 Eucreas is indicated in the treatment of adult patients who are unable to achieve sufficient
glycemic control at their maximally tolerated dose of oral metformin alone or who are
already treated with the combination of vildagliptin and metformin as separate tablets.
 Eucreas is indicated in combination with a sulfonylurea (i.e. triple combination therapy)
as an adjunct to diet and exercise in adult patients inadequately controlled with
metformin and a sulfonylurea.
 Eucreas is indicated in triple combination therapy with insulin as an adjunct to diet and
exercise to improve glycaemic control in adult patients when insulin at a stable dose and
metformin alone do not provide adequate glycaemic control.

4.2 Posology and method of administration

Posology
Adults with normal renal function (GFR ≥ 90 ml/min)
The dose of antihyperglycaemic therapy with Eucreas should be individualised on the basis of the
patient’s current regimen, effectiveness and tolerability while not exceeding the maximum
recommended daily dose of 100 mg vildagliptin. Based on the patient’s current dose of

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metformin,Eucreas may be initiated at either 50 mg /500 mg or 50 mg/850 mg or 50 mg/1000 mg
tablet strength twice daily, one tablet in the morning and the other in the evening.
- For patients inadequately controlled at their maximal tolerated dose of metformin
monotherapy:
The starting dose of Eucreas should provide vildagliptin as 50 mg twice daily (100 mg total daily
dose) plus the dose of metformin already being taken.
For patients switching from co-administration of vildagliptin and metformin as separate tablets:
Eucreas should be initiated at the dose of vildagliptin and metformin already being taken.
For patients inadequately controlled on dual combination with metformin and a sulfonylurea: The
doses of Eucreas should provide vildagliptin as 50 mg twice daily (100 mg total daily dose) and a
dose of metformin similar to the dose already being taken. When Eucreas is used in combination
with a sulfonylurea, a lower dose of the sulfonylurea may be considered to reduce the risk of
hypoglycaemia.
For patients inadequately controlled on dual combination therapy with insulin and the maximal
tolerated dose of metformin: The doses of Eucreas should provide vildagliptin as 50 mg twice
daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.
The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with a
thiazolidinedione have not been established.
Special populations
Elderly (≥ 65 years)
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal
function, elderly patients taking Eucreas should have their renal function monitored regularly.
(see section 4.4 and 5.2).
Renal impairment
A GFR should be assessed before initiation of treatment with metformin-containing
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 assessed
more frequently, e.g. 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 in patients with GFR<60 ml/min.

If no adequate strength of Eucreas is available, individual monocomponents should be

used instead of the fixed dose combination.

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GFR ml/min Metformin Vildagliptin

60-89 Maximum daily dose is 3000 mg. No dose adjustment.

Dose reduction may be considered

in relation to declining renal function.

45-59 Maximum daily dose is 2000 mg. Maximal total daily dose is
50 mg.
The starting dose is at most half of
the maximum dose.

30-44 Maximum daily dose is 1000 mg.

The starting dose is at most half of

the maximum dose.

<30 Metformin is contraindicated.

Hepatic impairment
Eucreas should not be used in patients with hepatic impairment, including those with pre-
treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the
upper limit of normal (ULN) (see sections 4.3, 4.4 and 4.8).

Paediatric population
Eucreas is not recommended for use in children and adolescents (< 18 years). The safety and
efficacy of Eucreas in children and adolescents (< 18 years) have not been established. No data
are available.
Method of administration

Oral use.

Taking Eucreas with or just after food may reduce gastrointestinal symptoms associated with
metformin (see also section 5.2).

4.3 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 failure (GFR < 30 ml/min) (see section 4.4) − Acute conditions with the potential
to alter renal function, such as:
- dehydration,
- severe infection,
- shock,
- intravascular administration of iodinated contrast agents (see section 4.4).
− Acute or chronic disease which may cause tissue hypoxia, such as:
- cardiac or respiratory failure,
- recent myocardial infarction,

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 - shock.
− Hepatic impairment (see sections 4.2, 4.4 and 4.8)
− Acute alcohol intoxication, alcoholism
− Breast-feeding (see section 4.6)

4.4 Special warnings and precautions for use

General
Eucreas is not a substitute for insulin in insulin-requiring patients and should not be used in
patients with type 1 diabetes.
Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at
acute worsening of renal function, or cardiorespiratory illness or sepsis. Metformin
accumulation occurs at acute worsening of renal function and increases the risk of lactic
acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake),

metformin should be temporarily discontinued and contact with a health care
professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives,
diuretics and NSAIDs) should be initiated with caution in metformin-treated patients.
Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency,
inadequately controlled diabetes, ketosis, prolonged fasting and any conditions
associated with hypoxia, as well as concomitant use of medicinal products that may
cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers

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.
In case of suspected symptoms, the patient should stop taking metformin and seek
immediate medical attention. Diagnostic laboratory findings are decreased blood pH
(< 7.35), increased plasma lactate levels (> 5 mmol/l) and an increased anion gap and
lactate/pyruvate ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced

nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis.
Metformin should be discontinued prior to or at the time of the imaging procedure and
not restarted until at least 48 hours after, provided that renal function has been re-
evaluated and found to be stable (see sections 4.2 and 4.5).

Renal function
GFR should be assessed before treatment initiation and regularly thereafter (see
section 4.2). Metformin is contraindicated in patients with GFR < 30 ml/min and should
be temporarily discontinued in the presence of conditions that alter renal function (see
section 4.3).

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Hepatic impairment
Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN
should not be treated with Eucreas (see sections 4.2, 4.3 and 4.8).
Liver enzyme monitoring
Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In
these cases, the patients were generally asymptomatic without clinical sequelae and liver function
tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed
prior to the initiation of treatment with Eucreas in order to know the patient’s baseline value.
Liver function should be monitored during treatment with Eucreas 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 LFTs until the abnormality(ies) return(s) to normal. Should an
increase in AST or in ALT of 3x ULN or greater persist, withdrawal of Eucreas therapy is
recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction
should discontinue Eucreas.
Following withdrawal of treatment with Eucreas and LFT normalization, treatment with Eucreas
should not be re-initiated.
Skin disorders
Skin lesions, including blistering and ulceration have been reported with vildagliptin 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
Sulfonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination
with a sulfonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulfonylurea
may be considered to reduce the risk of hypoglycaemia.

Surgery
Metformin must be discontinued at the time of surgery under general, spinal or epidural
anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or
resumption of oral nutrition and provided that renal function has been re-evaluated and
found to be stable.

4.5 Interaction with other medicinal products and other forms of interaction

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There have been no formal interaction studies for Eucreas. The following statements reflect the
information available on the individual active substances.
Vildagliptin
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.
Results from clinical trials conducted with the oral antidiabetics pioglitazone, metformin and
glyburide in combination with vildagliptin have shown no clinically relevant pharmacokinetic
interactions in the target population.
Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin (CYP2C9
substrate) in healthy subjects have shown no clinically relevant pharmacokinetic interactions after
co-administration with vildagliptin.
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. However, this has not been established in
the target population.

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 hypoglycemic effect of vildagliptin may be
reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
sympathomimetics.
Metformin
Combinations not recommended
Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in

cases of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Metformin must be discontinued prior to or at the time of the imaging procedure and not
restarted until at least 48 hours after, provided that renal function has been re-evaluated
and found to be stable (see sections 4.2 and 4.4).
Cationic active substances
Cationic active substances that are eliminated by renal tubular secretion (e.g. cimetidine) may
interact with metformin by competing for common renal tubular transport systems and hence
delay the elimination of metformin, which may increase the risk of lactic acidosis. A study in
healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased
metformin systemic exposure (AUC) by 50%. Therefore, close monitoring of glycemic control,
dose adjustment within the recommended posology and changes in diabetic treatment should be
considered when cationic medicinal products that are eliminated by renal tubular secretion are co-
administered (see section 4.4).

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Combinations requiring precautions for use
Some medicinal products can adversely affect renal function which may increase the risk of lactic
acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,
angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using
such products in combination with metformin, close monitoring of renal function is necessary.

Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycemic activity. The patient
should be informed and more frequent blood glucose monitoring performed, especially at the
beginning of treatment. If necessary, the dosage of Eucreas may need to be adjusted during
concomitant therapy and on its discontinuation.
Angiotensin converting enzyme (ACE) inhibitors may decrease the blood glucose levels. If
necessary, the dosage of the antihyperglycemic medicinal product should be adjusted during
therapy with the other medicinal product and on its discontinuation.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequate data from the use of Eucreas in pregnant women. For vildagliptin studies
in animals have shown reproductive toxicity at high doses. For metformin, studies in animals
have not shown reproductive toxicity. Studies in animals performed with vildagliptin and
metformin have not shown evidence of teratogenicity, but foetotoxic effects at maternotoxic
doses (see section 5.3). The potential risk for humans is unknown. Eucreas should not be used
during pregnancy.
Breast-feedingStudies in animals have shown excretion of both metformin and vildagliptin in
milk. It is unknown whether vildagliptin is excreted in human milk, but metformin is excreted in
human milk in low amounts. Due to both the potential risk of neonate hypoglycaemia related to
metformin and the lack of human data with vildagliptin, Eucreas should not be used during
breast-feeding (see section 4.3).
Fertility
No studies on the effect on human fertility have been conducted for Eucreas (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Patients
who may experience dizziness as an undesirable effect should avoid driving vehicles or using
machines.
4.8 Undesirable effects
There have been no therapeutic clinical trials conducted with Eucreas. However, bioequivalence
of Eucreas with co-administered vildagliptin and metformin has been demonstrated (see section
5.2). The data presented here relate to the co-administration of vildagliptin and metformin, where
vildagliptin has been added to metformin. There have been no studies of metformin added to
vildagliptin.
Summary of the safety profile
The majority of adverse reactions were mild and transient, not requiring treatment
discontinuations. No association was found between adverse reactions and age, ethnicity, duration
of exposure or daily dose.

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Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. 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 ≥ 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.
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 ACE inhibitor. The majority of events were mild in severity and resolved with ongoing
vildagliptin treatment.
Tabulated list of adverse reactions
Adverse reactions reported in patients who received vildagliptin in double-blind studies as
monotherapy and add-on therapies are listed below by system organ class and absolute frequency.
Adverse reactions listed in Table 5 are based on information available from the metformin
Summary of Product Characteristics available in the EU. 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, undesirable effects are presented in order of decreasing
seriousness.

Table 1 Adverse reactions reported in patients who received vildagliptin 100 mg daily
as add-on therapy to metformin compared to placebo plus metformin in double-
blind studies (N=208)
Nervous system disorders
Common Tremor
Common Headache
Common Dizziness
Uncommon Fatigue
Gastrointestinal disorders
Common Nausea
Metabolism and nutrition disorders
Common Hypoglycaemia

Description of selected adverse reactions

In controlled clinical trials with the combination of vildagliptin 100 mg daily plus metformin, no
withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily plus
metformin or the placebo plus metformin treatment groups.
In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin
in combination with metformin (1%) and uncommon in patients receiving placebo + metformin
(0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.
In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily was added
to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).
Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or
unforeseen risks when vildagliptin was added on to metformin.
Combination with a sulfonylurea

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

Metabolism and nutritional disorders

Common Hypoglycemia

Nervous system disorders

Common Dizziness, Tremor
Skin and subcutaneous tissue disorders
Common Hyperhidrosis
General disorder 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 versus 0.6% in the placebo + metformin + glimepiride treatment
group.
The incidence of hypoglycemia was common in both treatment groups (5.1% for the vildagliptin
+ metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group).
One severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, effect on mean body weight was neutral (+0.6 kg in the vildagliptin group
and -0.1 kg in the placebo group).
Combination 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 Decreased blood glucose

Nervous system disorders

Common Headache, chills
Gastrointestinal disorders
Common Nausea, gastro-oesophageal reflux disease
Uncommon Diarrhoea, flatulence

Description of selected adverse reactions

In controlled clinical trials using vildagliptin 50 mg twice daily in combination with 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 hypoglycemia was similar in both treatment groups (14.0% in the vildagliptin
group vs 16.4% in the placebo group). Two patients reported severe hypoglycemic events in the
vildagliptin group, and 6 patients in the placebo group.
At the end of the study, effect on mean body weight was neutral (+0.6 kg change from baseline in
the vildagliptin group and no weight change in the placebo group).

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Additional information on the individual active substances 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)
Nervous system disorders

Common Dizziness

Uncommon Headache

Gastrointestinal disorders

Uncommon Constipation

Musculoskeletal and connective tissue disorders

Uncommon Arthralgia

Metabolism and nutrition disorders

Uncommon Hypoglycaemia

Infections and infestations

Very rare Upper respiratory tract infection

Very rare Nasopharyngitis

Vascular disorders

Uncommon Oedema peripheral

Description of selected adverse reactions

The overall incidence of withdrawals from controlled monotherapy trials due to adverse reactions
was no greater for patients treated with vildagliptin at doses of 100 mg daily (0.3%) than for
placebo (0.6%) or comparators (0.5%).
In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4%
(7 of 1,855) of patients treated with vildagliptin 100 mg daily compared to 0.2% (2 of 1,082) of
patients in the groups treated with an active comparator or placebo, with no serious or severe
events reported.
In clinical trials, 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 trials of up to 2 years’ duration did not show any additional safety signals or unforeseen
risks with vildagliptin monotherapy.
Metformin
Table 5 Adverse reactions for metformin component
Metabolism and nutrition disorders
Very Rare Decrease of vitamin B absorption and lactic acidosis*
12
Nervous system disorders
Common Metallic taste

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Gastrointestinal disorders
Very common Nausea, vomiting, diarrhea, abdominal pain and loss of appetite
Hepatobiliary disorders
Very rare Liver function test abnormalities or hepatitis**
Skin and subcutaneous tissue disorder
Very rare Skin reactions such as erythema, pruritus and urticaria

*A decrease in vitamin B12 absorption with decrease in serum levels has been very rarely
observed in patients treated long-term with metformin. Consideration of such etiology is
recommended if a patient presents with megaloblastic anemia.
**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin
discontinuation have been reported.
Gastrointestinal undesirable effects occur most frequently during initiation of therapy and resolve
spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2
daily doses during or after meals. A slow increase in the dose may also improve gastrointestinal
tolerability.

Post-marketing experience

Table 6 Post-marketing adverse reactions

Gastrointestinal disorders
Not known Pancreatitis
Hepatobiliary disorders
Not known Hepatitis (reversible upon discontinuation of
the medicinal product)
Abnormal liver function tests (reversible upon
discontinuation of the medicinal product)
Musculoskeletal and connective tissue
disorders

Not known Myalgia

Skin and subcutaneous tissue disorders

Not known Urticaria
Bullous or exfoliative skin lesions

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.
Any suspected adverse events should be reported to the Ministry of Health according to the
National Regulation by using an online form
http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@mo
h.gov.il

4.9 Overdose

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No data are available with regard to overdose of Eucreas.
Vildagliptin
Information regarding overdose with vildagliptin is limited.

Symptoms
Information on the likely symptoms of overdose with vildagliptin was taken from a rising dose
tolerability study in healthy subjects given vildagliptin for 10 days. At 400 mg, there were three
cases of muscle pain, and individual cases of mild and transient paresthesia, fever, edema and a
transient increase in lipase levels. At 600 mg, one subject experienced edema of the feet and
hands, and increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and
myoglobin levels. Three other subjects experienced edema of the feet, with paresthesia in two
cases. All symptoms and laboratory abnormalities resolved without treatment after
discontinuation of the study medicinal product.
Metformin
A large overdose of metformin (or co-existing risk of lactic acidosis) may lead to lactic acidosis,
which is a medical emergency and must be treated in hospital.
Management
The most effective method of removing metformin is hemodialysis. However, vildagliptin cannot
be removed by hemodialysis, although the major hydrolysis metabolite (LAY 151) can.
Supportive management is recommended.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering
drugs, ATC code: A10BD08.
Mechanism of action
Eucreas combines two antihyperglycemic agents with complimentary mechanisms of action to
improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the islet
enhancer class, and metformin hydrochloride, a member of the biguanide class.
Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4
(DPP-4) inhibitor. Metformin acts primarily by decreasing endogenous hepatic glucose
production.
Pharmacodynamic effects
Vildagliptin
Vildagliptin acts primarily by inhibiting DPP-4, the enzyme responsible for the degradation of the
incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic
polypeptide).
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
and GIP.
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-β (Homeostasis Model Assessment–β),
proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled

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meal tolerance test. In non-diabetic (normal glycemic) 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.

Metformin
Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce
hypoglycaemia or increased weight gain.
Metformin may exert its glucose-lowering effect via three mechanisms:
- by reduction of hepatic glucose production through inhibition of gluconeogenesis and
glycogenolysis;
- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose \
uptake and utilisation;
- by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase and
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and
GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces serum levels of total cholesterol, LDL cholesterol and
triglycerides.
The prospective randomized UKPDS (UK Prospective Diabetes Study) study has established the
long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for
overweight patients treated with metformin after failure of diet alone showed:
- a significant reduction in the absolute risk of any diabetes-related complication in the
metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000
patient-years), p=0.0023, and versus the combined 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 versus the combined sulfonylurea and insulin monotherapy groups 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 added to patients whose glycemic control was not satisfactory despite treatment with
metformin monotherapy resulted after 6-month treatment in additional statistically significant

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mean reductions in HbA1c compared to placebo (between group differences of -0.7% to -1.1% for
vildagliptin 50 mg and 100 mg, respectively). The proportion of patients who achieved a decrease
in HbA1c of ≥ 0.7% from baseline was statistically significantly higher in both vildagliptin plus
metformin groups (46% and 60%, respectively) versus the metformin plus placebo group (20%).

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 randomized, 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 (≥ 1,500 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 randomized, 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

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HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycemia 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 or 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%).
Cardiovascular risk
A meta-analysis of independently and prospectively adjudicated cardiovascular events from 25
phase III clinical studies of up to more than 2 years duration was performed and showed that
vildagliptin treatment was not associated with an increase in cardiovascular risk versus
comparators. The composite endpoint of adjudicated cardiovascular cerebrovascular (CCV)
events [acute coronary syndrome (ACS), transient ischemic attack (with imaging evidence of
infarction), stroke or CCV death], was similar for vildagliptin versus combined active and
placebo comparators [Mantel–Haenszel risk ratio 0.84 (95% confidence interval 0.63-1.12)]. In
total, 99 out of 8956 patients reported an event in the vildagliptin group vs 91 out of 6061 patients
in the comparator group.
5.2 Pharmacokinetic properties
Eucreas
Absorption
Bioequivalence has been demonstrated between Eucreas at three dose strengths (50 mg/500 mg,
50 mg/850 mg and 50 mg/1000 mg) versus free combination of vildagliptin and metformin
hydrochloride tablets at the corresponding doses.
Food does not affect the extent and rate of absorption of vildagliptin from Eucreas. The rate and
extent of absorption of metformin from Eucreas 50 mg/1000 mg were decreased when given with
food as reflected by the decrease in C by 26%, AUC by 7% and delayed T (2.0 to 4.0 h).
max max

The following statements reflect the pharmacokinetic properties of the individual active
substances of Eucreas.
Vildagliptin
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 C (19%) compared to dosing in the fasting state.
max
However, the magnitude of change is not clinically significant, so that vildagliptin 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

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product of the cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis
product (4% of dose). DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in
vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by CYP 450 enzymes to
any quantifiable extent, and 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 metabolized by CYP 1A2, CYP 2C8,
CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
14
Following oral administration of [ C] vildagliptin, approximately 85% of the dose was excreted
into the urine and 15% of the dose was recovered in the feces. 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 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.
Age: 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 not considered to be clinically relevant,
however. DPP-4 inhibition by vildagliptin is not affected by age.
Hepatic impairment: In subjects with mild, moderate or severe hepatic impairment (Child-Pugh
A-C) there were no clinically significant changes (maximum ~30%) in exposure to vildagliptin.
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 renal function.
Ethnic group: Limited data suggest that race does not have any major influence on vildagliptin
pharmacokinetics.
Metformin
Absorption
After an oral dose of metformin, the maximum plasma concentration (Cmax) is achieved after
about 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in
healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption are non-linear. At the usual metformin doses and
dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally
less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (C ) did not
max
exceed 4 μg/ml, even at maximum doses.

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Food slightly delays and decreases the extent of the absorption of metformin. Following
administration of a dose of 850 mg, the plasma peak concentration was 40% lower, AUC was
decreased by 25% and time to peak plasma concentration was prolonged by 35 minutes. The
clinical relevance of this decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The mean volume of
distribution (Vd) ranged between 63-276 litres.

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 h. When renal
function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the
elimination half-life is prolonged, leading to increased levels of metformin in plasma.
5.3 Preclinical safety data
Animal studies of up to 13-week duration have been conducted with the combined substances in
Eucreas. No new toxicities associated with the combination were identified. The following data
are findings from studies performed with vildagliptin or metformin individually.
Vildagliptin
Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg
(7-fold human exposure based on C ).
max
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 feces, mucoid feces, diarrhea 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-
fetal 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 fetal 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 hemangiosarcomas 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

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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.
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
toxicity to reproduction.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Hydroxypropylcellulose
Magnesium stearate
Film-coating:
Hypromellose
Titanium dioxide (E 171)
Iron oxide, yellow (E 172)
Polyethylene glycol 4000
Talc
Iron oxide, red (E 172) (50/500 mg only)

6.2 Incompatibilities
Not applicable.
6.3 Special precautions for storage
Store below 300C in the original package in order to protect from moisture.
6.4 Nature and contents of container
PA/Al/PVC blister with Aluminium foil
Available in packs containing:
60 film-coated tablets.

6.5 Special precautions for disposal

No special requirements.

Manufacturer:
Novartis Pharma Produktions GmbH, Wehr, Germany
for Novartis Pharma AG, Basel, Switzerland

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Registration Holder:
Novartis Israel Ltd.,
36 Shacham St., Petach-Tikva.

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