ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Eucreas 50 mg/850 mg film-coated tablets
2.
Each film-coated tablet contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride
(corresponding to 660 mg of metformin).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Yellow, ovaloid film-coated tablet with bevelled edge, imprinted with “NVR” on one side and “SEH”
on the other side.
4.
Eucreas is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve
sufficient glycaemic 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.
Adults
Based on the patient’s current dose of metformin, Eucreas may be initiated at either the 50 mg/850 mg
or 50 mg/1000 mg tablet strength twice daily, one tablet in the morning and the other in the evening.
The recommended daily dose is 100 mg vildagliptin plus 2000 mg metformin hydrochloride.
Patients receiving vildagliptin and metformin from separate tablets may be switched to Eucreas
containing the same doses of each component.
Doses higher than 100 mg of vildagliptin are not recommended.
There is no clinical experience of vildagliptin and metformin in triple combination with other
antidiabetic agents.
Taking Eucreas with or just after food may reduce gastrointestinal symptoms associated with
metformin (see also section 5.2).
Additional information on special populations
Renal impairment
Eucreas should not be used in patients with creatinine clearance < 60 ml/min (see sections 4.3, 4.4 and
5.2).
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).
2
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
sections 4.4 and 5.2).
Paediatric population (< 18 years)
Eucreas is not recommended for use in children and adolescents due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substances or to any of the excipients
Diabetic ketoacidosis or diabetic pre-coma
Renal failure or renal dysfunction defined as creatinine clearance < 60 ml/min (see section 4.4)
Acute conditions with the potential to alter renal function, such as:
-
-
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,
-
shock.
Hepatic impairment (see sections 4.2, 4.4 and 4.8)
Acute alcohol intoxication, alcoholism
Lactation (see section 4.6)
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 is a very rare but serious metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. In patients with impaired liver function, lactate
clearance may be restricted. The incidence of lactic acidosis can and should be reduced by also
assessing other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting,
excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia (see also
sections 4.3 and 4.5).
Diagnosis of lactic acidosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l
and increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with
the medicinal product should be discontinued and the patient hospitalised immediately (see section
4.9).
Renal impairment
As metformin is excreted by the kidney, serum creatinine concentrations should be monitored
regularly:
-
at least two to four times a year in patients with serum creatinine levels at the upper limit of
normal and in elderly patients.
3
dehydration,
-
at least once a year in patients with normal renal function
Renal impairment in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with an NSAID.
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 normalisation, treatment with Eucreas
should not be re-initiated.
Cardiac failure
Experience with vildagliptin therapy in patients with congestive heart failure of New York Heart
Association (NYHA) functional class I-II is limited and therefore vildagliptin should be used
cautiously in these patients. There is no experience of vildagliptin use in clinical trials in patients with
NYHA functional class III-IV and therefore use is not recommended in these patients.
Metformin is contraindicated in patients with heart failure, therefore Eucreas is contraindicated in this
patient population (see section 4.3).
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. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin
disorders, such as blistering or ulceration, is recommended.
Surgery
As Eucreas contains metformin, the treatment should be discontinued 48 hours before elective surgery
with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, Eucreas should be discontinued prior to, or
at the time of, the test and not reinstituted until 48 hours afterwards, and only after renal function has
been re-evaluated and found to be normal (see section 4.5).
4
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.
As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be
reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
sympathomimetics.
Metformin
Combinations not recommended
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Eucreas (see
section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
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 glycaemic 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).
Intravascular administration of iodinated contrast media may lead to renal failure, resulting in
metformin accumulation with the risk of lactic acidosis. Metformin should be discontinued prior to, or
at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has
been re-evaluated and found to be normal.
Combinations requiring precautions for use
Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycaemic 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 antihyperglycaemic medicinal product should be adjusted during therapy with the
other medicinal product and on its discontinuation.
5
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-feeding
Studies 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 lactation (see section 4.3).
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.
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.
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.
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.
6
Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on
therapy to metformin (Table 1) and as monotherapy (Table 2) are listed below by system organ class
and absolute frequency. Adverse reactions listed in Table 3 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)
Metabolism and nutrition disorders
Common
Hypoglycaemia
Nervous system disorders
Common
Tremor
Common
Headache
Uncommon
Fatigue
Gastrointestinal disorders
Common
Nausea
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 hypoglycaemic 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
.
7
Common
Dizziness
Additional information on the individual active substances of the fixed combination
Vildagliptin
Table 2
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
Hypoglycaemia
Nervous system disorders
Common
Dizziness
Uncommon
Headache
Vascular disorders
Uncommon
Oedema peripheral
Gastrointestinal disorders
Uncommon Constipation
Musculoskeletal and connective tissue disorders
Uncommon
Arthralgia
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 3
Known adverse reactions for metformin component
Metabolism and nutrition disorders
Decrease of vitamin B
12
absorption and lactic acidosis*
Nervous system disorders
Common
Metallic taste
Gastrointestinal disorders
Very common
Nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
Hepatobiliary disorders
Very rare Liver function test abnormalities or hepatitis**
Skin and subcutaneous tissue disorders
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 aetiology is recommended if a
patient presents with megaloblastic anaemia.
**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin
discontinuation have been reported.
8
Very Rare
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
During post-marketing experience the following additional adverse drug reactions have been reported
(frequency not known): urticaria, pancreatitis
.
No data are available with regard to overdose of Eucreas.
Vildagliptin
Information regarding overdose with vildagliptin is limited.
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 paraesthesia, fever, oedema and a transient
increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and
increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin
levels.Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All
symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study
medicinal product.
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 haemodialysis. However, vildagliptin cannot be
removed by haemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportive
management is recommended.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code:
A10BD08
Eucreas combines two antihyperglycaemic agents with complimentary mechanisms of action to
improve glycaemic 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.
Vildagliptin added to patients whose glycaemic control was not satisfactory despite treatment with
metformin monotherapy resulted after 6-month treatment in additional statistically significant mean
reductions in HbA
1c
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
HbA
1c
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%).
9
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 HbA
1c
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 HbA
1c
were -0.4% with vildagliptin added to metformin
and -0.5% with glimepiride added to metformin, from a mean baseline HbA
1c
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 HbA
1c
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 HbA
1c
were -0.81% with vildagliptin added to
metformin (mean baseline HbA
1c
8.4%) and -0.85% with gliclazide added to metformin (mean
baseline HbA
1c
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 HbA
1c
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 HbA
1c
of 8.6%.
The decrease in HbA
1c
observed in patients with a baseline ≥10.0% was greater.
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- (Homeostasis Model Assessment–), proinsulin to insulin ratio and
measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic
(normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose
levels.
By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to
glucose, resulting in more glucose-appropriate glucagon secretion.
The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin
hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to
reduced glycaemia.
The known effect of increased GLP-1 levels delaying gastric emptying is not observed with
vildagliptin treatment.
10
Metformin
Metformin is a biguanide with antihyperglycaemic 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 randomised 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 sulphonylurea 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 sulphonylurea 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).
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
max
by 26%, AUC by 7% and delayed T
max
(2.0 to 4.0 h).
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
max
(19%) compared to dosing in the fasting state. However, the magnitude of
11
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 (V
ss
) is 71 litres, suggesting extravascular distribution.
Biotransformation
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the
dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of
the cyano moiety, accounting for 57% of the dose, followed by the 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 metabolised 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 metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19,
CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
Following oral administration of [
14
C] vildagliptin, approximately 85% of the dose was excreted into
the urine and 15% of the dose was recovered in the faeces. Renal excretion of the unchanged
vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration
to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively.
The mean elimination half-life after intravenous administration is approximately 2 hours. The
elimination half-life after oral administration is approximately 3 hours.
Linearity / non-linearity
The C
max
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 (C
max
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 (C
max
) 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 faeces was 20-30%.
12
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
max
) did not exceed
4 µg/ml, even at maximum doses.
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 (V
d
) 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 faeces, mucoid faeces, diarrhoea and, at higher doses,
faecal blood were observed in dogs. A no-effect level was not established.
Vildagliptin was not mutagenic in conventional
in vitro
and
in vivo
tests for genotoxicity.
A fertility and early embryonic development study in rats revealed no evidence of impaired fertility,
reproductive performance or early embryonic development due to vildagliptin. Embryofoetal toxicity
was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in
association with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-fold
human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of
developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect
dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in
rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a
transient decrease in body weight and reduced motor activity in the F1 generation.
13
A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately
200 times human exposure at the maximum recommended dose). No increases in tumour incidence
attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in
mice at oral doses up to 1000 mg/kg. An increased incidence of mammary adenocarcinomas and
haemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and
100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice
is considered not to represent a significant risk to humans based on the lack of genotoxicity of
vildagliptin and its principal metabolite, the occurrence of tumours only in one species, and the high
systemic exposure ratios at which tumours were observed.
In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses
≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At
5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters
were observed. They were reversible despite continued treatment and were not associated with
histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating
histopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUC
exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin
lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.
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.
6.1 List of excipients
Tablet core:
Hydroxypropylcellulose
Magnesium stearate
Film-coating:
Hypromellose
Titanium dioxide (E 171)
Iron oxide, yellow (E 172)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
6.4 Special precautions for storage
Store in the original package (blister) in order to protect from moisture.
14
6.5 Nature and contents of container
Aluminium/Aluminium (PA/Al/PVC//Al) blister
Available in packs containing 10, 30, 60, 120,180 or 360 film-coated tablets and in multi-packs
containing 120 (2x60), 180 (3x60) or 360 (6x60) film-coated tablets.
Not all pack sizes and tablet strengths may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/07/425/001–006
EU/1/07/425/013–015
9.
14.11.2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
15
1.
Eucreas 50 mg/1000 mg film-coated tablets
2.
Each film-coated tablet contains 50 mg of vildagliptin and 1000 mg of metformin hydrochloride
(corresponding to 780 mg of metformin).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Dark yellow, ovaloid film-coated tablet with bevelled edge, imprinted with “NVR” on one side and
“FLO” on the other side.
4.
Eucreas is indicated in the treatment of type 2 diabetes mellitus patients who are unable to achieve
sufficient glycaemic 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.
Adults
Based on the patient’s current dose of metformin, Eucreas may be initiated at either the 50 mg/850 mg
or 50 mg/1000 mg tablet strength twice daily, one tablet in the morning and the other in the evening.
The recommended daily dose is 100 mg vildagliptin plus 2000 mg metformin hydrochloride.
Patients receiving vildagliptin and metformin from separate tablets may be switched to Eucreas
containing the same doses of each component.
Doses higher than 100 mg of vildagliptin are not recommended.
There is no clinical experience of vildagliptin and metformin in triple combination with other
antidiabetic agents.
Taking Eucreas with or just after food may reduce gastrointestinal symptoms associated with
metformin (see also section 5.2).
Additional information on special populations
Renal impairment
Eucreas should not be used in patients with creatinine clearance < 60 ml/min (see sections 4.3, 4.4 and
5.2).
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).
16
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
sections 4.4 and 5.2).
Paediatric population (< 18 years)
Eucreas is not recommended for use in children and adolescents due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substances or to any of the excipients
Diabetic ketoacidosis or diabetic pre-coma
Renal failure or renal dysfunction defined as creatinine clearance < 60 ml/min (see section 4.4)
Acute conditions with the potential to alter renal function, such as:
-
-
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,
-
shock.
Hepatic impairment (see sections 4.2, 4.4 and 4.8)
Acute alcohol intoxication, alcoholism
Lactation (see section 4.6)
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 is a very rare but serious metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. In patients with impaired liver function, lactate
clearance may be restricted. The incidence of lactic acidosis can and should be reduced by also
assessing other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting,
excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia (see also
sections 4.3 and 4.5).
Diagnosis of lactic acidosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l
and increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with
the medicinal product should be discontinued and the patient hospitalised immediately (see section
4.9).
Renal impairment
As metformin is excreted by the kidney, serum creatinine concentrations should be monitored
regularly:
-
at least two to four times a year in patients with serum creatinine levels at the upper limit of
normal and in elderly patients.
17
dehydration,
-
at least once a year in patients with normal renal function
Renal impairment in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with an NSAID.
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 normalisation, treatment with Eucreas
should not be re-initiated.
Cardiac failure
Experience with vildagliptin therapy in patients with congestive heart failure of New York Heart
Association (NYHA) functional class I-II is limited and therefore vildagliptin should be used
cautiously in these patients. There is no experience of vildagliptin use in clinical trials in patients with
NYHA functional class III-IV and therefore use is not recommended in these patients.
Metformin is contraindicated in patients with heart failure, therefore Eucreas is contraindicated in this
patient population (see section 4.3).
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. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin
disorders, such as blistering or ulceration, is recommended.
Surgery
As Eucreas contains metformin, the treatment should be discontinued 48 hours before elective surgery
with general anaesthesia and should not usually be resumed earlier than 48 hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, Eucreas should be discontinued prior to, or
at the time of, the test and not reinstituted until 48 hours afterwards, and only after renal function has
been re-evaluated and found to be normal (see section 4.5).
18
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.
As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be
reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
sympathomimetics.
Metformin
Combinations not recommended
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Eucreas (see
section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
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 glycaemic 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).
Intravascular administration of iodinated contrast media may lead to renal failure, resulting in
metformin accumulation with the risk of lactic acidosis. Metformin should be discontinued prior to, or
at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has
been re-evaluated and found to be normal.
Combinations requiring precautions for use
Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycaemic 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 antihyperglycaemic medicinal product should be adjusted during therapy with the
other medicinal product and on its discontinuation.
19
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-feeding
Studies 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 lactation (see section 4.3).
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.
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.
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.
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.
20
Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on
therapy to metformin (Table 1) and as monotherapy (Table 2) are listed below by system organ class
and absolute frequency. Adverse reactions listed in Table 3 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)
Metabolism and nutrition disorders
Common
Hypoglycaemia
Nervous system disorders
Common
Tremor
Common
Headache
Uncommon
Fatigue
Gastrointestinal disorders
Common
Nausea
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 hypoglycaemic 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
.
21
Common
Dizziness
Additional information on the individual active substances of the fixed combination
Vildagliptin
Table 2
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
Hypoglycaemia
Nervous system disorders
Common
Dizziness
Uncommon
Headache
Vascular disorders
Uncommon
Oedema peripheral
Gastrointestinal disorders
Uncommon Constipation
Musculoskeletal and connective tissue disorders
Uncommon
Arthralgia
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 3
Known adverse reactions for metformin component
Metabolism and nutrition disorders
Decrease of vitamin B
12
absorption and lactic acidosis*
Nervous system disorders
Common
Metallic taste
Gastrointestinal disorders
Very common
Nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
Hepatobiliary disorders
Very rare Liver function test abnormalities or hepatitis**
Skin and subcutaneous tissue disorders
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 aetiology is recommended if a
patient presents with megaloblastic anaemia.
**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin
discontinuation have been reported.
22
Very Rare
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
During post-marketing experience the following additional adverse drug reactions have been reported
(frequency not known): urticaria, pancreatitis
.
No data are available with regard to overdose of Eucreas.
Vildagliptin
Information regarding overdose with vildagliptin is limited.
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 paraesthesia, fever, oedema and a transient
increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and
increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin levels.
Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and
laboratory abnormalities resolved without treatment after discontinuation of the study medicinal
product.
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 haemodialysis. However, vildagliptin cannot be
removed by haemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportive
management is recommended.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code:
A10BD08
Eucreas combines two antihyperglycaemic agents with complimentary mechanisms of action to
improve glycaemic 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.
Vildagliptin added to patients whose glycaemic control was not satisfactory despite treatment with
metformin monotherapy resulted after 6-month treatment in additional statistically significant mean
reductions in HbA
1c
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
HbA
1c
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%).
23
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 HbA
1c
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 HbA
1c
were -0.4% with vildagliptin added to metformin
and -0.5% with glimepiride added to metformin, from a mean baseline HbA
1c
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 HbA
1c
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 HbA
1c
were -0.81% with vildagliptin added to
metformin (mean baseline HbA
1c
8.4%) and -0.85% with gliclazide added to metformin (mean
baseline HbA
1c
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 HbA
1c
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 HbA
1c
of 8.6%.
The decrease in HbA
1c
observed in patients with a baseline ≥10.0% was greater.
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- (Homeostasis Model Assessment–), proinsulin to insulin ratio and
measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic
(normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose
levels.
By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to
glucose, resulting in more glucose-appropriate glucagon secretion.
The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin
hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to
reduced glycaemia.
The known effect of increased GLP-1 levels delaying gastric emptying is not observed with
vildagliptin treatment.
24
Metformin
Metformin is a biguanide with antihyperglycaemic 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 randomised 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 sulphonylurea 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 sulphonylurea 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).
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
max
by 26%, AUC by 7% and delayed T
max
(2.0 to 4.0 h).
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
max
(19%) compared to dosing in the fasting state. However, the magnitude of
25
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 (V
ss
) is 71 litres, suggesting extravascular distribution.
Biotransformation
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the
dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of
the cyano moiety, accounting for 57% of the dose, followed by the 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 metabolised 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 metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19,
CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
Following oral administration of [
14
C] vildagliptin, approximately 85% of the dose was excreted into
the urine and 15% of the dose was recovered in the faeces. Renal excretion of the unchanged
vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration
to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively.
The mean elimination half-life after intravenous administration is approximately 2 hours. The
elimination half-life after oral administration is approximately 3 hours.
Linearity / non-linearity
The C
max
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 (C
max
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 (T
max
) 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 faeces was 20-30%.
26
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
max
) did not exceed
4 µg/ml, even at maximum doses.
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 (V
d
) 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 faeces, mucoid faeces, diarrhoea and, at higher doses,
faecal blood were observed in dogs. A no-effect level was not established.
Vildagliptin was not mutagenic in conventional
in vitro
and
in vivo
tests for genotoxicity.
A fertility and early embryonic development study in rats revealed no evidence of impaired fertility,
reproductive performance or early embryonic development due to vildagliptin. Embryofoetal toxicity
was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in
association with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-fold
human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of
developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect
dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in
rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a
transient decrease in body weight and reduced motor activity in the F1 generation.
27
A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately
200 times human exposure at the maximum recommended dose). No increases in tumour incidence
attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in
mice at oral doses up to 1000 mg/kg. An increased incidence of mammary adenocarcinomas and
haemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and
100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice
is considered not to represent a significant risk to humans based on the lack of genotoxicity of
vildagliptin and its principal metabolite, the occurrence of tumours only in one species, and the high
systemic exposure ratios at which tumours were observed.
In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses
≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At
5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters
were observed. They were reversible despite continued treatment and were not associated with
histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating
histopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUC
exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin
lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.
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.
6.1 List of excipients
Tablet core:
Hydroxypropylcellulose
Magnesium stearate
Film-coating:
Hypromellose
Titanium dioxide (E 171)
Iron oxide, yellow (E 172)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
6.4 Special precautions for storage
Store in the original package (blister) in order to protect from moisture.
28
6.5 Nature and contents of container
Aluminium/Aluminium (PA/Al/PVC//Al) blister
Available in packs containing 10, 30, 60, 120,180 or 360 film-coated tablets and in multi-packs
containing 120 (2x60), 180 (3x60) or 360 (6x60) film-coated tablets.
Not all pack sizes and tablet strengths may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/07/425/007–012
EU/1/07/425/016–018
9.
14.11.2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
29
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
30
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Novartis Pharma GmbH
Roonstrasse 25
D-90429 Nürnberg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 5 (18 February 2010) of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent
updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
31
ANNEX III
LABELLING AND PACKAGE LEAFLET
32
A. LABELLING
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK
1.
Eucreas 50 mg/850 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 850 mg metformin hydrochloride (corresponding to
660 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
10 film-coated tablets
30 film-coated tablets
60 film-coated tablets
120 film-coated tablets
180 film-coated tablets
360 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
34
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/001
10 film-coated tablets
EU/1/07/425/003
60 film-coated tablets
EU/1/07/425/004
120 film-coated tablets
EU/1/07/425/005
180 film-coated tablets
EU/1/07/425/006
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/850 mg
35
EU/1/07/425/002
30 film-coated tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Eucreas 50 mg/850 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX)
1.
Eucreas 50 mg/850 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 850 mg metformin hydrochloride (corresponding to
660 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
Component of a multipack comprising 2 packs, each containing 60 tablets.
60 film-coated tablets
Component of a multipack comprising 3 packs, each containing 60 tablets.
60 film-coated tablets
Component of a multipack comprising 6 packs, each containing 60 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
37
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/013
120 film-coated tablets
EU/1/07/425/015
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/850 mg
38
EU/1/07/425/014
180 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX)
1.
Eucreas 50 mg/850 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 850 mg metformin hydrochloride (corresponding to
660 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
120 film-coated tablets
Multipack comprising 2 packs, each containing 60 tablets.
180 film-coated tablets
Multipack comprising 3 packs, each containing 60 tablets.
360 film-coated tablets
Multipack comprising 6 packs, each containing 60 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
39
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/013
120 film-coated tablets
EU/1/07/425/015
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/850 mg
40
EU/1/07/425/014
180 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX FOR UNIT PACK
1.
Eucreas 50 mg/1000 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 1000 mg metformin hydrochloride (corresponding to
780 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
10 film-coated tablets
30 film-coated tablets
60 film-coated tablets
120 film-coated tablets
180 film-coated tablets
360 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
41
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/007
10 film-coated tablets
EU/1/07/425/009
60 film-coated tablets
EU/1/07/425/010
120 film-coated tablets
EU/1/07/425/011
180 film-coated tablets
EU/1/07/425/012
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/1000 mg
42
EU/1/07/425/008
30 film-coated tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Eucreas 50 mg/1000 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACKS (WITHOUT BLUE BOX)
1.
Eucreas 50 mg/1000 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 1000 mg metformin hydrochloride (corresponding to
780 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
Component of a multipack comprising 2 packs, each containing 60 tablets.
60 film-coated tablets
Component of a multipack comprising 3 packs, each containing 60 tablets.
60 film-coated tablets
Component of a multipack comprising 6 packs, each containing 60 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
44
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/016
120 film-coated tablets
EU/1/07/425/018
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/1000 mg
45
EU/1/07/425/017
180 film-coated tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACKS (INCLUDING BLUE BOX)
1.
Eucreas 50 mg/1000 mg film-coated tablets
vildagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin and 1000 mg metformin hydrochloride (corresponding to
780 mg of metformin).
3.
LIST OF EXCIPIENTS
4.
120 film-coated tablets
Multipack comprising 2 packs, each containing 60 tablets.
180 film-coated tablets
Multipack comprising 3 packs, each containing 60 tablets.
360 film-coated tablets
Multipack comprising 6 packs, each containing 60 tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
46
9.
SPECIAL STORAGE CONDITIONS
Store in the original package (blister) in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/07/425/016
120 film-coated tablets
EU/1/07/425/018
360 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Eucreas 50 mg/1000 mg
47
EU/1/07/425/017
180 film-coated tablets
B. PACKAGE LEAFLET
48
PACKAGE LEAFLET: INFORMATION FOR THE USER
Eucreas 50 mg/850 mg film-coated tablets
Eucreas 50 mg/1000 mg film-coated tablets
vildagliptin/metformin hydrochloride
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Eucreas is and what it is used for
2.
Before you take Eucreas
3.
How to take Eucreas
5.
How to store Eucreas
6.
Further information
1.
WHAT EUCREAS IS AND WHAT IT IS USED FOR
The active substances of Eucreas belong to a group of medicines called “oral antidiabetics”.
Eucreas is used to treat patients with type 2 diabetes. This type of diabetes is also known as non-
insulin-dependent diabetes mellitus.
Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body
makes does not work as well as it should. It can also develop if the body produces too much glucagon.
Both insulin and glucagon are made in the pancreas. Insulin helps to lower the level of sugar in the
blood, especially after meals. Glucagon triggers the liver to make sugar, causing the blood sugar level
to rise.
Eucreas contains two active substances called vildagliptin and metformin. Both of these substances
help to control the level of sugar in the blood. The substance vildagliptin works by making the
pancreas produce more insulin and less glucagon. The substance metformin works by helping the body
to make better use of insulin.
2.
BEFORE YOU TAKE EUCREAS
Do not take Eucreas
-
if you are allergic (hypersensitive) to vildagliptin, metformin or any of the other ingredients of
Eucreas (listed in section 6). If you think you may be allergic to any of these, talk to your doctor
before taking Eucreas.
-
if you have or have had serious complications of your 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 serious problems with your
blood circulation or difficulties in breathing which could be a sign of heart problems.
-
if you have kidney problems.
49
4.
Possible side effects
-
if you have a severe infection or are seriously dehydrated (have lost a lot of water from your
body).
-
if you are going to have a contrast x-ray (a specific type of x-ray involving an injectable dye).
Please also see information about this in section “Take special care with Eucreas”.
-
if you have liver problems.
-
if you drink alcohol excessively (whether every day or only from time to time).
-
if you are breast-feeding (see also “Pregnancy and breast-feeding”).
Take special care with Eucreas
Stop taking this medicine and talk to your doctor if you experience one or more of the following
symptoms
which may be related to a condition called “lactic acidosis”:
-
feeling cold or uncomfortable
-
severe nausea or vomiting
-
pain in or around your stomach (abdominal pain)
-
drowsiness or dizziness
-
rapid breathing
If you have previously taken vildagliptin but had to stop taking it because of side effects (liver
disease), you should not take this product.
Diabetic skin lesions are a common complication of diabetes. You are advised to follow the
recommendations for skin and foot care that you are given by your doctor or nurse. You are also
advised to pay particular attention to new onset of blisters or ulcers while taking Eucreas. Should these
occur, you should promptly consult your doctor.
If you have stopped using Eucreas due to surgery (you should stop at least 48 hours before planned
surgery with general anesthesia and should not start again until at least 48 hours afterwards) or due to
an x-ray involving an injectable dye, talk to your doctor before taking Eucreas again.
A test to determine your liver function will be performed before the start of Eucreas treatment, at
three-month intervals for the first year and periodically thereafter. This is so that signs of increased
liver enzymes can be detected as early as possible.
Elderly patients (65-74 years) taking Eucreas should have their kidney function monitored regularly.
This will happen more often in patients with kidney problems. Eucreas is not recommended for
patients aged 75 years or older.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. This is particularly important if you are already
taking any medicine to treat a heart condition or problems with your blood sugar, kidneys or blood
pressure such as medicines containing
-
beta-2 agonists generally used to treat respiratory disorders
-
other medicines used to treat diabetes
-
diuretics (also called water tablets)
-
ACE inhibitors generally used to treat high blood pressure
-
certain medicines affecting the thyroid, or
-
certain medicines affecting the nervous system.
Taking Eucreas with food and drink
Take the tablets either with or just after food. This will lower the risk of an upset stomach.
Avoid alcohol while taking Eucreas since alcohol may increase the risk of lactic acidosis (please see
section “Possible side effects”).
50
-
muscle pain
-
glucocorticoids generally used to treat inflammation
Pregnancy and breast-feeding
-
Tell your doctor if you are pregnant, if you think you might be pregnant, or if you are planning
to become pregnant. Your doctor will discuss with you the potential risk of taking Eucreas
during pregnancy.
-
Do not use Eucreas if you are breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
If you feel dizzy while taking Eucreas, do not drive or use any tools or machines.
3.
HOW TO TAKE EUCREAS
Always take Eucreas exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
How much to take
The amount of Eucreas that people have to take varies depending on their condition. Your doctor will
tell you exactly the dose of Eucreas to take.
When and how to take Eucreas
-
Swallow the tablets whole with a glass of water,
-
Take one tablet in the morning and the other in the evening with or just after food. Taking the
tablet just after food will lower the risk of an upset stomach.
Continue to follow any advice about diet that your doctor has given you. In particular, if you are
following a diabetic weight control diet, continue with this while you are taking Eucreas.
At least once a year, your doctor will check that your kidneys are working normally. Your doctor will
test your blood and urine for sugar regularly.
If you take more Eucreas than you should
If you take too many Eucreas tablets, or if someone else takes your tablets,
talk to a doctor or
pharmacist immediately
. Medical attention may be necessary. If you have to go to a doctor or
hospital, take the pack and this leaflet with you.
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 then anyway.
Do not take a double dose (two tablets at once) to make up for a forgotten tablet.
If you stop taking Eucreas
Do not stop taking Eucreas unless your doctor tells you to. If you have any questions about how long
to take this medicine, talk to your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
51
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Eucreas can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 patient in 10
common: affects 1 to 10 patients in 100
uncommon: affects 1 to 10 patients in 1,000
rare: affects 1 to 10 patients in 10,000
very rare: affects less than 1 patient in 10,000
not known: frequency cannot be estimated from the available data.
Some symptoms need immediate medical attention
You should
stop taking Eucreas and see your doctor immediately
if you experience the following
side effects:
-
Angioedema (rare): Symptoms include swollen face, tongue or throat, difficulty swallowing,
difficulty breathing, sudden onset of 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-coloured urine, which may indicate liver disease (hepatitis).
Other side effects
Some patients have experienced the following side effects while taking Eucreas:
Very common
:
-
nausea
-
vomiting
-
diarrhoea
-
pain in and around the stomach (abdominal pain)
-
loss of appetite.
Common
:
-
dizziness
-
headache
-
trembling that cannot be controlled
-
metallic taste
-
low blood glucose.
Uncommon
:
-
joint pain
-
tiredness
-
constipation
-
swollen hands, ankle or feet (oedema).
Rare
:
-
signs of liver disease (hepatitis)
Very rare
:
-
sore throat, runny nose, fever
-
signs of a high level of lactic acid in the blood (known as lactic acidosis) such as drowsiness or
dizziness, severe nausea or vomiting, abdominal pain, irregular heart beat or deep, rapid
breathing.
-
redness of the skin, itching
-
decreased vitamin B12 levels (paleness, tiredness, mental symptoms such as confusion or
memory disturbances).
Since this product has been marketed, the following side effects have also been reported (frequency
not known):
-
itchy rash
-
inflammation of the pancreas.
52
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE EUCREAS
-
Keep out of the reach and sight of children.
-
Do not use Eucreas after the expiry date which is stated on the blister and carton. The expiry
date refers to the last day of that month.
-
Store in the original package (blister) in order to protect from moisture.
6.
FURTHER INFORMATION
What Eucreas contains
-
The active substances are vildagliptin and metformin hydrochloride.
-
Each Eucreas 50 mg/850 mg film-coated tablet contains 50 mg vildagliptin and 850 mg
metformin hydrochloride (corresponding to 660 mg of metformin).
-
Each Eucreas 50 mg/1000 mg film-coated tablet contains 50 mg vildagliptin and 1000 mg
metformin hydrochloride (corresponding 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 tablets with “NVR” on one side and
“SEH” on the other.
Eucreas 50 mg/1000 mg film-coated tablets are dark yellow, oval tablets 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 multi-
packs containing 120 (2x60), 180 (3x60) or 360 (6x60) film-coated tablets. Not all pack sizes and
tablet strengths may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
53
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
54
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
55
Source: European Medicines Agency
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