ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Galvus 50 mg tablets
2.
Each tablet contains 50 mg of vildagliptin.
Excipient: Each tablet contains 47.82 mg anhydrous lactose.
For a full list of excipients, see section 6.1.
3.
Tablet
White to light yellowish, round (8 mm diameter), flat-faced, bevelled-edge tablet. One side is
debossed with “NVR”, and the other side with “FB”.
4.
Vildagliptin is indicated in the treatment of type 2 diabetes mellitus:
As dual oral therapy in combination with
-
metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of
monotherapy with metformin,
-
a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose
of a sulphonylurea and for whom metformin is inappropriate due to contraindications or
intolerance,
-
a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a
thiazolidinedione is appropriate.
Adults
When used in dual combination with metformin or a thiazolidinedione, the recommended daily dose
of vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in
the evening.
When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg
once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no
more effective than vildagliptin 50 mg once daily.
Doses higher than 100 mg are not recommended.
The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a
thiazolidinedione or with metformin and a sulphonylurea has not been established.
Galvus can be administered with or without a meal (see also section 5.2).
2
Additional information on special populations
Renal impairment
No dose adjustment is required in patients with mild renal impairment (creatinine clearance
≥ 50 ml/min). The use of Galvus is not recommended in patients with moderate or severe renal
impairment or in haemodialysis patients with end-stage renal disease (ESRD) (see also sections 4.4
and 5.2).
Hepatic impairment
Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal
(ULN) (see also sections 4.4 and 5.2).
Elderly (≥ 65 years)
No dose adjustments are necessary in elderly patients (see also sections 5.1 and 5.2).
Paediatric population (< 18 years)
Galvus is not recommended for use in children and adolescents due to a lack of data on safety and
efficacy.
Hypersensitivity to the active substance or to any of the excipients.
General
Galvus is not a substitute for insulin in insulin-requiring patients. Galvus should not be used in
patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Renal impairment
There is limited experience in patients with moderate to severe renal impairment or in patients with
ESRD on haemodialysis. Therefore, the use of Galvus is not recommended in these patients.
Hepatic impairment
Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment
ALT or AST > 3x ULN.
Liver enzyme monitoring
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients
were generally asymptomatic without clinical sequelae and liver function test results returned to
normal after discontinuation of treatment. Liver function tests should be performed prior to the
initiation of treatment with Galvus in order to know the patient’s baseline value. Liver function should
be monitored during treatment with Galvus at three-month intervals during the first year and
periodically thereafter. Patients who develop increased transaminase levels should be monitored with a
second liver function evaluation to confirm the finding and be followed thereafter with frequent liver
function tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT of 3x
ULN or greater persist, withdrawal of Galvus therapy is recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue
Galvus.
Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should
not be reinitiated.
3
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.
Skin disorders
Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-
clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased
incidence in clinical trials, there was limited experience in patients with diabetic skin complications.
Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as
blistering or ulceration, is recommended.
Excipients
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Vildagliptin has a low potential for interactions with co-administered medicinal products. Since
vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP
450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers
of these enzymes.
Combination with pioglitazone, metformin and glyburide
Results from studies conducted with these oral antidiabetics have shown no clinically relevant
pharmacokinetic interactions.
Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)
Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic
interactions. However, this has not been established in the target population.
Combination with amlodipine, ramipril, valsartan or simvastatin
Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan
and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed
after co-administration with vildagliptin.
As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be
reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
sympathomimetics.
Pregnancy
There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals have
shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown.
Due to lack of human data, Galvus should not be used during pregnancy.
Breast-feeding
It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of
vildagliptin in milk. Galvus should not be used during lactation.
No studies on the effects on the ability to drive and use machines have been performed. Patients who
experience dizziness as an undesirable effect should avoid driving vehicles or using machines.
4
Safety data were obtained from a total of 3,784 patients exposed to vildagliptin at a daily dose of
50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in controlled trials of at least
12 weeks duration. Of these patients, 2,264 patients received vildagliptin as monotherapy and
1,520 patients received vildagliptin in combination with another medicinal product. 2,682 patients
were treated with vildagliptin 100 mg daily (either 50 mg twice daily or 100 mg once daily) and
1,102 patients were treated with vildagliptin 50 mg once daily.
The majority of adverse reactions in these trials were mild and transient, not requiring treatment
discontinuations. No association was found between adverse reactions and age, ethnicity, duration of
exposure or daily dose.
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients
were generally asymptomatic without clinical sequelae and liver function returned to normal after
discontinuation of treatment.
In data from controlled monotherapy and add-on therapy trials of up to
24 weeks in duration, the incidence of ALT or AST elevations 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
angiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild in
severity and resolved with ongoing vildagliptin treatment.
Adverse reactions reported in patients who received Galvus in double-blind studies as monotherapy
and add-on therapies are listed below for each indication by system organ class and absolute
frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be
estimated from the available data). Within each frequency grouping, undesirable effects are presented
in order of decreasing seriousness.
Combination with metformin
In controlled clinical trials with the combination of vildagliptin 100 mg daily + metformin, no
withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily + metformin
or the placebo + metformin treatment groups.
In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin
100 mg daily 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).
5
Table 1
Adverse reactions reported in patients who received Galvus 100 mg daily in
combination with metformin in double-blind studies (N=208)
Metabolism and nutrition disorders
Common
Hypoglycaemia
Nervous system disorders
Common
Tremor
Common
Headache
Uncommon
Dizziness
Gastrointestinal disorders
Common
Nausea
Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or
unforeseen risks when vildagliptin was added on to metformin.
Combination with a sulphonylurea
In controlled clinical trials with the combination of vildagliptin 50 mg + a sulphonylurea, the overall
incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + sulphonylurea
vs 0% in the placebo + sulphonylurea treatment group.
In clinical trials, the incidence of hypoglycaemia when vildagliptin 50 mg once daily was added to
glimepiride was 1.2% versus 0.6% for placebo + glimepiride. No severe hypoglycaemic events were
reported in the vildagliptin arms.
In clinical trials, weight did not change from baseline when vildagliptin 50 mg daily was added to
glimepiride (-0.1 kg and -0.4 kg for vildagliptin and placebo, respectively).
Table 2
Adverse reactions reported in patients who received Galvus 50 mg in combination
with a sulphonylurea in double-blind studies (N=170)
Infections and infestations
Very rare Nasopharyngitis
Metabolism and nutrition disorders
Common
Hypoglycaemia
Nervous system disorders
Common
Tremor
Common
Headache
Common
Asthenia
Gastrointestinal disorders
Uncommon
Constipation
Combination with a thiazolidinedione
In controlled clinical trials with the combination of vildagliptin 100 mg daily+ a thiazolidinedione, no
withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily +
thiazolidinedione or the placebo + thiazolidinedione treatment groups.
In clinical trials, the incidence of hypoglycaemia was uncommon in patients receiving vildagliptin +
pioglitazone (0.6%) but common in patients receiving placebo + pioglitazone (1.9%). No severe
hypoglycaemic events were reported in the vildagliptin arms.
In the pioglitazone add-on study, the absolute weight increases with placebo, Galvus 100 mg daily
were 1.4 and 2.7 kg, respectively.
6
Common
Fatigue
Common
Dizziness
The incidence of peripheral oedema when vildagliptin 100 mg daily was added to a maximum dose of
background pioglitazone (45 mg once daily) was 7.0%, compared to 2.5% for background
pioglitazone alone.
Table 3
Adverse reactions reported in patients who received Galvus 100 mg daily in
combination with a thiazolidinedione in double-blind studies (N=158)
Metabolism and nutrition disorders
Common
Weight increase
Uncommon
Hypoglycaemia
Nervous system disorders
Uncommon
Headache
Uncommon
Asthenia
Vascular disorders
Common
Oedema peripheral
In addition, in controlled monotherapy trials with vildagliptin the overall incidence of withdrawals 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).
Table 4
Adverse reactions reported in patients who received Galvus 100 mg daily as
monotherapy in double-blind studies (N=1,855)
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
Clinical trials of up to 2 years’ duration did not show any additional safety signals or unforeseen risks
with vildagliptin monotherapy.
Post-marketing experience
During post-marketing experience the following additional adverse drug reactions have been reported
(frequency not known): urticaria, pancreatitis.
7
Information regarding overdose with vildagliptin is limited.
Information on the likely symptoms of overdose was taken from a rising dose tolerability study in
healthy subjects given Galvus for 10 days. At 400 mg, there were three cases of muscle pain, and
individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase
levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine
phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin
levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All
symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study
medicinal product.
Management
In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed
by haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed by
haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH02
Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.
The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity,
resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1
(glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
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.
More than 15,000 patients with type 2 diabetes participated in double-blind placebo- or active-
controlled clinical trials of up to more than 2 years’ treatment duration. In these studies, vildagliptin
was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily or
100 mg once daily. More than 5,000 male and more than 4,000 female patients received vildagliptin
50 mg once daily or 100 mg daily. More than 1,900 patients receiving vildagliptin 50 mg once daily or
100 mg daily were ≥ 65 years. In these trials, vildagliptin was administered as monotherapy in drug-
naïve patients with type 2 diabetes or in combination in patients not adequately controlled by other
antidiabetic medicinal products.
8
Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in
combination with metformin, a sulphonylurea, and a thiazolidinedione, as measured by clinically
relevant reductions in HbA
1c
from baseline at study endpoint (see Table 5).
In clinical trials, the magnitude of HbA
1c
reductions with vildagliptin was greater in patients with
higher baseline HbA
1c
.
In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline HbA
1c
by
-1% compared to -1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was not achieved.
Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse
reactions versus those treated with metformin.
In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared to
rosiglitazone (8 mg once daily). Mean reductions were -1.20% with vildagliptin and -1.48% with
rosiglitazone in patients with mean baseline HbA
1c
of 8.7%. Patients receiving rosiglitazone
experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced no
weight gain (-0.3 kg). The incidence of peripheral oedema was lower in the vildagliptin group than in
the rosiglitazone group (2.1% vs. 4.1% respectively).
In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to gliclazide (up
to 320 mg/day). After two years, mean reduction in HbA
1c
was -0.5% for vildagliptin and -0.6% for
gliclazide, from a mean baseline HBA
1c
of 8.6%. Statistical non-inferiority was not achieved.
Vildagliptin was associated with fewer hypoglycaemic events (0.7%) than gliclazide (1.7%).
In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily)
in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions from
baseline 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.
9
Table 5
Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and in
add-on combination therapy trials (primary efficacy ITT population)
Monotherapy placebo
controlled studies
Mean
baseline
HbA
1c
(%)
Mean change
from baseline in
HbA
1c
(%) at
week 24
Placebo-
corrected mean
change in HbA
1c
(%) at week 24
(95%CI)
Study 2301: Vildagliptin 50 mg
twice daily (N=90)
8.6
-0.8
-0.5* (-0.8, -0.1)
Study 2384: Vildagliptin 50 mg
twice daily (N=79)
8.4
-0.7
-0.7* (-1.1, -0.4)
* p< 0.05 for comparison versus
placebo
Add-on
/
Combination studies
Vildagliptin 50 mg twice daily +
metformin (N=143)
8.4
-0.9
-1.1* (-1.4, -0.8)
Vildagliptin 50 mg daily +
glimepiride (N=132)
8.5
-0.6
-0.6* (-0.9, -0.4)
Vildagliptin 50 mg twice daily +
pioglitazone (N=136)
8.7
-1.0
-0.7* (-0.9, -0.4)
* p< 0.05 for comparison versus
placebo + comparator
5.2 Pharmacokinetic properties
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%). However, the magnitude of change is not clinically significant, so
that Galvus can be given with or without food. The absolute bioavailability is 85%.
Distribution
The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between
plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after
intravenous administration (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). In vitro data in human kidney microsomes suggest that the kidney may be one of the major
organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4
contributes partially to the hydrolysis of vildagliptin based on an
in vivo
study using DPP-4 deficient
rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Accordingly, the
metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP
450 inhibitors and/or inducers.
In vitro
studies demonstrated that vildagliptin does not inhibit/induce
CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications
metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
Following oral administration of [
14
C] vildagliptin, approximately 85% of the dose was excreted into
the urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptin
accounted for 23% of the dose after oral administration. After intravenous administration to healthy
subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean
10
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, however, not considered to be clinically relevant. DPP-4
inhibition by vildagliptin is not affected by age.
Hepatic impairment
The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in patients
with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6
for mild to 12 for severe) in comparison with healthy subjects. The exposure to vildagliptin after a
single dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%,
respectively), while the exposure to vildagliptin for patients with severe impairment was increased by
22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is
not considered to be clinically relevant. There was no correlation between the severity of the hepatic
disease and changes in the exposure to vildagliptin.
Renal impairment
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.
5.3 Preclinical safety data
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. Embryo-foetal toxicity
was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in
association with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-fold
human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of
developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect
11
dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in
rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a
transient decrease in body weight and reduced motor activity in the F1 generation.
A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately
200 times human exposure at the maximum recommended dose). No increases in tumour incidence
attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in
mice at oral doses up to 1,000 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.
6.
6.1 List of excipients
Lactose, anhydrous
Cellulose, microcrystalline
Sodium starch glycolate (type A)
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Aluminium/Aluminium (PA/Al/PVC//Al) blister
Available in packs containing 7, 14, 28, 30, 56, 60, 90, 112, 180 or 336 tablets and in multipacks
containing 336 (3x112) tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
12
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/07/414/001-010
EU/1/07/414/018
9.
26.09.2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
13
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
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 7 (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
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON OF UNIT PACK
1.
Galvus 50 mg tablets
vildagliptin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin.
3.
LIST OF EXCIPIENTS
Contains lactose (see leaflet for further information).
4.
7 tablets
14 tablets
28 tablets
30 tablets
56 tablets
60 tablets
90 tablets
112 tablets
180 tablets
336 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
18
9.
SPECIAL STORAGE CONDITIONS
Store in the original package 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/1/07/414/001
7 tablets
EU/1/07/414/002
14 tablets
EU/1/07/414/003
28 tablets
EU/1/07/414/004
30 tablets
EU/1/07/414/006
60 tablets
EU/1/07/414/007
90 tablets
EU/1/07/414/008
112 tablets
EU/1/07/414/009
180 tablets
EU/1/07/414/010
336 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Galvus 50 mg
19
EU/1/07/414/005
56 tablets
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX)
1.
Galvus 50 mg tablets
vildagliptin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin.
3.
LIST OF EXCIPIENTS
Contains lactose (see leaflet for further information).
4.
336 tablets
Multipack comprising 3 packs, each containing 112 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 in order to protect from moisture.
20
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/1/07/414/018
336 tablets (3x112)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Galvus 50 mg
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX)
1.
Galvus 50 mg tablets
vildagliptin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg vildagliptin.
3.
LIST OF EXCIPIENTS
Contains lactose (see leaflet for further information).
4.
112 tablets
Component of a multipack comprising 3 packs, each containing 112 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 in order to protect from moisture.
22
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/1/07/414/018
336 tablets (3x112)
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Galvus 50 mg
23
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Galvus 50 mg tablets
vildagliptin
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
24
B. PACKAGE LEAFLET
25
PACKAGE LEAFLET: INFORMATION FOR THE USER
Galvus 50 mg tablets
Vildagliptin
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, diabetes nurse 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 Galvus is and what it is used for
3.
How to take Galvus
4.
Possible side effects
5.
How to store Galvus
6.
Further information
1.
WHAT GALVUS IS AND WHAT IT IS USED FOR
Galvus belongs to a group of medicines called “oral antidiabetics”.
Galvus is used to treat patients with type 2 diabetes. It is used when diabetes cannot be controlled by
diet and exercise alone. It helps to control the level of sugar in the blood.
Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body
makes does not work as well as it should. It can also develop if the body produces too much glucagon.
Insulin is a substance which helps to lower the level of sugar in the blood, especially after meals.
Glucagon is a substance which triggers the production of sugar by the liver, causing the blood sugar
level to rise. The pancreas makes both of these substances.
Galvus works by making the pancreas produce more insulin and less glucagon. This helps to control
the blood sugar level.
Your doctor will prescribe Galvus together with certain other antidiabetic medicines which you will
already be taking to control diabetes, if one medicine alone is not enough to control your blood sugar
level.
Even though you are now starting a medicine for your diabetes, it is important that you continue to
follow the diet and/or exercise which has been recommended for you.
26
2.
Before you take Galvus
2.
BEFORE YOU TAKE GALVUS
Do not take Galvus:
if you are allergic (hypersensitive) to vildagliptin or any of the other ingredients of Galvus (see
section 6: Further information). If you think you may be allergic to vildagliptin or any of the
other ingredients of Galvus, do not take this medicine and talk to your doctor.
Take special care with Galvus:
If any of these apply to you, tell your doctor before taking Galvus.
if you have type 1 diabetes (i.e. your body does not produce insulin).
if you have moderate or severe kidney disease.
if you are on dialysis.
if you have liver disease.
if you suffer from heart failure.
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 Galvus. Should these
occur, you should promptly consult your doctor.
The use of Galvus in children and adolescents is not recommended.
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.
Your doctor may wish to alter your dose of Galvus if you are taking other medicines (such as
medicines so called thiazides, corticosteroids, thyroid products and certain products affecting the
nervous system).
Taking Galvus with food and drink
You can take Galvus with or without food.
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should consult their doctor before taking
Galvus. You should not use Galvus during pregnancy.
It is not known if Galvus passes into breast milk. You should not use Galvus if you are breast-feeding
or plan to breast-feed.
Driving and using machines
If you feel dizzy while taking Galvus, do not drive or use machines.
Important information about some of the ingredients of Galvus
Galvus contains lactose (milk sugar). If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
27
3.
HOW TO TAKE GALVUS
Always take Galvus 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 Galvus people have to take varies depending on their condition. Your doctor will tell
you exactly how many tablets of Galvus to take.
T
he usual dose of Galvus is either:
50 mg daily taken as one dose in the morning if you are taking Galvus with another medicine
called a sulphonylurea, or
100 mg daily taken as 50 mg in the morning and 50 mg in the evening if you are taking Galvus
with another medicine called metformin or a glitazone.
Your doctor will prescribe Galvus together with another medicine to control your blood sugar level.
When and how to take Galvus
Take this medicine in the morning or in the morning and evening.
Swallow the tablets whole with some water.
How long to take Galvus
Take Galvus every day for as long as your doctor tells you. You may have to take this treatment
over a long period of time.
Your doctor will regularly monitor your condition to check that the treatment is having the
desired effect.
Do not stop taking Galvus unless your doctor tells you to. If you have questions about how long
to take this medicine, talk to your doctor.
If you take more Galvus than you should
If you take too many Galvus tablets, or if someone else has taken your medicine,
talk to your doctor
straight away.
Medical attention may be needed. If you need to see a doctor or go to the hospital, take
the pack with you.
If you forget to take Galvus
If you forget to take a dose of this medicine, take it as soon as you remember. Then take your next
dose at the usual time. If it is almost time for your next dose, skip the dose you missed. Do not take a
double dose to make up for a forgotten tablet.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Galvus 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.
28
Some symptoms need immediate medical attention:
You should stop taking Galvus and see your doctor immediately if you experience the following side
effects:
Angioedema (rare): Symptoms include swollen face, tongue or throat, difficulty swallowing,
difficulties breathing, sudden onset rash or hives, which may indicate a reaction called
“angioedema”.
Liver disease (hepatitis) (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 had the following side effects while taking Galvus and metformin:
Common: Trembling, headache, dizziness, nausea
,
low blood glucose
Uncommon: Tiredness
Some patients have had the following side effects while taking Galvus and a sulphonylurea:
Common: Trembling, headache, dizziness, weakness
,
low blood glucose
Uncommon: Constipation
Very rare: Sore throat, runny nose
Some patients have had the following side effects while taking Galvus and a glitazone:
Common: Weight increase, swollen hands, ankle or feet (oedema)
Uncommon: Headache, weakness
,
low blood glucose
Some patients have had the following side effects while taking Galvus alone:
Common: Dizziness
Uncommon: Headache, constipation, swollen hands, ankle or feet (oedema), joint pain
,
low
blood glucose
Very rare: Sore throat, runny nose, fever
Since this product has been marketed, the following side effects have also been reported (frequency
not known):
Itchy rash
Inflammation of the pancreas
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 GALVUS
Keep out of the reach and sight of children.
Do not use Galvus after the expiry date which is stated on the blister and the carton. The expiry
date refers to the last day of that month.
Store in the original package in order to protect from moisture.
Do not use any Galvus pack that is damaged or shows signs of tampering.
6.
FURTHER INFORMATION
What Galvus contains
The active substance is vildagliptin.
Each tablet contains 50 mg vildagliptin.
The other ingredients are lactose anhydrous, microcrystalline cellulose, sodium starch glycolate
(type A) and magnesium stearate.
29
What Galvus looks like and contents of the pack
Galvus 50 mg tablets are round, white to light yellowish and flat, with “NVR” on one side and “FB”
on the other.
Galvus 50 mg tablets are available in packs containing 7, 14, 28, 30, 56, 60, 90, 112, 180 or
336 tablets and in multipacks containing 336 (3x112) tablets.
Not all pack sizes may be marketed 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
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
30
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
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
31
Source: European Medicines Agency
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