Vildagliptin is indicated in the treatment of type 2 diabetes mellitus in adults:
As monotherapy
- in patients inadequately controlled by diet and exercise alone and for whom metformin is
inappropriate due to contraindications or intolerance.
As dual oral therapy in combination with
- metformin, in patients with insufficient glycaemic control despite maximal tolerated dose
of monotherapy with metformin,
- a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated
dose of a sulphonylurea and for whom metformin is inappropriate due to
contraindications or intolerance,
- a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of
a thiazolidinedione is appropriate.
As triple oral therapy in combination with
- a sulphonylurea and metformin when diet and exercise plus dual therapy with these
medicinal products do not provide adequate glycaemic control.
Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when
diet and exercise plus a stable dose of insulin do not provide adequate glycaemic control.

Posology
Adults
When used as monotherapy, in combination with metformin, in combination with
thiazolidinedione, in combination with metformin and a sulphonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg,
administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.
When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50
mg once daily administered in the morning. In this patient population, vildagliptin 100 mg daily
was no more effective than vildagliptin 50 mg once daily.
When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be
considered to reduce the risk of hypoglycaemia.
Doses higher than 100 mg are not recommended.
If a dose of Gleptal is missed, it should be taken as soon as the patient remembers. A double
dose should not be taken on the same day.
The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a
thiazolidinedione have not been established.
Additional information on special populations
Elderly (≥ 65 years)
No dose adjustments are necessary in elderly patients.
Renal impairment
No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥ 50
ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease
(ESRD), the recommended dose of Gleptal is 50 mg once daily.
Hepatic impairment
Gleptal should not be used in patients with hepatic impairment, including patients with pretreatment
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper
limit of normal (ULN) .
Paediatric population
Gleptal is not recommended for use in children and adolescents (< 18 years). The safety and
efficacy of Gleptal in children and adolescents (< 18 years) have not been established. No data
are available.
Method of administration
Oral use
Gleptal can be administered with or without a meal.

General
Gleptal is not a substitute for insulin in insulin-requiring patients. Gleptal should not be used in
patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Renal impairment
There is limited experience in patients with ESRD on haemodialysis. Therefore Gleptal should be
used with caution in these patients.
Hepatic impairment
Gleptal should not be used in patients with hepatic impairment, including patients with pretreatment
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 Gleptal in order to know the patient's baseline value. Liver
function should be monitored during treatment with Gleptal 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 Gleptal therapy is
recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue
Gleptal.
Following withdrawal of treatment with Gleptal and LFT normalisation, treatment with Gleptal
should not be reinitiated.
Cardiac failure
A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional class
I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular
function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical
experience in patients with NYHA functional class III treated with vildagliptin is still limited and
results are inconclusive.
There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV
and therefore use is not recommended in these patients.
Skin disorders
Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in
non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an
increased incidence in clinical trials, there was limited experience in patients with diabetic skin
complications.
Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions.
Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such
as blistering or ulceration, is recommended.

Acute pancreatitis
Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients
should be informed of the characteristic symptom of acute pancreatitis.
If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed,
vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute
pancreatitis.
Hypoglycaemia
Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination
with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea
may be considered to reduce the risk of hypoglycaemia.
Excipients
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.
Combination with ACE-inhibitors
There may be an increased risk of angioedema in patients concomitantly taking ACEinhibitors.(
see section 4.8).
As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be
reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
sympathomimetics.

Pregnancy
There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals
have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to
lack of human data, Gleptal 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. Gleptal should not be used during breast-feeding.
Fertility
No studies on the effect on human fertility have been conducted for Gleptal.

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

Summary of the safety profile
Safety data were obtained from a total of 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, nonprogressive
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.

Tabulated list of adverse reactions
Adverse reactions reported in patients who received Gleptal in double-blind studies as
monotherapy and add-on therapies are listed below for each indication by system organ class
and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not
known (cannot be estimated from the available data). Within each frequency grouping, adverse
reactions are presented in order of decreasing seriousness.

Combination with metformin
Table 1 Adverse reactions reported in patients who received Gleptal 100 mg daily in
combination with metformin in double-blind studies (N=208)

Description of selected adverse reactions
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).
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

Table 2 Adverse reactions reported in patients who received Gleptal 50 mg in combination
with a sulphonylurea in double-blind studies (N=170)

Description of selected adverse reactions
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).
Combination with a thiazolidinedione

Table 3 Adverse reactions reported in patients who received Gleptal 100 mg daily in
combination with a thiazolidinedione in double-blind studies (N=158)

Description of selected adverse reactions
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, Gleptal 100 mg
daily were 1.4 and 2.7 kg, respectively.
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.

Monotherapy
Table 4 Adverse reactions reported in patients who received Gleptal 100 mg daily as
monotherapy in double-blind studies (N=1,855)

Description of selected adverse reactions
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).
Clinical trials of up to 2 years' duration did not show any additional safety signals or unforeseen
risks with vildagliptin monotherapy.

Combination with metformin and a sulphonylurea
Table 5 Adverse reactions reported in patients who received Gleptal 50 mg twice daily in
combination with metformin and a sulphonylurea (N=157)

Description of selected adverse reactions
There were no withdrawals due to adverse reactions reported in the vildagliptin + metformin +
glimepiride treatment group versus 0.6% in the placebo + metformin + glimepiride treatment
group.
The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin
+ metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group).
One severe hypoglycaemic event was reported in the vildagliptin group.
At the end of the study, effect on mean body weight was neutral (+0.6 kg in the vildagliptin group
and -0.1 kg in the placebo group).
Combination with insulin

Table 6 Adverse reactions reported in patients who received Gleptal 100 mg daily in
combination with insulin (with or without metformin) in double-blind studies (N=371)

Description of selected adverse reactions
In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or
without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was
0.3% in the vildagliptin treatment group and there were no withdrawals in the placebo group.
The incidence of hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin
group vs 16.4% in the placebo group). Two patients reported severe hypoglycaemic events in the
vildagliptin group, and 6 patients in the placebo group.
At the end of the study, effect on mean body weight was neutral (+0.6 kg change from baseline in
the vildagliptin group and no weight change in the placebo group).

Post-marketing experience
Table 7 Post-marketing adverse reactions

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions to The National
Pharmacovigilance and Drug Safety Center (NPC)
Fax: +966-11-205-7662
SFDA call center 19999
Toll free phone: 8002490000
Email: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

Information regarding overdose with vildagliptin is limited.
Symptoms
Information on the likely symptoms of overdose was taken from a rising dose tolerability study in
healthy subjects given 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), aspartate aminotransferase (AST), C-reactive
protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with
paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment
after discontinuation of the study medicinal product.
Management
In the event of an overdose, supportive management is recommended. Vildagliptin cannot be
removed by haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed
by haemodialysis.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors,
ATC code: A10BH02
Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.
Mechanism of action
The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity,
resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1
(glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
Pharmacodynamic effects
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the
sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion.
Treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved
markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin
to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal
tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate
insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells
to glucose, resulting in more glucose-appropriate glucagon secretion.
The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased
incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose
production, leading to reduced glycaemia.
The known effect of increased GLP-1 levels delaying gastric emptying is not observed with
vildagliptin treatment.

Clinical efficacy and safety
More than 15,000 patients with type 2 diabetes participated in double-blind placebo- or activecontrolled
clinical trials of up to more than 2 years' treatment duration. In these studies,
vildagliptin was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50
mg twice daily or 100 mg once daily. More than 5,000 male and more than 4,000 female patients
received vildagliptin 50 mg once daily or 100 mg daily. More than 1,900 patients receiving
vildagliptin 50 mg once daily or 100 mg daily were ≥ 65 years. In these trials, vildagliptin was
administered as monotherapy in drug-naïve patients with type 2 diabetes or in combination in
patients not adequately controlled by other antidiabetic medicinal products.
Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in
combination with metformin, a sulphonylurea, and a thiazolidinedione, as measured by clinically
relevant reductions in HbA1c from baseline at study endpoint (see Table 8).
In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients with
higher baseline HbA1c.
In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline
HbA1c by -1% compared to -1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was not achieved. Patients treated with vildagliptin reported significantly lower incidences of
gastrointestinal adverse reactions versus those treated with metformin.
In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared to
rosiglitazone (8 mg once daily). Mean reductions were -1.20% with vildagliptin and -1.48% with
rosiglitazone in patients with mean baseline HbA1c of 8.7%. Patients receiving rosiglitazone
experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced
no weight gain (-0.3 kg). The incidence of peripheral oedema was lower in the vildagliptin group
than in the rosiglitazone group (2.1% vs. 4.1% respectively).
In a clinical trial of 2 years' duration, vildagliptin (50 mg twice daily) was compared to gliclazide
(up to 320 mg/day). After two years, mean reduction in HbA1c was -0.5% for vildagliptin and -
0.6% for gliclazide, from a mean baseline HBA1c of 8.6%. Statistical non-inferiority was not
achieved. Vildagliptin was associated with fewer hypoglycaemic events (0.7%) than gliclazide
(1.7%).
In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once
daily) in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean
reductions from baseline HbA1c of 8.4% were -0.9% with vildagliptin added to metformin and -
1.0% with pioglitazone added to metformin. A mean weight gain of +1.9 kg was observed in
patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving
vildagliptin added to metformin.
In a clinical trial of 2 years' duration, vildagliptin (50 mg twice daily) was compared to glimepiride
(up to 6 mg/day – mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily
dose: 1894 mg). After 1 year mean reductions in HbA1c were -0.4% with vildagliptin added to
metformin and -0.5% with glimepiride added to metformin, from a mean baseline HbA1c of 7.3%.
Body weight change with vildagliptin was -0.2 kg vs +1.6 kg with glimepiride. The incidence of
hypoglycaemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride
group (16.2%). At study endpoint (2 years), the HbA1c was similar to baseline values in both
treatment groups and the body weight changes and hypoglycaemia differences were maintained.
In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose:
229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline 1928
mg/day). After 1 year, mean reductions in HbA1cwere -0.81% with vildagliptin added to metformin
(mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (mean baseline
HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 – 0.20). Body weight change
with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.
In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin
(gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial
therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily
reduced HbA1c by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin
1000 mg twice daily by -1.36% and vildagliptin 50 mg twice daily by -1.09% from a mean baseline
HbA1c of 8.6%. The decrease in HbA1c observed in patients with a baseline ≥10.0% was greater.
A 24-week, multi-centre, randomised, double-blind, placebo-controlled trial was conducted to
evaluate the treatment effect of vildagliptin 50 mg once daily compared to placebo in 515 patients
with type 2 diabetes and moderate renal impairment (N=294) or severe renal impairment
(N=221). 68.8% and 80.5% of the patients with moderate and severe renal impairment
respectively were treated with insulin (mean daily dose of 56 units and 51.6 units respectively) at
baseline. In patients with moderate renal impairment vildagliptin significantly decreased HbA1c compared with placebo (difference of -0.53%) from a mean baseline of 7.9%. In patients
with severe renal impairment, vildagliptin significantly decreased HbA1c compared with placebo
(difference of -0.56%) from a mean baseline of 7.7%.
A 24-week randomised, double-blind, placebo-controlled trial was conducted in 318 patients to
evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin
(≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and
glimepiride significantly decreased HbA1c compared with placebo.The placebo-adjusted mean
reduction from a mean baseline HbA1c of 8.8% was -0.76%.
A 24-week randomised, double-blind, placebo-controlled trial was conducted in 449 patients to
evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable
dose of basal or premixed insulin (mean daily dose 41 units), with concomitant use of metformin
(N=276) or without concomitant metformin (N=173). Vildagliptin in combination with insulin
significantly decreased HbA1c compared with placebo. In the overall population, the placeboadjusted
mean reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups
treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in
HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycaemia in the overall
population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients
receiving vildagliptin experienced no weight gain (+0.2 kg) while those receiving placebo
experienced weight reduction (-0.7 kg).
In another 24-week study in patients with more advanced type 2 diabetes not adequately
controlled on insulin (short and longer acting, average insulin dose 80 IU/day), the mean
reduction in HbA1c when vildagliptin (50 mg twice daily) was added to insulin was statistically
significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of
hypoglycaemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).
A 52-week multi-centre, randomised, double-blind trial was conducted in patients with type 2
diabetes and congestive heart failure (NYHA functional class I-III) to evaluate the effect of
vildagliptin 50 mg twice daily (N=128) compared to placebo (N=126) on left-ventricular ejection
fraction (LVEF). Vildagliptin was not associated with a change in left-ventricular function or
worsening of pre-existing CHF. Adjudicated cardiovascular events were balanced overall. There
were more cardiac events in vildagliptin treated patients with NYHA class III heart failure
compared to placebo. However, there were imbalances in baseline cardiovascular risk favouring
placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly
decreased HbA1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8% at
week 16. In the subgroup with NYHA class III, the decrease in HbA1c compared to placebo was
lower (difference 0.3%) but this conclusion is limited by the small number of patients (n=44). The
incidence of hypoglycaemia in the overall population was 4.7% and 5.6% in the vildagliptin and
placebo groups, respectively 

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

Table 8 Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and in
add-on combination therapy trials (primary efficacy ITT population)

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
vildagliptin in all subsets of the paediatric population with type 2 diabetes mellitus.

Absorption
Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak
plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma
concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of
vildagliptin with food resulted in a decreased Cmax (19%). However, the magnitude of change is
not clinically significant, so that Gleptal 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 steadystate
after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

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

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

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

Characteristics in specific groups of patients
Gender
No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between
male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4
inhibition by vildagliptin is not affected by gender.
Elderly
In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily)
was increased by 32%, with an 18% increase in peak plasma concentration as compared to
young healthy subjects (18-40 years). These changes are, however, not considered to be
clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age.
Hepatic impairment
The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in
patients with mild, moderate and severe hepatic impairment based on the Child-Pugh scores
(ranging from 6 for mild to 12 for severe) in comparison with healthy subjects. The exposure to
vildagliptin after a single dose in patients with mild and moderate hepatic impairment was

decreased (20% and 8%, respectively), while the exposure to vildagliptin for patients with severe
impairment was increased by 22%. The maximum change (increase or decrease) in the exposure
to vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation
between the severity of the hepatic disease and changes in the exposure to vildagliptin.
Renal impairment
A multiple-dose, open-label trial was conducted to evaluate the pharmacokinetics of the lower
therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic
renal impairment defined by creatinine clearance (mild: 50 to <80 ml/min, moderate: 30 to <50
ml/min and severe: <30 ml/min) compared to normal healthy control subjects.
Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and
severe renal impairment, respectively, compared to normal healthy subjects. AUC of the
metabolites LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with
mild, moderate and severe renal impairment, respectively. Limited data from patients with end
stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with
severe renal impairment. LAY151 concentrations were approximately 2-3-fold higher than in
patients with severe renal impairment.
Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3-4 hour haemodialysis
session starting 4 hours post dose).
Ethnic group
Limited data suggest that race does not have any major influence on vildagliptin
pharmacokinetics.

Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg
(7-fold human exposure based on Cmax).
Accumulation of foamy alveolar macrophages in the lung was observed in rats and mice. The noeffect
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.
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.

Lactose, anhydrous
Cellulose, microcrystalline
Sdium starch glycolate (type A)
Magnesium stearate

Not applicable.

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

Aluminium/Aluminium blister

Not applicable.