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
Adult
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 VDIA 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 (see also sections 5.1 and 5.2).
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 VDIA is 50 mg once daily (see also sections 4.4,
5.1 and 5.2).
Hepatic Impairment
VDIA 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) (see also sections 4.4 and 5.2). Paediatric Population
VDIA is not recommended for use in children and adolescents (< 18 years). The safety and
efficacy of VDIA in children and adolescents (< 18 years) have not been established. No
data are available (see also section 5.1).
Method Of Administration
Oral use
VDIA can be administered with or without a meal (see also section 5.2).

General
VDIA is not a substitute for insulin in insulin-requiring patients. VDIA 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, VDIA
should be used with caution in these patients (see also sections 4.2, 5.1 and 5.2).
Hepatic impairment
VDIA should not be used in patients with hepatic impairment, including patients with pretreatment
ALT or AST > 3x ULN (see also sections 4.2 and 5.2).
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 VDIA in order to know the patient's
baseline value. Liver function should be monitored during treatment with VDIA at threemonth
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 VDIA therapy is recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should
discontinue VDIA.
Following withdrawal of treatment with VDIA and LFT normalisation, treatment with VDIA
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 (see section 5.1).
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 (see section 5.3). The potential risk
for humans is unknown. Due to lack of human data, VDIA 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. VDIA should not be used during breast-feeding.
Fertility
No studies on the effect on human fertility have been conducted for VDIA (see section 5.3).

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, 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.
Tabulated Summary Of Adverse Reactions
Adverse reactions reported in patients who received VDIA 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 VDIA 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 VDIA 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 VDIA 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, VDIA 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 VDIA 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 VDIA 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 VDIA 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.
To Report Any Side Effects
• Saudi Arabia
The National Pharmacovigilance Centre (NPC):
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Ext 2317-2356-2340
• SFDA Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc
• Other GCC States:
• Please contact the relevant competent authority.

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 VDIA 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), Creactive
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
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.
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 noninferiority
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 noninferiority
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 HbA1c were -0.81% with
vildagliptin added to metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide
added to metformin (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved
(95% CI -0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a
weight gain of +1.4 kg with gliclazide.
In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin
(gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as
initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg
twice daily reduced HbA1c by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -
1.61%, metformin 1000 mg twice daily by -1.36% and vildagliptin 50 mg twice daily by -
1.09% from a mean baseline HbA1c of 8.6%. The decrease in HbA1c observed in patients with
a baseline ≥10.0% was greater.
A 24-week, 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 placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted
mean reduction in 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-H RR) 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%) vildagliptintreated
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 (see
section 4.2 for information on paediatric use).

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 VDIA can be given with or without food. The absolute
bioavailability is 85%. 

Distribution
The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally
between plasma and red blood cells. The mean volume of distribution of vildagliptin at
steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular
distribution.
Biotransformation
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69%
of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the
hydrolysis 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
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 noeffect
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 preand
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 noeffect
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.

Composition of Vildagliptin 50 mg tablet
Materials
Lactose, anhydrous
Cellulose, microcrystalline
Sodium starch glycolate
Magnesium stearate

Not applicable.

Store below 30°C, Store in the original package in order to protect from moisture

Aluminium/Aluminium blister.
Available in packs containing 28 and 56 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with
local requirements, Keep out of the reach & sight of children