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 100mg, 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 50mg once daily administered in the morning. In this patient
population, vildagliptin 100mg daily was no more effective than vildagliptin 50mg
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 100mg are not recommended.
If a dose of JALRA 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 JALRA is 50 mg
once daily (see also sections 4.4, 5.1 and 5.2).
Hepatic impairment
JALRA 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).
Paediatric population
JALRA is not recommended for use in children and adolescents (< 18 years). The safety and
efficacy of JALRA in children and adolescents (< 18 years) have not been established. No data
are available (see also section 5.1).
Method of administration
Oral use
JALRA can be administered with or without a meal (see also section 5.2).
 

General
JALRA is not a substitute for insulin in insulin-requiring patients. JALRA 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
JALRA should be used with caution in these patients (see also sections 4.2, 5.1 and
5.2).
Hepatic impairment
JALRA should not be used in patients with hepatic impairment, including patients
with pre-treatment 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 JALRA in
order to know the patient's baseline value. Liver function should be monitored
during treatment with JALRA 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 JALRA
therapy is recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue
JALRA.
Following withdrawal of treatment with JALRA and LFT normalisation, treatment with JALRA
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 leftventricular 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.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain.
Resolution of pancreatitis has been observed after discontinuation of vildagliptin. If pancreatitis
is suspected, vildagliptin and other potentially suspect medicinal products should be
discontinued.
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.
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
Pregnancy category: B
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, JALRA 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. JALRA should not be used during breastfeeding.
Fertility
No studies on the effect on human fertility have been conducted for JALRA (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 50mg (once daily) or 100mg (50mg twice daily or 100mg 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 100mg daily (either 50mg twice daily or 100mg once
daily) and 1,102 patients were treated with vildagliptin 50mg 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 list of adverse reactions
Adverse reactions reported in patients who received JALRA 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

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

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

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, JALRA 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

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

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

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

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 JALRA 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.
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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 glucosedependent
insulin secretion. Treatment with vildagliptin 50-100mg 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 placeboor
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 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 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 noninferiority
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 25 phase III clinical studies of up to more than 2 years duration was
performed and showed that vildagliptin treatment was not associated with an
increase in cardiovascular risk versus comparators. The composite endpoint of
adjudicated cardiovascular and cerebrovascular (CCV) events [acute coronary
syndrome (ACS), transient ischaemic attack (with imaging evidence of infarction),
stroke or CCV death], was similar for vildagliptin versus combined active and
placebo comparators [Mantel–Haenszel risk ratio 0.84 (95% confidence interval
0.63 1.12)]. In total, 99 out of 8956 patients reported an event in the vildagliptin
group vs 91 out of 6061 patients in the comparator group.

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 JALRA 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 comedications that are
CYP 450 inhibitors and/or inducers.
In vitro studies demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes.
Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolized
by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
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 (100mg 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 750mg/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 dose of 50mg/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 ≥ 150mg/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 100mg/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 100mg 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 100mg 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
Sodium starch glycolate (type A)
Magnesium stearate
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Not applicable.
 

Store in the original package in order to protect from moisture.
Do not Store above 30 °C .
 

Aluminium/Aluminium (PA/Al/PVC//Al) blister
Available in packs containing 28 and 56 tablets
 

No special requirements.