JALRA M is indicated in the treatment of type 2 diabetes mellitus:
- JALRA M is indicated in the treatment of adult patients who are unable to achieve sufficient
glycaemic control at their maximally tolerated dose of oral metformin alone or who are already
treated with the combination of vildagliptin and metformin as separate tablets.
- JALRA M is indicated in combination with a sulphonylurea (i.e. triple combination
therapy) as an adjunct to diet and exercise in adult patients inadequately controlled
with metformin and a sulphonylurea.
- JALRA M is indicated in triple combination therapy with insulin as an adjunct to
diet and exercise to improve glycaemic control in adult patients when insulin at a
stable dose and metformin alone do not provide adequate glycaemic control.
 

Posology
Adults
The dose of antihyperglycaemic therapy with JALRA M should be individualised
on the basis of the patient's current regimen, effectiveness and tolerability while not
exceeding the maximum recommended daily dose of 100 mg vildagliptin.
JALRA M may be initiated at either the 50 mg/850 mg or 50 mg/1000 mg tablet
strength twice daily, one tablet in the morning and the other in the evening.
- For patients inadequately controlled at their maximal tolerated dose of metformin
monotherapy:
The starting dose of JALRA M should provide vildagliptin as 50 mg twice daily (100 mg total
daily dose) plus the dose of metformin already being taken.
- For patients switching from co-administration of vildagliptin and metformin as
separate tablets:
JALRA M should be initiated at the dose of vildagliptin and metformin already being taken.
- For patients inadequately controlled on dual combination with metformin and a sulphonylurea:
The doses of JALRA M should provide vildagliptin as 50 mg twice daily (100 mg total daily
dose) and a dose of metformin similar to the dose already being taken.
When JALRA M is used in combination with a sulphonylurea, a lower dose of the
sulphonylurea may be considered to reduce the risk of hypoglycaemia.
- For patients inadequately controlled on dual combination therapy with insulin and the maximal
tolerated dose of metformin:
The dose of JALRA M should provide vildagliptin dosed as 50 mg twice daily (100 mg total
daily dose) and a dose of metformin similar to the dose already being taken.
The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with a
thiazolidinedione have not been established.
Special populations
Elderly (≥ 65 years)
As metformin is excreted via the kidney, and elderly patients have a tendency to
decreased renal function, elderly patients taking JALRA M should have their
renal function monitored regularly (see sections 4.4 and 5.2).
Renal impairment
JALRA M should not be used in patients with creatinine clearance < 60 ml/min
(see sections 4.3, 4.4 and 5.2).
Hepatic impairment
JALRA M should not be used in patients with hepatic impairment, including
those with pre-treatment alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 3 times the upper limit of normal (ULN) (see sections
4.3, 4.4 and 4.8).
Paediatric population
JALRA M is not recommended for use in children and adolescents (< 18 years).
The safety and efficacy of JALRA M in children and adolescents (< 18 years) have not been
established. No data are available.
Method of administration
Oral use.
Taking JALRA M with or just after food may reduce gastrointestinal
symptoms associated with metformin (see also section 5.2).
 

− Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 − Diabetic ketoacidosis or diabetic pre-coma − Renal failure or renal dysfunction defined as creatinine clearance < 60 ml/min (see section 4.4) − Acute conditions with the potential to alter renal function, such as: - dehydration, - severe infection, - shock, - intravascular administration of iodinated contrast agents (see section 4.4). − Acute or chronic disease which may cause tissue hypoxia, such as: - cardiac or respiratory failure, - recent myocardial infarction, - shock. − Hepatic impairment (see sections 4.2, 4.4 and 4.8) − Acute alcohol intoxication, alcoholism − Breast-feeding (see section 4.6)

General
JALRA M is not a substitute for insulin in insulin-requiring patients and should not
be used in patients with type 1 diabetes.
Lactic acidosis
Lactic acidosis is a very rare but serious metabolic complication that can occur due
to metformin accumulation. Reported cases of lactic acidosis in patients on
metformin have occurred primarily in diabetic patients with significant renal failure.
In patients with impaired liver function, lactate clearance may be restricted. The
incidence of lactic acidosis can and should be reduced by also assessing other
associated risk factors, such as poorly controlled diabetes, ketosis, prolonged
fasting, excessive alcohol intake, hepatic insufficiency and any conditions
associated with hypoxia (see also sections 4.3 and 4.5).
Diagnosis of lactic acidosis
Lactic acidosis is characterized by malaise, myalgias, respiratory distress, increasing
somnolence, nonspecific abdominal distress, acidotic dyspnoea, abdominal pain and hypothermia
followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels
above 5 mmol/l and increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is
suspected, treatment with the medicinal product should be discontinued and the patient
hospitalized immediately (see section 4.9).
Renal impairment
As metformin is excreted by the kidney, serum creatinine concentrations should be
monitored regularly:
- at least once a year in patients with normal renal function
- at least two to four times a year in patients with serum creatinine levels at the
upper limit of normal and in elderly patients.
Renal impairment in elderly patients is frequent and asymptomatic. Special caution
should be exercised in situations where renal function may become impaired, for
example when initiating antihypertensive or diuretic therapy or when starting
treatment with an NSAID.
Hepatic impairment
Patients with hepatic impairment, including those with pre-treatment ALT or AST >
3x ULN, should not be treated with JALRA M (see sections 4.2, 4.3 and 4.8).
Liver enzyme monitoring
Rare cases of hepatic dysfunction (including hepatitis) have been reported with
vildagliptin. In these cases, the patients were generally asymptomatic without
clinical sequelae and liver function tests (LFTs) returned to normal after
discontinuation of treatment. LFTs should be performed prior to the initiation of
treatment with JALRA M in order to know the patient's baseline value. Liver
function should be monitored during treatment with JALRA M at three-month
intervals during the first year and periodically thereafter. Patients who develop
increased transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent LFTs until
the abnormality(ies) return(s) to normal. Should an increase in AST or in ALT of 3x ULN
or greater persist, withdrawal of JALRA M therapy is recommended. Patients who develop
jaundice or other signs suggestive of liver dysfunction should discontinue JALRA M.
Following withdrawal of treatment with JALRA M and LFT normalisation,
treatment with JALRA M should not be re-initiated.
Skin disorders
Skin lesions, including blistering and ulceration have been reported with vildagliptin
in extremities of monkeys in non-clinical toxicology studies (see section 5.3).
Although skin lesions were not observed at an increased incidence in clinical trials,
there was limited experience in patients with diabetic skin complications.
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.
Surgery
As JALRA M contains metformin, the treatment should be discontinued 48
hours before elective surgery with general anaesthesia and should not usually
be resumed earlier than 48 hours afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies
can lead to renal failure. Therefore, due to the metformin active substance,
JALRA M should be discontinued prior to, or at the time of, the test and not
reinstituted until
48 hours afterwards, and only after renal function has been re-evaluated and found
to be normal (see section 4.5).
 

There have been no formal interaction studies for JALRA M. The following
statements reflect the information available on the individual active substances.
Vildagliptin
Vildagliptin has a low potential for interactions with co-administered medicinal
products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and
does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active
substances that are substrates, inhibitors or inducers of these enzymes.
Results from clinical trials conducted with the oral antidiabetics pioglitazone,
metformin and glyburide in combination with vildagliptin have shown no clinically
relevant pharmacokinetic interactions in the target population.
Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin
(CYP2C9 substrate) in healthy subjects have shown no clinically relevant
pharmacokinetic interactions after co-administration with vildagliptin.
Drug-drug interaction studies in healthy subjects were conducted with amlodipine,
ramipril, valsartan and simvastatin. In these studies, no clinically relevant
pharmacokinetic interactions were observed after co-administration with vildagliptin.
However, this has not been established in the target population.
As with other oral antidiabetic medicinal products the hypoglycaemic effect of
vildagliptin may be reduced by certain active substances, including thiazides,
corticosteroids, thyroid products and sympathomimetics.
Metformin
Combinations not recommended
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in
the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active
substance of JALRA M (see section 4.4). Consumption of alcohol and medicinal
products containing alcohol should be avoided.
Cationic active substances that are eliminated by renal tubular secretion (e.g.
cimetidine) may interact with metformin by competing for common renal tubular
transport systems and hence delay the elimination of metformin, which may
increase the risk of lactic acidosis. A study in healthy volunteers showed that
cimetidine, administered as 400 mg twice daily, increased metformin systemic
exposure (AUC) by 50%. Therefore, close monitoring of glycaemic control, dose
adjustment within the recommended posology and changes in diabetic treatment
should be considered when cationic medicinal products that are eliminated by renal
tubular secretion are co-administered (see section 4.4).
Intravascular administration of iodinated contrast media may lead to renal failure,
resulting in metformin accumulation with the risk of lactic acidosis. Metformin should
be discontinued prior to, or at the time of the test and not reinstituted until 48 hours
afterwards, and only after renal function has been re-evaluated and found to be
normal.
Combinations requiring precautions for use
Glucocorticoids, beta-2-agonists, and diuretics have intrinsic hyperglycaemic
activity. The patient should be informed and more frequent blood glucose
monitoring performed, especially at the beginning of treatment. If necessary, the
dosage of JALRA M may need to be adjusted during concomitant therapy and on
its discontinuation.
Angiotensin converting enzyme (ACE) inhibitors may decrease the blood glucose
levels. If necessary, the dosage of the antihyperglycaemic medicinal product should
be adjusted during therapy with the other medicinal product and on its
discontinuation.
 

Pregnancy
Pregnancy category: B
There are no adequate data from the use of JALRA M in pregnant women. For
vildagliptin studies in animals have shown reproductive toxicity at high doses. For
metformin, studies in animals have not shown reproductive toxicity. Studies in
animals performed with vildagliptin and metformin have not shown evidence of
teratogenicity, but foetotoxic effects at maternotoxic doses (see section 5.3). The
potential risk for humans is unknown. JALRA M should not be used during
pregnancy.
Breast-feeding
Studies in animals have shown excretion of both metformin and vildagliptin in milk.
It is unknown whether vildagliptin is excreted in human milk, but metformin is
excreted in human milk in low amounts. Due to both the potential risk of neonate
hypoglycaemia related to metformin and the lack of human data with vildagliptin,
JALRA M should not be used during breast-feeding (see section 4.3).
Fertility
No studies on the effect on human fertility have been conducted for JALRA M
(see section 5.3).
 

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

There have been no therapeutic clinical trials conducted with JALRA M. However,
bioequivalence of JALRA M with co-administered vildagliptin and metformin has
been demonstrated (see section 5.2). The data presented here relate to the coadministration
of vildagliptin and metformin, where vildagliptin has been added to
metformin. There have been no studies of metformin added to vildagliptin.
Summary of the safety profile
The majority of adverse reactions were mild and transient, not requiring treatment
discontinuations. No association was found between adverse reactions and age,
ethnicity, duration of exposure or daily dose.
Rare cases of hepatic dysfunction (including hepatitis) have been reported with
vildagliptin. In these cases, the patients were generally asymptomatic without
clinical sequelae and liver function returned to normal after discontinuation of
treatment. In data from controlled monotherapy and add-on therapy trials of up to 24
weeks in duration, the incidence of ALT or AST elevations ≥ 3x ULN (classified as
present on at least 2 consecutive measurements or at the final on-treatment visit)
was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice
daily and all comparators, respectively. These elevations in transaminases were
generally asymptomatic, non-progressive in nature and not associated with
cholestasis or jaundice.
Rare cases of angioedema have been reported on vildagliptin at a similar rate to
controls. A greater proportion of cases were reported when vildagliptin was
administered in combination with an ACE inhibitor. The majority of events were mild
in severity and resolved with ongoing vildagliptin treatment.
Tabulated list of adverse reactions
Adverse reactions reported in patients who received vildagliptin in double-blind
studies as monotherapy and add-on therapies are listed below by system organ
class and absolute frequency. Adverse reactions listed in Table 5 are based on
information available from the metformin Summary of Product Characteristics
available in the EU. Frequencies are defined as very common (≥1/10); common
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);
very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness.
Table 1 Adverse reactions reported in patients who received vildagliptin 100
mg daily as add-on therapy to metformin compared to placebo plus metformin
in double-blind studies (N=208)

Description of selected adverse reactions
In controlled clinical trials with the combination of vildagliptin 100 mg daily plus
metformin, no withdrawal due to adverse reactions was reported in either the
vildagliptin 100 mg daily plus metformin or the placebo plus metformin treatment
groups.
In clinical trials, the incidence of hypoglycaemia was common in patients receiving
vildagliptin in combination with metformin (1%) and uncommon in patients receiving
placebo + metformin (0.4%). No severe hypoglycaemic events were reported in the
vildagliptin arms.
In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily
was added to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo,
respectively).
Clinical trials of up to more than 2 years' duration did not show any additional safety
signals or unforeseen risks when vildagliptin was added on to metformin.
Combination with a sulphonylurea
Table 2 Adverse reactions reported in patients who received vildagliptin 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 3 Adverse reactions reported in patients who received vildagliptin 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).
Additional information on the individual active substances of the fixed combination
Vildagliptin
Table 4 Adverse reactions reported in patients who received vildagliptin 100 mg daily as
monotherapy in double-blind studies (N=1855)

Description of selected adverse reactions
The overall incidence of withdrawals from controlled monotherapy trials due to
adverse reactions was no greater for patients treated with vildagliptin at doses of
100 mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).
In comparative controlled monotherapy studies, hypoglycaemia was uncommon,
reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 100 mg daily
compared to 0.2% (2 of 1,082) of patients in the groups treated with an active
comparator or placebo, with no serious or severe events reported.
In clinical trials, weight did not change from baseline when vildagliptin 100 mg daily
was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo,
respectively).
Clinical trials of up to 2 years' duration did not show any additional safety signals or
unforeseen risks with vildagliptin monotherapy.
Metformin
Table 5 Adverse reactions for metformin component
Metabolism and nutrition disorders

No data are available with regard to overdose of JALRA M.
Vildagliptin
Information regarding overdose with vildagliptin is limited.
Symptoms
Information on the likely symptoms of overdose with vildagliptin was taken from a
rising dose tolerability study in healthy subjects given vildagliptin for 10 days. At 400
mg, there were three cases of muscle pain, and individual cases of mild and
transient paraesthesia, fever, oedema and a transient increase in lipase levels. At
600 mg, one subject experienced oedema of the feet and hands, and increases in
creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin
levels. Three other subjects experienced oedema of the feet, with paraesthesia in
two cases. All symptoms and laboratory abnormalities resolved without treatment
after discontinuation of the study medicinal product.
Metformin
A large overdose of metformin (or co-existing risk of lactic acidosis) may lead to
lactic acidosis, which is a medical emergency and must be treated in hospital.
Management
The most effective method of removing metformin is haemodialysis. However,
vildagliptin cannot be removed by haemodialysis, although the major hydrolysis
metabolite (LAY 151) can. Supportive management is recommended.
 

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood
glucose lowering drugs, ATC code: A10BD08
Mechanism of action
JALRA M combines two antihyperglycaemic agents with complimentary
mechanisms of action to improve glycaemic control in patients with type 2 diabetes:
vildagliptin, a member of the islet enhancer class, and metformin hydrochloride, a
member of the biguanide class.
Vildagliptin, a member of the islet enhancer class, is a potent and selective
dipeptidyl-peptidase-4 (DPP-4) inhibitor. Metformin acts primarily by decreasing
endogenous hepatic glucose production.
Pharmacodynamic effects
Vildagliptin
Vildagliptin acts primarily by inhibiting DPP-4, the enzyme responsible for the
degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP
(glucose-dependent insulinotropic polypeptide).
The administration of vildagliptin results in a rapid and complete inhibition of DPP-4
activity resulting in increased fasting and postprandial endogenous levels of the
incretin hormones GLP-1 and GIP.
By increasing the endogenous levels of these incretin hormones, vildagliptin
enhances the sensitivity of beta cells to glucose, resulting in improved glucosedependent
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.
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and
postprandial plasma glucose. It does not stimulate insulin secretion and therefore
does not produce hypoglycaemia or increased weight gain.
Metformin may exert its glucose-lowering effect via three mechanisms:
- by reduction of hepatic glucose production through inhibition of gluconeogenesis
and glycogenolysis;
- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose
uptake and utilisation;
- by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen
synthase and increases the transport capacity of specific types of membrane
glucose transporters (GLUT-1 and GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable
effects on lipid metabolism. This has been shown at therapeutic doses in controlled,
medium-term or long-term clinical studies: metformin reduces serum levels of total
cholesterol, LDL cholesterol and triglycerides.
The prospective randomised UKPDS (UK Prospective Diabetes Study) study has
established the long-term benefit of intensive blood glucose control in type 2
diabetes. Analysis of the results for overweight patients treated with metformin after
failure of diet alone showed:
- a significant reduction in the absolute risk of any diabetes-related complication in
the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3
events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and
insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034;
- a significant reduction in the absolute risk of diabetes-related mortality: metformin
7.5 events/ 1,000 patient-years, diet alone 12.7 events/1,000 patient-years,
p=0.017;
- a significant reduction in the absolute risk of overall mortality: metformin 13.5
events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years
(p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups
18.9 events/1,000 patient-years (p=0.021);
- a significant reduction in the absolute risk of myocardial infarction: metformin 11
events/ 1,000 patient-years, diet alone 18 events/1,000 patient-years (p=0.01).
Clinical efficacy and safety
Vildagliptin added to patients whose glycaemic control was not satisfactory despite
treatment with metformin monotherapy resulted after 6-month treatment in
additional statistically significant mean reductions in HbA1c compared to placebo
(between group differences of -0.7% to -1.1% for vildagliptin 50 mg and 100 mg,
respectively). The proportion of patients who achieved a decrease in HbA1c of ≥
0.7% from baseline was statistically significantly higher in both vildagliptin plus
metformin groups (46% and 60%, respectively) versus the metformin plus placebo
group (20%).
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 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%).
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.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of
studies with vildagliptin in combination with metformin in all subsets of the paediatric
population with type 2 diabetes mellitus (see section 4.2 for information on
paediatric use).
 

JALRA M
Absorption
Bioequivalence has been demonstrated between JALRA M at three dose
strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) versus free
combination of vildagliptin and metformin hydrochloride tablets at the
corresponding doses.
Food does not affect the extent and rate of absorption of vildagliptin from
JALRA M. The rate and extent of absorption of metformin from JALRA M 50
mg/1000 mg were decreased when given with food as reflected by the decrease in
Cmax by 26%, AUC by 7% and delayed Tmax (2.0 to 4.0 h).
The following statements reflect the pharmacokinetic properties of the individual
active substances of JALRA M.
Vildagliptin
Absorption
Following oral administration in the fasting state, vildagliptin is rapidly absorbed with
peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to
peak plasma concentration to 2.5 hours, but does not alter the overall exposure
(AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%)
compared to dosing in the fasting state. However, the magnitude of change is not
clinically significant, so that vildagliptin can be given with or without food. The
absolute bioavailability is 85%.
Distribution
The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes
equally between plasma and red blood cells. The mean volume of distribution of
vildagliptin at steady-state after intravenous administration (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 amide hydrolysis product (4% of dose). DPP-4 contributes partially
to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats.
Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent, and
accordingly the metabolic clearance of vildagliptin is not anticipated to be affected
by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies
demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore,
vildagliptin is not likely to affect metabolic clearance of co-medications metabolised
by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination
Following oral administration of [14C] vildagliptin, approximately 85% of the dose
was excreted into the urine and 15% of the dose was recovered in the faeces.
Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after
oral administration. After intravenous administration to healthy subjects, the total
plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The
mean elimination half-life after intravenous administration is approximately 2 hours.
The elimination half-life after oral administration is approximately 3 hours.
Linearity / non-linearity
The 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 patients
Gender: No clinically relevant differences in the pharmacokinetics of vildagliptin
were observed between male and female healthy subjects within a wide range of
age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected by
gender.
Age: In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin
(100 mg once daily) was increased by 32%, with an 18% increase in peak plasma
concentration as compared to young healthy subjects (18-40 years). These
changes are not considered to be clinically relevant, however. DPP-4 inhibition by
vildagliptin is not affected by age.
Hepatic impairment: In subjects with mild, moderate or severe hepatic impairment
(Child-Pugh A-C) there were no clinically significant changes (maximum ~30%) in
exposure to vildagliptin.
Renal impairment: In subjects with mild, moderate, or severe renal impairment,
systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) and
total body clearance was reduced compared to subjects with normal renal function.
Ethnic group: Limited data suggest that race does not have any major influence on
vildagliptin pharmacokinetics.
Metformin
Absorption
After an oral dose of metformin, the maximum plasma concentration (Cmax) is
achieved after about 2.5 h.. Absolute bioavailability of a 500 mg metformin tablet is
approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is
assumed that the pharmacokinetics of metformin absorption are non-linear. At the
usual metformin doses and dosing schedules, steady state plasma concentrations
are reached within 24-48 h and are generally less than 1 μg/ml. In controlled clinical
trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/ml, even at
maximum doses.
Food slightly delays and decreases the extent of the absorption of metformin.
Following administration of a dose of 850 mg, the plasma peak concentration was
40% lower, AUC was decreased by 25% and time to peak plasma concentration
was prolonged by 35 minutes. The clinical relevance of this decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The
mean volume of distribution (Vd) ranged between 63-276 litres.
Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified
in humans.
Elimination
Metformin is eliminated by renal excretion. Renal clearance of metformin is > 400
ml/min, indicating that metformin is eliminated by glomerular filtration and tubular
secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased
in proportion to that of creatinine and thus the elimination half-life is prolonged,
leading to increased levels of metformin in plasma.
 

Animal studies of up to 13-week duration have been conducted with the combined
substances in JALRA M. No new toxicities associated with the combination were
identified. The following data are findings from studies performed with vildagliptin or
metformin individually.
Vildagliptin
Intra-cardiac impulse conduction delays were observed in dogs with a no-effect
dose of 15 mg/kg (7-fold human exposure based on 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. 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
1000 mg/kg. An increased incidence of mammary adenocarcinomas and
haemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold
human exposure) and 100 mg/kg (16-fold human exposure), respectively. The
increased incidence of these tumours in mice is considered not to represent a
significant risk to humans based on the lack of genotoxicity of vildagliptin and its
principal metabolite, the occurrence of tumours only in one species, and the high
systemic exposure ratios at which tumours were observed.
In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been
recorded at doses ≥ 5 mg/kg/day. These were consistently located on the
extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to
human AUC exposure at the 100 mg dose), only blisters were observed. They were
reversible despite continued treatment and were not associated with
histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with
correlating histopathological changes were noted at doses ≥ 20 mg/kg/day
(approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions
of the tail were observed at ≥ 80 mg/kg/day. Skin lesions were not reversible in the
monkeys treated at 160 mg/kg/day during a 4-week recovery period.
Metformin
Non-clinical data on metformin reveal no special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity,
carcinogenic potential and toxicity to reproduction.
 

Tablet core:
Hydroxypropylcellulose
Magnesium stearate
Film-coating:
Hypromellose
Titanium dioxide
Iron oxide, yellow
PEG 4000
Talc
 

Not applicable.
 

18 months

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

Aluminium/Aluminium (PA/Alu/PVC/Alu) blister
Available in packs containing 60 film-coated tablets
 

No special requirements.