Dalmevin 50 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

20-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

20-04-2018

Aktiva substanser:
vildagliptin
Tillgänglig från:
Medochemie Ltd,
ATC-kod:
A10BH02
INN (International namn):
vildagliptin
Dos:
50 mg
Läkemedelsform:
Tablett
Sammansättning:
laktos (vattenfri) Hjälpämne; vildagliptin 50 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 7 tabletter; Blister, 14 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 90 tabletter; Blister, 112 tabletter; Blister, 180 tabletter; Blister, 336 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
54670
Tillstånd datum:
2017-07-20

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

02-09-2021

Produktens egenskaper Produktens egenskaper - engelska

28-02-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

20-07-2017

Läs hela dokumentet

Package leaflet: Information for the user

Dalmevin 50 mg tablets

Vildagliptin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or diabetes nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Dalmevin is and what it is used for

What you need to know before you take Dalmevin

How to take Dalmevin

Possible side effects

How to store Dalmevin

Contents of the pack and other information

1.

What Dalmevin is and what it is used for

The active substance of Dalmevin, vildagliptin, belongs to a group of medicines called “oral

antidiabetics”.

Dalmevin is used to treat adult patients with type 2 diabetes. It is used when diabetes cannot be

controlled by diet and exercise alone. It helps to control the level of sugar in the blood. Your doctor

will prescribe Dalmevin either alone or together with certain other antidiabetic medicines which you

will already be taking, if these have not proved sufficiently effective to control diabetes.

Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body

makes does not work as well as it should. It can also develop if the body produces too much glucagon.

Insulin is a substance which helps to lower the level of sugar in the blood, especially after meals.

Glucagon is a substance which triggers the production of sugar by the liver, causing the blood sugar

level to rise. The pancreas makes both of these substances.

How Dalmevin works

Dalmevin works by making the pancreas produce more insulin and less glucagon. This helps to

control the blood sugar level. This medicine has been shown to reduce blood sugar, which may help to

prevent complications from your diabetes. Even though you are now starting a medicine for your

diabetes, it is important that you continue to follow the diet and/or exercise which has been

recommended for you.

2.

What you need to know before you take Dalmevin

Do not take Dalmevin:

If you are allergic to vildagliptin or any of the other ingredients of this medicine (listed in section

6). If you think you may be allergic to vildagliptin or any of the other ingredients of Dalmevin, do

not take this medicine and talk to your doctor.

Warnings and precautions

Talk to your doctor, pharmacist or diabetes nurse before taking Dalmevin:

If you have type 1 diabetes (i.e. your body does not produce insulin) or if you have a condition

called diabetic ketoacidosis.

If you are taking an anti-diabetic medicine known as a sulphonylurea (your doctor may want to

reduce your dose of the sulphonylurea when you take it together with Dalmevin in order to avoid

low blood glucose [hypoglycaemia]).

If you have moderate or severe kidney disease (you will need to take a lower dose of Dalmevin).

If you are on dialysis.

If you have liver disease.

If you suffer from heart failure.

If you have or have had a disease of the pancreas.

If you have previously taken vildagliptin but had to stop taking it because of liver disease, you should

not take this medicine.

Diabetic skin lesions are a common complication of diabetes. You are advised to follow the

recommendations for skin and foot care that you are given by your doctor or nurse. You are also

advised to pay particular attention to new onset of blisters or ulcers while taking Dalmevin. Should

these occur, you should promptly consult your doctor.

A test to determine your liver function will be performed before the start of Dalmevin treatment, at

three-month intervals for the first year and periodically thereafter. This is so that signs of increased

liver enzymes can be detected as early as possible.

Children and adolescents

The use of Dalmevin in children and adolescents up to 18 years of age is not recommended.

Other medicines and Dalmevin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Your doctor may wish to alter your dose of Dalmevin if you are taking other medicines such as:

thiazides or other diuretics (also called water tablets),

corticosteroids (generally used to treat inflammation),

thyroid medicines,

certain medicines affecting the nervous system.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

You should not use Dalmevin during pregnancy. It is not known if Dalmevin passes into breast milk.

You should not use Dalmevin if you are breast-feeding or plan to breast-feed.

Driving and using machines

If you feel dizzy while taking Dalmevin, do not drive or use machines.

Dalmevin contains lactose

Dalmevin contains lactose (milk sugar). If you have been told by your doctor that you have an

intolerance to some sugars, contact your doctor before taking this medicine.

3.

How to take Dalmevin

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

How much to take and when

The amount of Dalmevin people have to take varies depending on their condition. Your doctor will

tell you exactly how many tablets of Dalmevin to take. The maximum daily dose is 100 mg.

The usual dose of Dalmevin is either:

50 mg daily taken as one dose in the morning if you are taking Dalmevin with another medicine

called a sulphonylurea.

100 mg daily taken as 50 mg in the morning and 50 mg in the evening if you are taking Dalmevin

alone, with another medicine called metformin or a glitazone, with a combination of metformin

and a sulphonylurea, or with insulin.

50 mg daily in the morning if you have moderate or severe kidney disease or if you are on

dialysis.

How to take Dalmevin

Swallow the tablets whole with some water.

How long to take Dalmevin

Take Dalmevin every day for as long as your doctor tells you. You may have to take this

treatment over a long period of time.

Your doctor will regularly monitor your condition to check that the treatment is having the

desired effect.

If you take more Dalmevin than you should

If you take too many Dalmevin tablets, or if someone else has taken your medicine,

talk to your

doctor straight away

. Medical attention may be needed. If you need to see a doctor or go to the

hospital, take the pack with you.

If you forget to take Dalmevin

If you forget to take a dose of this medicine, take it as soon as you remember. Then take your next

dose at the usual time. If it is almost time for your next dose, skip the dose you missed. Do not take a

double dose to make up for a forgotten tablet.

If you stop taking Dalmevin

Do not stop taking Dalmevin unless your doctor tells you to.

If you have questions about how long to take this medicine, talk to your doctor.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some symptoms need immediate medical attention:

You should stop taking Dalmevin and see your doctor immediately if you experience the following

side effects:

Angioedema (rare: may affect up to 1 in 1,000 people): Symptoms include swollen face, tongue

or throat, difficulty swallowing, difficulties breathing, sudden onset rash or hives, which may

indicate a reaction called “angioedema”.

Liver disease (hepatitis) (rare): Symptoms include yellow skin and eyes, nausea, loss of appetite

or dark-coloured urine, which may indicate liver disease (hepatitis).

Inflammation of the pancreas (pancreatitis) (frequency not known): Symptoms include severe and

persistent pain in the abdomen (stomach area), which might reach through to your back, as well as

nausea and vomiting.

Other side effects

Some patients have had the following side effects while taking Dalmevin and metformin:

Common (may affect up to 1 in 10 people): Trembling, headache, dizziness, nausea, low blood

glucose

Uncommon (may affect up to 1 in 100 people): Tiredness

Some patients have had the following side effects while taking Dalmevin and a sulphonylurea:

Common: Trembling, headache, dizziness, weakness, low blood glucose

Uncommon: Constipation

Very rare (may affect up to 1 in 10,000 people): Sore throat, runny nose

Some patients have had the following side effects while taking Dalmevin and a glitazone:

Common: Weight increase, swollen hands, ankle or feet (oedema)

Uncommon: Headache, weakness, low blood glucose

Some patients have had the following side effects while taking Dalmevin alone:

Common: Dizziness

Uncommon: Headache, constipation, swollen hands, ankle or feet (oedema), joint pain, low blood

glucose

Very rare: Sore throat, runny nose, fever

Some

patients

have

following

side

effects

while

taking

Dalmevin,

metformin

sulphonylurea:

Common: Dizziness, tremor, weakness, low blood glucose, excessive sweating

Some patients have had the following side effects while taking Dalmevin and insulin (with or without

metformin):

Common: Headache, chills, nausea (feeling sick), low blood glucose, heartburn

Uncommon: Diarrhoea, flatulence

Since this product has been marketed, the following side effects have also been reported:

Frequency not known (cannot be estimated from the available data): Itchy rash, inflammation of

the pancreas, localised peeling of skin or blisters, muscle pain

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or diabetes nurse. This includes any

possible side effects not listed in this leaflet. You can also report side effects directly via the national

reporting system. By reporting side effects, you can help provide more information on the safety of

this medicine.

5.

How to store Dalmevin

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date

refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Dalmevin contains

The active substance is vildagliptin. Each tablet contains 50 mg vildagliptin.

The other ingredients are: microcrystalline cellulose, lactose anhydrous, sodium starch glycolate

(Type A) and magnesium stearate.

What Dalmevin looks like and contents of the pack

Dalmevin 50 mg tablets are white to light yellowish, round flat bevel edged uncoated tablet plain on

both sides with diameter 8 mm.

Dalmevin 50 mg tablets are available in blisters in boxes containing 7, 14, 28, 30, 56, 60, 90, 112,

180, 336 tablets in blisters.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Medochemie Ltd, 1-10 Constantinoupoleos Street, 3011 Limassol, Cyprus

Manufacturer

Medochemie Ltd. - Central Factory, 1-10 Constantinoupoleos Street, 3011 Limassol, Cyprus

This medicinal product is authorized in the Member States of the EEA under the following

name:

Sweden

Dalmevin

Bulgaria

Далмевин 50 mg таблетки

Croatia

DALMEVIN 50mg tablete

Cyprus

DALMEVIN 50mg δισκία

Czech Republic

DALMEVIN

Estonia

DALMEVIN

Greece

DALMEVIN 50mg δισκία

Latvia

DALMEVIN 50mg tabletes

Lithuania

DALMEVIN 50mg tabletės

Malta

DALMEVIN 50mg tablets

Romania

DALMEVIN 50mg comprimate

Slovak Republic

DALMEVIN 50mg tablety

This leaflet was last revised in 2021-09-02

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Dalmevin 50 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of vildagliptin.

Excipient with known effect: each tablet contains 48 mg lactose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet

White to light yellowish, round flat bevel edged uncoated tablet plain on both sides with diameter 8mm.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

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.

4.2

Posology and method of administration

Posology

Adults

When used as monotherapy, in combination with metformin, in combination with thiazolidinedione,

in combination with metformin and a sulphonylurea, or in combination with insulin (with or without

metformin), the recommended daily dose of vildagliptin is 100 mg, administered as one dose of 50

mg in the morning and one dose of 50 mg in the evening.

When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg

once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no

more effective than vildagliptin 50 mg once daily.

When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be

considered to reduce the risk of hypoglycaemia.

Doses higher than 100 mg are not recommended.

If a dose of vildagliptin 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 vildagliptin is 50 mg once daily (see also sections 4.4, 5.1 and

5.2).

Hepatic impairment

Dalmevin 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

Dalmevin is not recommended for use in children and adolescents (< 18 years). The safety and

efficacy of vildagliptin in children and adolescents (< 18 years) have not been established. No data are

available (see also section 5.1).

Method of administration

Oral use

Dalmevin can be administered with or without a meal (see also section 5.2).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.

4.4

Special warnings and precautions for use

General

Vildagliptin is not a substitute for insulin in insulin-requiring patients. Dalmevin 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 Dalmevin should be

used with caution in these patients (see also sections 4.2, 5.1 and 5.2).

Hepatic impairment

Dalmevin 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 vildagliptin in order to know the patient’s baseline value. Liver function

should be monitored during treatment with vildagliptin 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 vildagliptin therapy is recommended.

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue

vildagliptin.

Following

withdrawal

treatment

with

vildagliptin

normalisation,

treatment

with

vildagliptin 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

worsening

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

bullous

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

Dalmevin contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

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 ACE-inhibitors (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.

4.6

Fertility, pregnancy and lactation

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, Dalmevin 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. Dalmevin should not be used during breast-feeding.

Fertility

No studies on the effect on human fertility have been conducted for vildagliptin (see section 5.3).

4.7

Effects on ability to drive and use machines

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.

4.8

Undesirable effects

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

transaminases

were

generally

asymptomatic,

non-progressive

nature

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

patients

received

vildagliptin

double-blind

studies

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

Adverse

reactions

reported

patients

received

vildagliptin

100mg

daily

combination with metformin in double-blind studies (N=208)

System organ class

Frequency

Adverse reactions

Metabolism and nutrition

disorders

Common

Hypoglycaemia

Common

Tremor

Common

Headache

Common

Dizziness

Nervous system disorders

Uncommon

Fatigue

Gastrointestinal disorders

Common

Nausea

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

daily

combination

with

metformin

(1%)

uncommon

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 in combination with

a sulphonylurea in double-blind studies (N=170)

System organ class

Frequency

Adverse reactions

Infections and infestations

Very rare

Nasopharyngitis

Metabolism and nutrition

disorders

Common

Hypoglycaemia

Common

Tremor

Common

Headache

Common

Dizziness

Nervous system disorders

Common

Asthenia

Gastrointestinal disorders

Uncommon

Constipation

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

Adverse

reactions

reported

patients

received

vildagliptin

daily

combination with a thiazolidinedione in double-blind studies (N=158)

System organ class

Frequency

Adverse reactions

Common

Weight increase

Metabolism and nutrition

disorders

Uncommon

Hypoglycaemia

Uncommon

Headache

Nervous system disorders

Uncommon

Asthenia

Vascular disorders

Common

Oedema peripheral

Description of selected adverse reactions

In controlled clinical trials with the combination of vildagliptin 100 mg daily+ a thiazolidinedione, no

withdrawal

adverse

reactions

reported

either

vildagliptin

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, vildagliptin 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

once

daily)

7.0%,

compared

2.5%

background

pioglitazone alone.

Monotherapy

Table

Adverse

reactions

reported

patients

received

vildagliptin

daily

monotherapy in double-blind studies (N=1,855)

System organ class

Frequency

Adverse reactions

Very rare

Upper respiratory tract infection

Infections and infestations

Very rare

Nasopharyngitis

Metabolism and nutrition

disorders

Uncommon

Hypoglycaemia

Common

Dizziness

Nervous system disorders

Uncommon

Headache

Vascular disorders

Uncommon

Oedema peripheral

Gastrointestinal disorders

Uncommon

Constipation

Musculoskeletal and connective

tissue disorders

Uncommon

Arthralgia

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.

clinical

trials,

weight

change

from

baseline

when

vildagliptin

daily

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 vildagliptin 50 mg twice daily in

combination with metformin and a sulphonylurea (N=157)

System organ class

Frequency

Adverse reactions

Metabolism and nutrition

disorders

Common

Hypoglycaemia

Common

Dizziness

Nervous system disorders

Common

Tremor

Skin and subcutaneous tissue

disorders

Common

Hyperhidrosis

General disorders and

administration site conditions

Common

Asthenia

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

Adverse

reactions

reported

patients

received

vildagliptin

daily

combination with insulin (with or without metformin) in double-blind studies (N=371)

System organ class

Frequency

Adverse reactions

Metabolism and nutrition

disorders

Common

Decreased blood glucose

Common

Headache

Nervous system disorders

Common

Chills

Common

Nausea

Common

Gastro-oesophageal reflux disease

Uncommon

Diarrhoea

Gastrointestinal disorders

Uncommon

Flatulence

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

System organ class

Frequency

Adverse reactions

Gastrointestinal disorders

Not known

Pancreatitis

Not known

Hepatitis (reversible upon discontinuation of

the medicinal product)

Hepatobiliary disorders

Not known

Abnormal liver function tests (reversible upon

discontinuation of the medicinal product)

Musculoskeletal and connective

tissue disorders

Not known

Myalgia

Not known

Urticaria

Skin and subcutaneous tissue

disorders

Not known

Exfoliative and bullous skin lesions, including

bullous pemphigoid

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system.

4.9

Overdose

Information regarding overdose with vildagliptin is limited.

Symptoms

Information on the likely symptoms of overdose was taken from a rising dose tolerability study in

healthy subjects given vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain, and

individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase

levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine

phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin

levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All

symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study

medicinal product.

Management

In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed

haemodialysis.

However,

major

hydrolysis

metabolite

(LAY

151)

removed

haemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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.

known

effect

increased

GLP-1

levels

delaying

gastric

emptying

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 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

patients

with

mean

baseline

HbA1c

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 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.

24-week,

multi-centre,

randomised,

double-blind,

placebo-controlled

trial

conducted

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

associated

with

increase

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%) vildagliptin-treated patients

and 32 (0.45%) comparator-treated patients with M-H RR 1.08 (95% CI 0.68-1.70).

Table 8 – Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and in add-on

combination therapy trials (primary efficacy ITT population)

Monotherapy placebo

controlled studies

Mean baseline HbA1c

(%)

Mean change from

baseline in HbA1c

(%) at week 24

Placebo-corrected

mean change in

HbA1c (%) at week

24 (95%CI)

Study 2301:

Vildagliptin 50 mg

twice daily (N=90)

-0.8

-0.5* (-0.8, -0.1)

Study 2384:

Vildagliptin 50 mg

twice daily (N=79)

-0.7

-0.7* (-1.1, -0.4)

*p<0.05 for comparison versus placebo

Add-on /

Combination studies

Mean baseline HbA1c

(%)

Mean change from

baseline in HbA1c

(%) at week 24

Placebo-corrected

mean change in

HbA1c (%) at week

24 (95%CI)

Vildagliptin 50 mg

twice daily +

metformin (N=143)

-0.9

-1.1* (-1.4, -0.8)

Vildagliptin 50 mg

daily + glimepiride

(N=132)

-0.6

-0.6* (-0.9, -0.4)

Vildagliptin 50 mg

twice daily +

pioglitazone (N=136)

-1.0

-0.7* (-0.9, -0.4)

Vildagliptin 50 mg

twice daily +

metformin +

glimepiride (N=152)

-1.0

-0.8* (-1.0, -0.5)

*p<0.05 for comparison versus placebo + comparator

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).

5.2

Pharmacokinetic properties

Absorption

Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma

concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to

2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food

resulted in a decreased Cmax (19%). 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 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

healthy

subjects,

total

plasma

renal

clearances

vildagliptin

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 were 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

normal

healthy

subjects.

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.

5.3

Preclinical safety data

Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg (7-

fold human exposure based on 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 no-effect dose of 75 mg/kg (10-

fold human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of

developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect

dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in

rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a

transient decrease in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately

200 times human exposure at the maximum recommended dose). No increases in tumour incidence

attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in

mice at oral doses up to 1,000 mg/kg. An increased incidence of mammary adenocarcinomas and

haemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and

100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice

is considered not to represent a significant risk to humans based on the lack of genotoxicity of

vildagliptin and its principal metabolite, the occurrence of tumours only in one species and the high

systemic exposure ratios at which tumours were observed.

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥ 5

mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5

mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters were

observed.

They

were

reversible

despite

continued

treatment

were

associated

with

histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating

histopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUC

exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin

lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Microcrystalline cellulose

Lactose anhydrous

Sodium starch glycolate (Type A)

Magnesium stearate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

30 months

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Boxes containing 7, 14, 28, 30, 56, 60, 90, 112, 180, 336 tablets in Alu-Alu (PA/Alu/PVC – Alu)

blisters are available.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements for disposal.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2019-02-28

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