Galvus Met 50/500mg Film-coated Tablet

Malaysia - English - NPRA (National Pharmaceutical Regulatory Agency, Bahagian Regulatori Farmasi Negara)

Buy It Now

Active ingredient:
METFORMIN HYDROCHLORIDE; VILDAGLIPTIN
Available from:
NOVARTIS CORPORATION (MALAYSIA) SDN. BHD.
INN (International Name):
METFORMIN HYDROCHLORIDE; VILDAGLIPTIN
Units in package:
60tablet Tablets; 10tablet Tablets; 30tablet Tablets
Manufactured by:
NOVARTIS SINGAPORE PHARMACEUTICAL MANUFACTURING PTD. LTD.
Authorization number:
MAL12035005ARZ

Documents in other languages

Patient Information leaflet Patient Information leaflet - Malay

22-05-2020

GALVUS

®

MET

Vidagliptin and Metformin fixed combination (50mg/500mg, 50mg/850mg, 50mg/1000mg)

1

Consumer Medication Information Leaflet (RiMUP)

What is in this leaflet

1.

What Galvus Met is used for

2.

How Galvus Met works

3.

Before you use Galvus Met

4.

How to use Galvus Met

5.

While you are using Galvus Met

6.

Side effects

7.

Storage and Disposal of Galvus

Met

8.

Product Description

9.

Manufacturer and Product

Registration Holder

10.

Date of revision

What Galvus Met

is used for

Galvus Met is available as tablets. Each

Galvus Met tablet contains two active

substances: vildagliptin and metformin

hydrochloride. Both substances belong to

a group of medicines called “oral

antidiabetics”.

Three dosage strengths are available

(vildagliptin/metformin hydrochloride)

50 mg/500 mg, 50 mg/850 mg and 50

mg/1,000 mg.

Galvus Met is a medicine used to treat

type 2 diabetes. It helps to control the

level of sugar in the blood. It is prescribed

together with diet and exercise in patients

who have already received treatment with

vildagliptin and metformin hydrochloride

together, or whose diabetes is not

adequately controlled with metformin

hydrochloride or vildagliptin alone, or as a

first diabetes treatment in patients whose

diabetes is not adequately controlled by

diet and exercise alone.

Galvus Met is also prescribed in

combination with a sulfonylurea, together

with diet and exercise in patients whose

diabetes is not adequately controlled with

metformin and a sulfonylurea.

Galvus Met is also prescribed as an add-

on to insulin, together with diet and

exercise, to improve control of blood

sugar (glycemic control) in patients when

a stable dose of insulin and metformin

alone do not provide adequate glycemic

control.

How Galvus Met works

Galvus Met works by making the

pancreas produce more insulin and less

glucagon (effect of vildagliptin) and also

by helping the body to make better use of

the insulin it produces (effect of

metformin hydrochloride). Galvus Met

helps to control the blood sugar level.

It is important that you continue to follow

the diet and/or exercise recommended to

you while you are on treatment with

Galvus Met.

Ask your doctor if you have any questions

about why this medicine has been

prescribed for you.

Before you use Galvus Met

Follow all of the doctor’s instructions

carefully. They may differ from the

general information contained in this

leaflet.

When you must not use it

If you are allergic (hypersensitive) to

vildagliptin, metformin hydrochloride

or to any of the other ingredients of

Galvus Met. If you think you may be

allergic, ask your doctor for advice.

If you have severely reduced kidney

function (this will be decided by your

doctor).

If you have recently had a heart

attack, have heart failure, or if you

have serious problems with your

blood circulation, including shock, or

breathing difficulties.

If you have lactic acidosis [too much

lactic acid in the blood (see “Risk of

lactic acidosis” below)] or

ketoacidosis. Ketoacidosis is a

condition in which substances called

‘ketone bodies’ accumulate in the

blood and which can lead to diabetic

pre-coma. Symptoms of acidosis may

include stomach pain, abnormal

breathing and drowsiness (if severe).

If you are going to have an operation

under general anesthetic, you must

stop taking Galvus Met for a couple

of days before and after the

procedure. Your doctor will decide

when you must stop and when to

restart your treatment with Galvus

Met.

If you are going to have a contrast x-

ray (a specific type of x-ray involving

an injectable dye), you must stop

taking Galvus Met before or at the

time of and for a few days after the

procedure.

Pregnant Women

Tell your doctor if you are pregnant, if

you think you might be pregnant, or if you

are planning to become pregnant. Your

doctor will discuss with you the potential

risk of taking Galvus Met during

pregnancy. Ask your doctor or pharmacist

for advice before taking any medicine

during pregnancy.

Breast-feeding mothers

Do not breast-feed during treatment with

Galvus Met. Ask your doctor or

pharmacist for advice before taking any

medicine while you are breast-feeding.

Before you start use it

Risk of lactic acidosis

Galvus Met may cause a very rare, but

very serious side effect called lactic

acidosis, particularly if your kidneys are

not working properly. The risk of

developing lactic acidosis is also

increased with uncontrolled diabetes,

serious infections, prolonged fasting or

alcohol intake, dehydration, liver

problems and any medical conditions in

which a part of the body has a reduced

supply of oxygen (such as acute severe

heart disease). If any of the above apply

to you, talk to your doctor for further

instructions.

Stop taking Galvus Met for a short time

if you have a condition that may be

associated with dehydration (significant

loss of body fluids) such as severe

vomiting, diarrhoea, fever, exposure to

heat or if you drink less fluid than

normal. Talk to your doctor for further

instructions.

Stop taking Galvus Met and contact a

doctor or the nearest hospital

immediately if you experience some of

the symptoms of lactic acidosis, as this

condition may lead to coma.

Symptoms of lactic acidosis include:

vomiting

stomach ache (abdominal pain)

muscle cramps

a general feeling of not being

well with severe tiredness

difficulty in breathing

Lactic acidosis is a medical emergency

2

Consumer Medication Information Leaflet (RiMUP)

and must be treated in a hospital.

Take special care with Galvus Met

Galvus Met is not a substitute for insulin.

You should therefore neither receive

Galvus Met for the treatment of type 1

diabetes (i.e. your body does not produce

insulin at all) nor for the treatment of a

condition called diabetic ketoacidosis.

Monitoring your Galvus Met treatment

Your doctor should ensure that the

following tests are performed:

Blood and urine tested for sugar

regularly

Check how your kidneys function:

at start of treatment

at least once a year while you are

on treatment

more frequently if you are

elderly or if you have worsening

kidney function

Check how your liver functions:

at start of treatment

every 3 months during the first

year of treatment and regularly

thereafter

if your doctor has told you to

stop your treatment with Galvus

Met because of liver problems,

you should never start taking

Galvus Met again.

General blood test at least once a year

A check of vitamin B12 levels may

also be carried out at least every two

to three years

Galvus Met and older people

Your doctor will check how well your

kidneys work. You may need more

frequent checks if you have kidney

problems.

Galvus Met and children

There is no information available on the

use of Galvus Met in children and

adolescents (aged below 18 years). The

use of Galvus Met in these patients is

therefore not recommended.

Taking Galvus Met with food and drink

It is recommended that you take your

tablets either with or just after taking

food. This will reduce the chance of you

getting an upset stomach.

Taking other medicines

Tell your doctor or pharmacist or

healthcare provider if you are taking or

have recently taken or might take any

other medicines, including medicines

obtained without a prescription.This is

particularly important with the following

medicines:

certain medicines used to treat

infections (e.g. vancomycin,

trimethoprim)

certain medicines used to treat

inflammation (e.g. corticosteroids)

certain medicines used to treat high

blood pressure (e.g. amiloride,

triamterene, nifedipine, enalapril,

losartan, diuretics)

certain medicines used to treat

irregular heartbeat (e.g. digoxin,

quinidine)

certain medicines used to reduce pain

(e.g. morphine, diclofenac)

certain medicines used to treat

stomach disorders (e.g. cimetidine,

ranitidine)

certain medicines used to treat some

psychiatric disorders (e.g.

phenothiazine)

certain medicines used to treat thyroid

disorders

oral contraceptives, certain medicines

used to reduce symptoms in women

experiencing menopause or

osteoporosis (e.g. estrogen)

Ask your doctor or pharmacist or

healthcare provider if you are not sure

whether your medicine is one of the

medicines listed above.

How to use Galvus Met

Always take this medicine exactly as your

doctor or pharmacist has told you.

Check with your doctor or pharmacist or

healthcare provider if you are not sure.

Do not exceed the recommended dose

prescribed by your doctor.

How much to use

Your doctor will tell you exactly how

many tablets of Galvus Met to take.

The usual dose of Galvus Met is one or

two tablets a day. Do not exceed two

tablets a day.

Depending on how you

respond to the treatment, your doctor may

suggest a higher or lower dose.

If you have reduced kidney function, your

doctor may prescribe a lower dose. Also if

you are taking an anti-diabetic medicine

known as a sulphonylurea your doctor

may prescribe a lower dose.

Your doctor will prescribe Galvus Met

either alone or in combination with other

antidiabetics, depending on your

condition.

When to use Galvus Met

Galvus Met should be taken in the

morning and/or in the evening. It is

recommended that you take your tablets

either with or just after taking food. This

will reduce the chance of you getting an

upset stomach.

The tablets should be swallowed whole

with a glass of water.

How long to use Galvus Met

Continue taking Galvus Met every day for

as long as your doctor tells you. You may

have to stay on this treatment for a long

period of time. Your doctor will regularly

monitor your condition to check that the

treatment is having the desired effect. If

your doctor has told you to stop treatment

with Galvus Met because of liver

problems, you should never start taking

Galvus Met again.

If you have questions about how long to

take Galvus Met, talk to your doctor or

your pharmacist or healthcare provider.

If you forget to use Galvus Met

It is recommended to take your medicine

at the same time each day. If you forget

to take Galvus Met, take it as soon as you

remember. Then take your next dose at its

usual time. However, if it is almost time

for your next dose, skip the dose

you missed. Do not take a double dose to

make up for the forgotten tablet.

If you use too much (overdose)

If you have accidentally taken too many

Galvus Met tablets, or if someone else has

taken your medicine, talk to a doctor

straight away. You may need medical

attention. Show the doctor the pack if

possible.

While you are using Galvus Met

Things you must do

3

Consumer Medication Information Leaflet (RiMUP)

If you are going to have an operation

under general anesthetic, you must

stop taking Galvus Met for a couple

of days before and after the

procedure. Your doctor will decide

when you must stop and when to

restart your treatment with Galvus

Met.

If you are going to have a contrast x-

ray (a specific type of x-ray involving

an injectable dye), you must stop

taking Galvus Met before or at the

time of and for a few days after the

procedure.

If you drink alcohol excessively,

either every day or only from time to

time.

If you have liver or kidney problems.

If your diabetes worsens suddenly, or

if you have abnormal blood sugar

tests or feel ill, contact your doctor.

If any of these apply to you, tell your

doctor.

Things you must not do

Do not stop taking the medicine unless

advised by your doctor.

Do not take any new medicines without

consulting your doctor.

Do not give Galvus Met to anyone else,

even if they have the same symptoms or

condition as you.

Things to be careful of

If you experience one or more of the

following symptoms: feeling cold

and uncomfortable, muscle pain,

drowsiness, severe nausea or

vomiting, abdominal pain, dizziness,

irregular heartbeat, or rapid breathing.

Very rarely, patients taking

metformin (one of the active

substances of Galvus Met) have

experienced a condition called lactic

acidosis (too much lactic acid in the

blood). This is more likely to occur in

patients whose kidneys are not

working properly.

If you experience nausea, sweating,

weakness, dizziness, trembling,

headache (signs of low blood sugar),

which could be due to lack of food,

too strenuous exercise without

sufficient food intake, or excessive

alcohol intake (usually not with

Galvus Met alone).

If you experience some of these

symptoms, stop taking

Galvus Met and

consult a doctor immediately.

Driving and using machines

If you feel dizzy while taking Galvus Met,

do not drive vehicles or use any tools or

machines until you are feeling normal

again.

Side effects

Like all medicines, Galvus Met can cause

side effects, although not everybody gets

them.

Some side effects could be serious

STOP taking Galvus Met and seek

medical help immediately if you have

experience any of the following:

Feeling cold and uncomfortable,

muscle pain, drowsiness, severe

nausea or vomiting, abdominal pain,

unexplained weight loss, dizziness,

irregular heartbeat, or rapid breathing

(symptoms of lactic acidosis). If this

happens you must stop taking Galvus

Met and contact a doctor or the

nearest hospital immediately, as lactic

acidosis may lead to coma.

Swollen face, tongue or throat,

difficulty swallowing, difficulty

breathing, sudden onset of rash or

hives (symptoms of severe allergic

reaction called ‘angioedema’).

Yellow skin and/or eyes, nausea, loss

of appetite, dark urine (possible

symptoms of liver problems).

Severe upper stomach pain (possible

symptoms of inflamed pancreas).

Headache, drowsiness, weakness,

dizziness, confusion, irritability,

hunger, fast heartbeat, sweating,

feeling jittery (possible symptoms of

low level of sugar in the blood known

as hypoglycemia)

If you experience any serious side effects,

stop taking this medicine and tell your

doctor immediately.

Very common: may affect more than 1 in

10 people

Nausea, vomiting, diarrhea,

abdominal pain, loss of appetite.

Common: may affect up to 1 in every 10

people

Dizziness, headache, trembling,

metallic taste in the mouth.

Uncommon: may affect up to 1 in every

100 people

Constipation, swollen hands, ankles

or feet (edema).

Very rare: may affect up to 1 in every

10,000 people

Skin reddening, itching, decrease in

the level of vitamin B12 in the blood,

abnormal liver function test results.

If you experience any serious side effects,

stop taking this medicine and tell your

doctor immediately.

Other possible side effects

Other side effects include the following

listed below. If these side effects become

severe, please tell your doctor, pharmacist

or healthcare provider.

Common side effects

(likely to occur in

fewer than 1 in 10 patients).

Uncommon side effects

(likely to occur in

fewer than 1 in 100 patients).

Some patients have had the following side

effects while taking Galvus Met and

insulin:

Common: Headache, chills, nausea,

heartburn, decreased blood sugar.

Uncommon: Diarrhea, flatulence.

Some patients have had the following side

effects while taking Galvus met and a

sulfonylurea:

Common: Dizziness, trembling,

weakness, excessive sweating.

Some patients have experienced other side

effects while taking Galvus Met alone or

in combination with another antidiabetic

medication:

Itchy rash, areas of peeling skin or

blisters, joint pain.

If you notice any side effects not listed in

this leaflet, please inform your doctor or

pharmacist or healthcare provider.

You may report any side effects or

adverse drug reactions directly to the

National Centre for Adverse Drug

Reaction Monitoring by visiting the

website npra.gov.my (Consumers

Reporting Side Effects to Medicines

(ConSERF) or Vaccines (AEFI).

4

Consumer Medication Information Leaflet (RiMUP)

Storage and Disposal of

Galvus Met

Storage

Keep this medicine out of the sight

and reach of children.

Do not store Galvus Met above 30°C.

Do not use after the expiry date

shown on the box.

Store in the original package.

Do not use any Galvus Met pack that

is damaged or shows signs of

tampering.

Disposal

Medicines should not be disposed of via

wastewater or household waste. Ask your

pharmacist how to dispose of medicines

no longer required. These measures will

help to protect the environment.

Product Description

What it looks like

Galvus Met is supplied as tablets. Three

dosage strengths are available and the

physical description of Galvus Met tablets

is as follows:

50 mg/500 mg: light yellow, ovaloid

beveled edge, film-coated tablet

imprinted with "NVR" on one side

and "LLO" on the other side.

50 mg/850 mg: yellow, ovaloid

beveled edge, film-coated tablet

imprinted with "NVR" on one side

and "SEH" on the other side.

50 mg/1,000 mg:

dark yellow,

ovaloid beveled edge, film-coated

tablet imprinted with "NVR" on one

side and "FLO" on the other side

Ingredients

Active ingredients

The active substances of Galvus Met

are vildagliptin and metformin

hydrochloride.

Inactive ingredients

The other ingredients (excipients) of

Galvus Met are hydroxypropyl

cellulose, hypromellose, iron oxide

yellow, iron oxide red, macrogol,

magnesium stearate, talc and titanium

dioxide.

MAL number:

MAL12035005ARZ (50/500 MG,

Singapore)

MAL20091864ARZ (50/850 MG,

Singapore)

MAL20091865ARZ (50/1000 MG,

Singapore)

MAL14125131ARSZ (50/500MG,Wehr)

MAL14125129ARSZ (50/850MG,Wehr)

MAL14125130ARSZ(50/1000MG,Wehr)

Manufacturer

Novartis Singapore Pharmaceutical

Manufacturing Pte. Ltd.

10 Tuas Bay Lane, 637461 Singapore

Manufacturer (2nd site)

Novartis Pharma Produktions GmbH,

Oflinger Strasse 44, 79664 Wehr, Baden-

Wurttemberg, Germany.

Product Registration Holder

Novartis Corporation (Malaysia) Sdn.

Bhd.

Level 22, Tower B, Plaza 33,

No. 1, Jalan Kemajuan,

Seksyen 13,

46200 Petaling Jaya

Date of revision

06-May-2020

Serial No.

NPRA (R1/3)21042020/072

Novartis

Page 2

Malaysia Package Insert

28-Nov-2016

Galvus Met

Galvus

Met

COMPOSITION AND PHARMACEUTICAL FORM

Vildagliptin: (S)-1-[2-(3-Hydroxy-adamantan-1-ylamino)acetyl]pyrrolidine-2-carbonitrile

Metformin hydrochloride: Imidodicarbinimidic, N,N-dimethyl-, monohydrochloride

Three strengths are available. One tablet of Galvus Met contains:

50 mg vildagliptin and 500 mg metformin hydrochloride (corresponding to 390 mg

metformin).

Light

yellow,

ovaloid

bevelled

edge,

film-coated

tablet

imprinted

with

"NVR" on one side and "LLO" on the other side.

50 mg vildagliptin and 850 mg metformin hydrochloride (corresponding to 660 mg

metformin). Yellow, ovaloid bevelled edge, film-coated tablet imprinted with "NVR" on

one side and "SEH" on the other side.

50 mg vildagliptin and 1,000 mg metformin hydrochloride (corresponding to 780 mg

metformin). Dark yellow, ovaloid bevelled edge, film-coated tablet imprinted with "NVR"

on one side and "FLO" on the other side.

Certain dosage strengths may not be available in all countries.

For a full list of excipients, see section EXCIPIENTS.

INDICATIONS

Galvus Met is indicated in the treatment of type 2 diabetes mellitus:

Galvus Met 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.

Galvus Met 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.

Galvus Met 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.

Galvus Met is also indicated as initial therapy in patients with T2DM whose diabetes is

not adequately controlled by diet and exercise alone.

DOSAGE AND ADMINISTRATION

The dose of antihyperglycaemic therapy with Galvus Met should be individualized on the

basis of the patient’s current regimen, effectiveness and tolerability while not exceeding the

maximum recommended daily dose of 100 mg vildagliptin. Galvus Met may be initiated at

Novartis

Page 3

Malaysia Package Insert

28-Nov-2016

Galvus Met

either the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily, one

tablet in the morning and the other in the evening.

patients

inadequately

controlled

their

maximal

tolerated

dose

metformin

monotherapy: The starting dose of Galvus Met 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: Galvus Met should be initiated at the dose of vildagliptin and metformin already

being taken.

patients

inadequately

controlled

dual

combination

with

metformin

sulphonylurea: The doses of Galvus Met 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 Galvus Met 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 Galvus Met 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.

For treatment naïve patients, Galvus Met may be initiated at 50mg/500mg once daily and

gradually titrated to a maximum dose of 50mg/1000mg twice daily after assessing the

adequacy of therapeutic response.

The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination

with a thiazolidinedione have not been established.

Taking Galvus Met with or just after food may reduce gastrointestinal symptoms associated

with metformin (see also section PHARMACOKINETICS).

Patients with renal impairment

A GFR should be assessed before initiation of treatment with metformin-containing products

(such as Galvus Met) and at least annually thereafter. In patients at an increased risk of further

progression of renal impairment and in the elderly, renal function should be assessed more

frequently, e.g. every 3 to 6 months.

The maximum daily dose of metformin should preferably be divided into 2 to 3 daily doses.

Factors that may increase the risk of lactic acidosis (see section SPECIAL WARNINGS AND

PRECAUTIONS) should be reviewed before considering initiation of metformin-containing

products (such as Galvus Met) in patients with GFR<60ml/min.

If no adequate strength of Galvus Met is available, individual monocomponents should be

used instead of the fixed dose combination.

Table 4-1 Dose adjustments in patients with renal impairment

GFR ml/min

Metformin

Vildagliptin

Novartis

Page 4

Malaysia Package Insert

28-Nov-2016

Galvus Met

60-89

Maximum

daily

dose

3000mg.

Dose

reduction may be considered in relation to

declining renal function.

Maximal

daily

dose

100mg.

45-59

Maximum

daily

dose

2000mg.

starting dose is at most half of the maximum

dose.

Maximal daily dose is 50mg.

30-44

Maximum

daily

dose

1000mg.

starting dose is at most half of the maximum

dose.

<30

Metformin is contraindicated.

Patients with hepatic impairment

Galvus Met should not be used in patients with hepatic impairment, including those with pre-

treatment aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper

limit of normal (ULN) (see section CONTRAINDICATIONS, SPECIAL WARNINGS AND

PRECAUTIONS FOR USE and UNDESIRABLE EFFECTS).

Elderly (

65 years)

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased

renal function, elderly patients taking metformin-containing products (such as Galvus Met)

should have their renal function monitored regularly (see section SPECIAL WARNINGS

AND PRECAUTIONS FOR USE and PHARMACOKINETICS).

Paediatric patients (< 18 years)

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

efficacy

Galvus

children

adolescents

(<

years)

have

been

established. No data are available.

CONTRAINDICATIONS

Hypersensitivity to the active substances or to any of the excipients

Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

Diabetic pre-coma

Severely

reduced

kidney

function

(GFR

<

ml/min)

(see

section

SPECIAL

WARNINGS AND PRECAUTIONS FOR USE)

Acute conditions with the potential to alter renal function, such as:

Dehydration

Severe infection

Shock

Intravascular administration of iodinated contrast agents (see section SPECIAL

WARNINGS AND PRECAUTIONS FOR USE)

Novartis

Page 5

Malaysia Package Insert

28-Nov-2016

Galvus Met

Acute or chronic disease which may cause tissue hypoxia, such as:

Cardiac or respiratory failure

Recent myocardial infarction

Shock

Hepatic impairment (see section DOSAGE AND ADMINISTRATION, SPECIAL

WARNINGS AND PRECAUTIONS FOR USE and UNDESIRABLE EFFECTS)

Acute alcohol intoxication, alcoholism

Breast-feeding (see section PREGNANCY AND LACTATION)

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

General

Galvus Met is not a substitute for insulin in patients requiring insulin and should not be used

in patients with type 1 diabetes.

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most often occurs with acute

worsening of renal function, or cardiorespiratory illness or sepsis. Metformin accumulation

occurs with acute worsening of renal function and increases the risk of lactic acidosis.

case

dehydration

(severe

diarrhoea

vomiting,

fever

reduced

fluid

intake),

metformin should be temporarily discontinued and contact with a health care professional is

recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics

and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors

for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled

diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as

concomitant use of medicinal products that may cause lactic acidosis.

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is

characterized

acidotic

dyspnoea,

abdominal

pain,

muscle

cramps,

asthenia

hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking

metformin

seek

immediate

medical

attention.

Diagnostic

laboratory

findings

decreased blood pH (<7.35), increased plasma lactate levels (≥5 mmol/L) and an increased

anion gap and lactate/pyruvate ratio.

Administration of iodinated contrast agent

Intravascular

administration

iodinated

contrast

agents

lead

contrast-induced

nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis.

Metformin should be discontinued prior to or at the time of the imaging procedure and not

restarted until at least 48 hours after, provided that renal function has been re-evaluated and

found to be stable (see section DOSAGE AND ADMINISTRATION and INTERACTIONS).

Novartis

Page 6

Malaysia Package Insert

28-Nov-2016

Galvus Met

Renal impairment

GFR should be assessed before treatment initiation and regularly thereafter (see section

DOSING AND ADMINISTRATION). Metformin is contraindicated in patients with GFR

<30 mL/min and should be temporarily discontinued in the presence of conditions that alter

renal function (see section CONTRAINDICATIONS).

Hepatic impairment

Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN,

should not be treated with Galvus Met (see sections DOSAGE AND ADMINISTRATION,

CONTRAINDICATIONS and UNDESIRABLE EFFECTS).

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 Galvus Met in order to know the patient’s

baseline value. Liver function should be monitored during treatment with Galvus Met 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

finding

followed

thereafter

with

frequent

LFTs

until

abnormality/abnormalities return to normal. Should an increase in AST or in ALT of 3x ULN

or greater persist, withdrawal of Galvus Met therapy is recommended. Patients who develop

jaundice or other signs suggestive of liver dysfunction should discontinue Galvus Met.

Following withdrawal of treatment with Galvus Met and LFT normalization, treatment with

Galvus Met should not be re-initiated.

Skin disorders

Skin lesions, including blistering and ulceration have been reported with vildagliptin in

extremities

monkeys

non-clinical

toxicology

studies

(see

section

PRECLINICAL

SAFETY DATA). Although skin lesions were not observed at an increased incidence in

clinical trials, there was limited experience in patients with diabetic skin complications.

Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions.

Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders,

such as blistering or ulceration, is recommended.

Acute pancreatitis

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients

should be informed of the characteristic symptom of acute pancreatitis.

Novartis

Page 7

Malaysia Package Insert

28-Nov-2016

Galvus Met

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

known

cause

hypoglycaemia.

Patients

receiving

vildagliptin

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 Galvus Met 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.

Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking

DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied

from one day to years. Patients experienced relief of symptoms upon discontinuation of the

medication. A subset of patients experienced a recurrence of symptoms when restarting the

same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for

severe joint pain and discontinue drug if appropriate.

INTERACTIONS

There have been no formal interaction studies for Galvus Met. 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

been

established in the target population.

Novartis

Page 8

Malaysia Package Insert

28-Nov-2016

Galvus Met

Combination with ACE-inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE-

inhibitors.(see section UNDESIRABLE EFFECTS).

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 Hydrochloride

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

Galvus

(see

section

SPECIAL

WARNINGS

PRECAUTIONS

USE).

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 SPECIAL WARNINGS AND PRECAUTIONS

FOR USE).

Intravascular administration of iodinated contrast media may lead to renal failure, resulting in

metformin accumulation with the risk of lactic acidosis. Metformin-containing products (such

as Galvus Met) 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

stable (see section DOSAGE AND ADMINISTRATION and section INTERACTIONS).

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 Galvus Met 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.

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Novartis

Page 9

Malaysia Package Insert

28-Nov-2016

Galvus Met

There are no adequate data from the use of Galvus Met 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

metformin

have

shown

evidence

teratogenicity,

foetotoxic

effects

maternotoxic doses (see section PRECLINICAL SAFETY DATA). The potential risk for

humans is unknown. Galvus Met 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, Galvus Met should not be used

during breast-feeding (see section CONTRAINDICATIONS).

Fertility

No studies on the effect on human fertility have been conducted for Galvus Met. (see section

PRECLINICAL SAFETY DATA)

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 may experience dizziness as an undesirable effect should avoid driving vehicles

or using machines.

UNDESIRABLE EFFECTS

There

have

been

therapeutic

clinical

trials

conducted

with

Galvus

Met.

However,

bioequivalence of Galvus Met with co-administered vildagliptin and metformin has been

demonstrated (see section PHARMACOKINETICS). The data presented here relate to the co-

administration of vildagliptin and metformin, where vildagliptin has been added to metformin.

There have been no studies of metformin added to vildagliptin.

majority

adverse

reactions

were

mild

transient,

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

twice

daily

comparators,

respectively.

These

elevations

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

Novartis

Page 10

Malaysia Package Insert

28-Nov-2016

Galvus Met

with an ACE inhibitor. The majority of events were mild in severity and resolved with

ongoing vildagliptin treatment.

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, undesirable effects 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)

Metabolism and nutrition disorders

Common

Hypoglycaemia

Nervous system disorders

Common

Tremor, dizziness, headache

Uncommon

Fatigue

Gastrointestinal disorders

Common

Nausea

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.

clinical

trials,

incidence

hypoglycaemia

common

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)

Metabolism and nutritional disorders

Common

Hypoglycaemia

Nervous system disorders

Common

Dizziness, tremor

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

General disorders and administration site conditions

Novartis

Page 11

Malaysia Package Insert

28-Nov-2016

Galvus Met

Common

Asthenia

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)

Metabolism and nutrition disorders

Common

Decreased blood glucose

Nervous system disorders

Common

Headache, chills

Gastrointestinal disorders

Common

Nausea, gastro-oesophageal reflux disease

Uncommon

Diarrhoea, flatulence

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.

incidence

hypoglycaemia

similar

both

treatment

groups

(14.0%

vildagliptin

group

16.4%

placebo

group).

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

Novartis

Page 12

Malaysia Package Insert

28-Nov-2016

Galvus Met

Vildagliptin

Table 4

Adverse reactions reported in patients who received vildagliptin 100

mg daily as monotherapy in double-blind studies (N=1855)

Infections and infestations

Very rare

Upper respiratory tract infection, nasopharyngitis

Metabolism and nutrition disorders

Uncommon

Hypoglycaemia

Nervous system disorders

Common

Dizziness

Uncommon

Headache

Vascular disorders

Uncommon

Oedema peripheral

Gastrointestinal disorders

Uncommon

Constipation

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia

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 Hydrochloride

Table 5

Adverse reactions for metformin component

Metabolism and Nutrition disorders

Very rare

Decrease of vitamin B

absorption, lactic acidosis*

Nervous system disorders

Common

Metallic taste

Gastrointestinal disorders

Very common

Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite

Hepatobiliary disorders

Very rare

Liver function test abnormalities, hepatitis**

Skin and subcutaneous tissue disorders

Very rare

Skin reactions such as erythema, pruritus, urticaria

*A decrease of vitamin B12 absorption with decrease of serum levels has been very rarely observed

in patients treated long-term with metformin. Consideration of such aetiology is recommended if a

Novartis

Page 13

Malaysia Package Insert

28-Nov-2016

Galvus Met

patient presents with megaloblastic anaemia.

**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin

discontinuation have been reported.

Gastrointestinal adverse reactions occur most frequently during initiation of therapy and

resolve spontaneously in most cases. To prevent them, it is recommended that metformin be

taken in 2 daily doses during or after meals. A slow increase in the dose may also improve

gastrointestinal tolerability.

Post-marketing experience

Table 6

Post-marketing adverse reactions

Gastrointestinal disorders

Not known

Pancreatitis

Hepatobiliary disorders

Not known

Hepatitis (reversible upon discontinuation of the medicinal product)

Abnormal liver function tests (reversible upon discontinuation of the

medicinal product)

Musculoskeletal and connective tissue disorders

Not known Myalgia

Skin and subcutaneous tissue disorders

Not known

Urticaria

Bullous or exfoliative skin lesions, including bullous pemphigoid

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions.

OVERDOSE

No data are available with regard to overdose of Galvus Met.

Vildagliptin

Information regarding overdose with vildagliptin is limited.

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.

Novartis

Page 14

Malaysia Package Insert

28-Nov-2016

Galvus Met

Metformin Hydrochloride

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.

PHARMACODYNAMICS

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose

lowering drugs, ATC code: A10BD08

Galvus Met 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.

Vildagliptin

Vildagliptin acts primarily by inhibiting DPP-4, the enzyme responsible for the degradation of

incretin

hormones

GLP-1

(glucagon-like

peptide-1)

(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 glucose-dependent insulin secretion.

Treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly

improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–

β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-

sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does

not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha

cells to glucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased

incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose

production, leading to reduced glycaemia.

The known effect of increased GLP-1 levels delaying gastric emptying is not observed with

vildagliptin treatment.

Novartis

Page 15

Malaysia Package Insert

28-Nov-2016

Galvus Met

Metformin Hydrochloride

Metformin

biguanide

with

antihyperglycaemic

effects,

lowering

both

basal

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

total

cholesterol,

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,

versus

combined

sulphonylurea

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),

versus

combined

sulphonylurea

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 HbA

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 HbA

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%).

Novartis

Page 16

Malaysia Package Insert

28-Nov-2016

Galvus Met

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

year,

mean

reductions

HbA1c

were

-0.81%

with

vildagliptin added to metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide

added to metformin (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved

(95% CI -0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a

weight gain of +1.4 kg with gliclazide.

In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin

(gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as

initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg

twice daily reduced HbA1c by -1.82% ,vildagliptin/metformin 50 mg/500 mg twice daily by -

1.61%, metformin 1000 mg twice daily by -1.36% and vildagliptin 50 mg twice daily by -

1.09% from a mean baseline HbA1c of 8.6%. The decrease in HbA1c observed in patients

with a baseline ≥10.0% was greater.

A 24-week 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

HbA1c

-0.63%

-0.84%,

respectively.

incidence

Novartis

Page 17

Malaysia Package Insert

28-Nov-2016

Galvus Met

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

HbA1c

when

vildagliptin

(50 mg

twice

daily)

added

insulin

statistically

significantly

greater

than

with

placebo

plus

insulin

(0.5%

0.2%).

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

37 phase III and IV monotherapy and combination therapy clinical studies of up to more than

2 years duration (mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) was

performed and showed that vildagliptin treatment was not associated with an increase in

cardiovascular risk versus comparators. The composite endpoint of adjudicated major adverse

cardiovascular events (MACE) including acute myocardial infarction, stroke or cardiovascular

death was similar for vildagliptin versus combined active and placebo comparators [Mantel–

Haenszel risk ratio (M-H RR) 0.82 (95% CI 0.61-1.11)]. A MACE occurred in 83 out of

9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator-treated

patients. Assessment of each individual MACE component showed no increased risk (similar

M-H RR). Confirmed heart failure (HF) events defined as HF requiring hospitalisation or new

onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%)

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

PHARMACOKINETICS

Galvus Met

Absorption

Bioequivalence has been demonstrated between Galvus Met 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 Galvus Met. The

rate and extent of absorption of metformin from Galvus Met 50 mg/1000 mg were decreased

when given with food as reflected by the decrease in C

by 26%, AUC by 7% and delayed

(2.0 to 4.0 h).

The following statements reflect the pharmacokinetic properties of the individual active

substances of Galvus Met.

Vildagliptin

Absorption

Novartis

Page 18

Malaysia Package Insert

28-Nov-2016

Galvus Met

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 C

(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

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

vivo

study

using

DPP-4

deficient

rats. Vildagliptin

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

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 [

C] 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 C

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

Novartis

Page 19

Malaysia Package Insert

28-Nov-2016

Galvus Met

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 (C

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 Hydrochloride

Absorption

After an oral dose of metformin, the maximum plasma concentration (C

) 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

) 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 (V

) ranged between 63-276 litres.

Biotransformation

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

eliminated

glomerular

filtration

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.

Novartis

Page 20

Malaysia Package Insert

28-Nov-2016

Galvus Met

PRECLINICAL SAFETY DATA

Animal studies of up to 13-week duration have been conducted with the combined substances

in Galvus Met. No new toxicities associated with the combination were identified. The

following

data

findings

from

studies

performed

with

vildagliptin

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 C

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

tumour

incidence

attributable

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

mg/kg

(59-fold

human

exposure)

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

doses

mg/kg/day

(approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions of the tail

Novartis

Page 21

Malaysia Package Insert

28-Nov-2016

Galvus Met

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 Hydrochloride

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.

EXCIPIENTS

Ferric oxide red, ferric oxide yellow, hypromellose, hydroxypropylcellulose, magnesium

stearate, polyethylene glycol, and talc.

Pharmaceutical formulations may vary between countries.

INCOMPATIBILITIES

Not applicable.

STORAGE

Do not store above 30ºC.

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

Galvus Met should not be used after the date marked “EXP” on the pack.

PACK SIZE

Available in Alu-Alu blister packs of 3x10 / 6x10 tablets.

Not all pack size may be marketed.

INSTRUCTIONS FOR USE AND HANDLING

No special requirements.

Note: Galvus Met should be kept out of the reach and sight of children.

PRODUCT REGISTRATION HOLDER

Novartis Corporation (Malaysia) Sdn. Bhd.

Level 22, Tower B, Plaza 33,

No. 1, Jalan Kemajuan, Seksyen 13,

46200 Petaling Jaya

International Package Leaflet

Information issued: 28 Nov 2016

Date of revision: 14 Mar 2018

Novartis

Page 22

Malaysia Package Insert

28-Nov-2016

Galvus Met

= registered trademark

Novartis Pharma AG, Basel, Switzerland

Similar products

Search alerts related to this product

View documents history

Share this information