Glucophage 500mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Metformin hydrochloride
Available from:
Mawdsley-Brooks & Company Ltd
ATC code:
A10BA02
INN (International Name):
Metformin hydrochloride
Dosage:
500mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 06010202

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3664350001

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 or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It

may harm them, even if their symptoms 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 Glucophage is and what it is used for

What you need to know before you take Glucophage

How to take Glucophage

Possible side effects

How to store Glucophage

Contents of the pack and other information

1.

What Glucophage is and what it is used for

Glucophage contains metformin, a medicine to treat diabetes. It belongs to

a group of medicines called biguanides.

Insulin is a hormone produced by the pancreas that makes your body take in

glucose (sugar) from the blood. Your body uses glucose to produce energy or

stores it for future use.

If you have diabetes, your pancreas does not make enough insulin or your body

is not able to use properly the insulin it produces. This leads to a high level of

glucose in your blood. Glucophage helps to lower your blood glucose to as

normal a level as possible.

If you are an overweight adult, taking Glucophage over a long period of

time also helps to lower the risk of complications associated with diabetes.

Glucophage is associated with either a stable body weight or modest weight loss.

Glucophage is used to treat patients with type 2 diabetes (also called ‘non-insulin

dependent diabetes’) when diet and exercise alone have not been enough to

control your blood glucose levels. It is used particularly in overweight patients.

Adults can take Glucophage on its own or together with other medicines to

treat diabetes (medicines taken by mouth or insulin).

Children 10 years and over and adolescents can take Glucophage on its own

or together with insulin.

2.

What you need to know before you take Glucophage

Do not take Glucophage

if you are allergic (hypersensitive) to metformin or any of the other

ingredients of this medicine (see ‘What Glucophage contains’ in section 6)

if you have liver problems

if you have severely reduced kidney function

if you have uncontrolled diabetes, with, for example, severe hyperglycaemia

(high blood glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic

acidosis (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 include stomach

pain, fast and deep breathing, sleepiness or your breath developing an

unusual fruity smell

if you lost too much water from your body (dehydration), such as due

to long-lasting or severe diarrhoea, or if you have vomited several

times in a row. Dehydration may lead to kidney problems, which can

put you at risk for lactic acidosis (see 'Warnings and precautions').

if

you have a severe infection, such as an infection affecting your lung

or bronchial system or your kidney. Severe infections may lead to kidney

problems, which can put you at risk for lactic acidosis (see 'Warnings

and precautions')

if you are treated for acute heart failure or have recently had a heart attack,

have severe problems with your circulation (such as shock) or have breathing

difficulties. This may lead to a lack in oxygen supply to tissue which can put

you at risk for lactic acidosis (see 'Warnings and precautions').

if you drink a lot of alcohol

If any of the above applies to you, talk to your doctor, before you start taking

this medicine.

Make sure you ask your doctor for advice, if:

you need to have an examination such as X-ray or scan involving the

injection of contrast medicines that contain iodine into your bloodstream

you need to have major surgery

You must stop taking Glucophage for a certain period of time before and after

the examination or the surgery. Your doctor will decide whether you need any

other treatment for this time. It is important that you follow your doctor’s

instructions precisely.

Warnings and precautions

Risk of lactic acidosis

Glucophage 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 (see further

information below), 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 Glucophage 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 Glucophage 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

reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

If you need to have major surgery you must stop taking Glucophage during

and for some time after the procedure. Your doctor will decide when you must

stop and when to restart your treatment with Glucophage.

Glucophage on its own does not cause hypoglycaemia (a blood glucose

level which is too low). However, if you take Glucophage together with

other medicines to treat diabetes that can cause hypoglycaemia (such as

sulphonylureas, insulin, meglitinides), there is a risk of hypoglycaemia. If

you experience symptoms of hypoglycaemia such as weakness, dizziness,

increased sweating, fast heart beating, vision disorders or difficulty in

concentration, it usually helps to eat or drink something containing sugar

During treatment with Glucophage, your doctor will check your kidney function

at least once a year or more frequently if you are elderly and/or if you have

worsening kidney function.

Other medicines and Glucophage

If you need to have an injection of a contrast medium that contains iodine into

your bloodstream, for example in the context of an X-ray or scan, you must

stop taking Glucophage before or at the time of injection. Your doctor will decide

when you must stop and when to restart your treatment with Glucophage.

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

medicines. You may need more frequent blood glucose and kidney function tests,

or your doctor may need to adjust the dosage of Glucophage. It is especially

important to mention the following:

medicines which increase urine production (diuretics).

medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors,

such as ibuprofen and celecoxib).

certain medicines for the treatment of high blood pressure (ACE inhibitors

and angiotensin II receptor antagonists).

beta-2 agonists such as salbutamol or terbutaline (used to treat asthma).

corticosteroids (used to treat a variety of conditions, such as severe

inflammation of the skin or in asthma).

medicines that may change the amount of Glucophage in your blood,

especially if you have reduced kidney function (such as verapamil, rifampicin,

cimetidine,

dolutegravir,

ranolazine,

trimethoprime,

vandetanib,

isavuconazole, crizotinib, olaparib).

other medicines used to treat diabetes.

Glucophage with alcohol

Avoid excessive alcohol intake while taking Glucophage since this may increase

the risk of lactic acidosis (see section ‘Warnings and precautions’).

TW2084798

Package leaflet: Information for the user

Film-coated tablets

Metformin hydrochloride

500 mg

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3664350001

Pregnancy and breast-feeding

During pregnancy, you need insulin to treat your diabetes. Tell your doctor if

you are, you think you might be or are planning to become pregnant, so that

he or she may change your treatment.

This medicine is not recommended if you are breast-feeding or if you are

planning to breast-feed your baby.

Driving and using machines

Glucophage on its own does not cause hypoglycaemia (a blood glucose level

which is too low). This means that it will not affect your ability to drive or use

machines.

However, take special care if you take Glucophage together with other medicines

to treat diabetes that can cause hypoglycaemia (such as sulphonylureas,

insulin, meglitinides). Symptoms of hypoglycaemia include weakness,

dizziness, increased sweating, fast heartbeat, vision disorders or difficulty in

concentration. Do not drive or use machines if you start to feel these symptoms.

3.

How to take Glucophage

Always take Glucophage exactly as your doctor has told you. Check with your

doctor or pharmacist if you are not sure.

Glucophage cannot replace the benefits of a healthy lifestyle. Continue to

follow any advice about diet that your doctor has given you and get some

regular exercise.

Recommended dose

Children 10 years and over and adolescents usually start with 500 mg

or 850 mg Glucophage once a day. The maximum daily dose is 2000 mg

taken as 2 or 3 divided doses. Treatment of children between 10 and

12 years of age is only recommended on specific advice from your doctor, as

experience in this age group is limited.

Adults

usually start with 500 mg or 850 mg Glucophage two or three

times a day. The maximum daily dose is 3000 mg taken as 3 divided doses.

If you have reduced kidney function, your doctor may prescribe a lower dose.

If you take insulin too, your doctor will tell you how to start Glucophage.

Monitoring

Your doctor will perform regular blood glucose tests and will adapt your dose

of Glucophage to your blood glucose levels. Make sure that you talk to your

doctor regularly. This is particularly important for children and adolescents

or if you are an older person.

Your doctor will also check at least once a year how well your kidneys work.

You may need more frequent checks if you are an older person or if your

kidneys are not working normally.

How to take Glucophage

Take Glucophage with or after a meal. This will avoid you having side effects

affecting your digestion.

Do not crush or chew the tablets. Swallow each tablet with a glass of water.

If you take one dose a day, take it in the morning (breakfast)

If you take two divided doses a day, take them in the morning (breakfast)

and evening (dinner)

If you take three divided doses a day, take them in the morning (breakfast),

at noon (lunch) and in the evening (dinner)

If, after some time, you think that the effect of Glucophage is too strong or too

weak, talk to your doctor or pharmacist.

If you take more Glucophage than you should

If you have taken more Glucophage than you should have, you may

experience lactic acidosis. Symptoms of lactic acidosis are non-specific

such as vomiting, bellyache (abdominal pain) with muscle cramps,

a general feeling of not being well with severe tiredness, and difficulty in

breathing. Further symptoms are reduced body temperature and heartbeat.

If

you experience some of these symptoms, you should seek immediately

medical attention, as lactic acidosis may lead to coma. Stop taking

Glucophage immediately and contact a doctor or the nearest hospital

straight away.

If you forget to take Glucophage

Do not take a double dose to make up for a forgotten dose. Take the next dose

at the usual time.

If you have any further questions on the use of this product, ask your doctor

or pharmacist.

4.

Possible side effects

Like all medicines, Glucophage can cause side effects, although not everybody

gets them. The following side effects may occur:

Glucophage may cause a very rare (may affect up to 1 user in 10,000), but

very

serious side effect called lactic acidosis (see section ‘Warnings and

precautions’). If this happens you must stop taking Glucophage and

contact

a doctor or the nearest hospital immediately, as lactic acidosis

may lead to coma.

Very common side effects (in more than 1 in 10 people)

digestive problems, such as feeling sick (nausea), being sick (vomiting),

diarrhoea, bellyache (abdominal pain) and loss of appetite. These side effects

most often happen at the beginning of the treatment with Glucophage. It

helps if you spread the doses over the day and if you take Glucophage with

or straight after a meal. If symptoms continue, stop taking Glucophage

and talk to your doctor.

Common side effects (in less than 1 in 10 people)

changes in taste.

Very rare side effects (in less than 1 in 10,000 people)

lactic acidosis. This is a very rare but serious complication particularly if your

kidneys are not working properly.

Symptoms of lactic acidosis are non-specific (see section ‘Warning and

precautions’)

a

bnormalities in liver function tests or hepatitis (inflammation of the liver;

this may cause tiredness, loss of appetite, weight loss, with or without

yellowing of the skin or whites of the eyes). If this happens to you, stop

taking Glucophage and talk to your doctor.

skin reactions such as redness of the skin (erythema), itching or an itchy

rash (hives).

low vitamin B

levels in the blood.

Children and adolescents

Limited data in children and adolescents showed that adverse events were

similar in nature and severity to those reported in adults.

Reporting of side effects

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

possible side effects not listed in this leaflet. You can also report side effects

directly via

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2

Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie,

e-mail: medsafety@hpra.ie

United Kingdom

Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety

of this medicine.

5.

How to store Glucophage

Keep out of the sight and reach of children. If a child is treated with Glucophage,

parents and caregivers are advised to oversee how this medicine is used.

This medicinal product does not require any special storage conditions.

Do not use Glucophage after the expiry date which is stated on the carton

or the bottle or the blister after ‘EXP’. The expiry date refers to the last day of

that month.

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

protect

environment.

6.

Contents of the pack and other information

What Glucophage contains

The active substance is metformin hydrochloride.

One film-coated tablet of Glucophage 500 mg contains 500 mg

metformin hydrochloride corresponding to 390 mg metformin base.

The other ingredients are povidone K 30, magnesium stearate, hypromellose.

What Glucophage looks like and contents of the pack

Glucophage 500 mg film-coated tablets are white, circular, 11 mm in

diameter and 5.7 mm high, convex, engraved with GL 500. The tablets are

supplied in blister packs of 1 (x100), 9, 20, 21, 30, 40, 50, 56, 60, 84, 90,

100, 120, 200, 500, 600 or 1000 tablets and in plastic bottles with child-

resistant caps of 21, 30, 40, 50, 60, 100, 120, 300, 400, 500, 600 or 1000 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

UK: Merck Serono Limited,

5 New Square,

Bedfont Lakes Business Park,

Feltham, Middlesex,

TW14 8HA, UK

IE: Merck Serono (Ireland) Limited,

4045 Kingswood Road,

Citywest Business Campus,

Dublin, D24 V06K,

Ireland

Manufacturer

Merck S.L.

Poligono Merck

Mollet Del Vallès 08100 Barcelona

Spain

This medicinal product is authorised in the Member States of the EEA

under the following names:

Glucophage: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Finland, France,

Germany, Greece, Iceland, Ireland, Italy, Latvia, Luxembourg, Malta, Norway,

Poland, Portugal, Romania, Slovakia, Slovenia, Sweden, United Kingdom

Merckformin: Hungary

This leaflet was last approved in August 2019

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

GLUCOPHAGE 500 mg film-coated tablet.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 500 mg metformin hydrochloride corresponding to 390 mg

metformin base.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

White, circular, convex film-coated tablets 11 mm in diameter and 5.7 mm high,

engraved with GL 500.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when

dietary management and exercise alone does not result in adequate glycaemic control.

In adults, Glucophage may be used as monotherapy or in combination with other

oral anti-diabetic agents or with insulin.

In children from 10 years of age and adolescents, Glucophage may be used as

monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic

adult patients treated with metformin as first-line therapy after diet failure (see section

5.1).

4.2

Posology and method of administration

Posology

Adults with normal renal function (GFR

90 mL/min)

Monotherapy and combination with other oral antidiabetic agents

The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2 or 3 times daily

given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements.

A slow increase of dose may improve gastrointestinal tolerability.

The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided

doses.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and

initiate metformin at the dose indicated above.

Combination with insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose

control. Metformin hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or

3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly

Due to the potential for decreased renal function in elderly subjects, the metformin dosage

should be adjusted based on renal function. Regular assessment of renal function is necessary

(see section 4.4).

Renal impairment

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

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

3-6 months.

(mL/min)

Total maximum daily dose

(to be divided into 2-3 daily

doses)

Additional considerations

60-89

3000 mg

Dose reduction may be considered in

relation to declining renal function.

45-59

2000 mg

30-44

1000 mg

Factors that may increase the risk of

lactic acidosis (see section 4.4) should be

reviewed before considering initiation of

metformin.

The starting dose is at most half of the

maximum dose.

<30

Metformin is contraindicated.

Paediatric population

Monotherapy and combination with insulin

Glucophage can be used in children from 10 years of age and adolescents.

The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily,

given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements.

A slow increase of dose may improve gastrointestinal tolerability. The maximum

recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

4.3

Contraindications

Hypersensitivity to metformin or to any of the excipients listed in section 6.1.

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

Diabetic pre-coma.

Severe renal failure (GFR < 30 mL/min).

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

infection, shock.

Disease which may cause tissue hypoxia (especially acute disease, or worsening of

chronic disease) such as: decompensated heart failure, respiratory failure, recent

myocardial infarction, shock.

Hepatic insufficiency, acute alcohol intoxication, alcoholism.

4.4

Special warnings and precautions for use

Lactic acidosis

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

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

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

In case of dehydration (severe diarrhoea or vomiting, fever or 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 (see sections 4.3 and

4.5).

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

characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and

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

metformin and seek immediate medical attention. Diagnostic laboratory findings are

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

anion gap and lactate/pyruvate ratio.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2.

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 4.3.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with

stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and

renal function.

For patients with acute and unstable heart failure, metformin is contraindicated (see section

4.3).

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced

nephropathy, resulting in metformin accumulation and an 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 sections 4.2 and 4.5.

Surgery

Metformin must be discontinued at the time of surgery under general, spinal or epidural

anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or

resumption of oral nutrition and provided that renal function has been evaluated and found to

be stable.

Paediatric population

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with

metformin is initiated.

No effect of metformin on growth and puberty has been detected during controlled clinical

studies of one-year duration but no long-term data on these specific points are available.

Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-

treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical

studies conducted in children and adolescents. Although efficacy and safety of metformin in

these children did not differ from efficacy and safety in older children and adolescents,

particular caution is recommended when prescribing to children aged between 10 and

12 years.

Other precautions

All patients should continue their diet with a regular distribution of carbohydrate intake

during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin alone does not cause hypoglycaemia, but caution is advised when it is used in

combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case

of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Metformin must 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 sections 4.2 and 4.4.

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of

lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE

inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When

starting or using such products in combination with metformin, close monitoring of renal

function is necessary.

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and

local routes) and sympathomimetics)

More frequent blood glucose monitoring may be required, especially at the beginning of

treatment. If necessary, adjust the metformin dosage during therapy with the respective

medicinal product and upon its discontinuation.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and

efficacy of metformin.

Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime,

vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus

lead to an increase in metformin plasma concentration.

Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and

renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs

are co-administered with metformin, as metformin plasma concentration may increase. If

needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may

alter the efficacy of metformin.

4.6

Fertility, pregnancy and lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with

increased risk of congenital abnormalities and perinatal mortality.

A limited amount of data from the use of metformin in pregnant women does not indicate an

increased risk of congenital abnormalities. Animal studies do not indicate harmful effects

with respect to pregnancy, embryonic or foetal development, parturition or postnatal

development (see section 5.3).

When the patient plans to become pregnant and during pregnancy, it is recommended that

diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as

close to normal as possible, to reduce the risk of malformations of the foetus.

Breast-feeding

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed

newborns/infants. However, as only limited data are available, breast-feeding is not

recommended during metformin treatment. A decision on whether to discontinue breast-

feeding should be made, taking into account the benefit of breast-feeding and the potential

risk to adverse effects on the child.

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as

high as 600 mg/kg/day, which is approximately three times the maximum recommended

human daily dose based on body surface area comparisons.

4.7.

Effects on ability to drive and use machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on

the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin is

used in combination with other antidiabetic agents (e.g. sulfonylureas, insulin, or

meglitinides).

4.8

Undesirable effects

During treatment initiation, the most common adverse reactions are nausea, vomiting,

diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To

prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase

slowly the doses.

The following adverse reactions may occur under treatment with metformin. Frequencies are

defined as follows: very common:

1/10; common >1/100, <1/10; uncommon >1/1,000,

<1/100; rare >1/10,000, <1/1,000; very rare <1/10,000.

Within each frequency grouping, adverse reactions are presented in order of decreasing

seriousness.

Metabolism and nutrition disorders

Very rare

Lactic acidosis (see section 4.4).

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use

of metformin. Consideration of such aetiology is recommended if a patient presents

with megaloblastic anaemia.

Nervous system disorders

Common

Taste disturbance

Gastrointestinal disorders

Very common

Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss

of appetite. These undesirable effects 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 or 3 daily doses during or after meals. A slow increase of the

dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders

Very rare

Isolated reports of liver function tests abnormalities or hepatitis resolving upon

metformin discontinuation.

Skin and subcutaneous tissue disorders

Very rare

Skin reactions such as erythema, pruritus, urticaria

Paediatric population

In published and post marketing data and in controlled clinical studies in a limited paediatric

population aged 10-16 years treated during 1 year, adverse event reporting was similar in

nature and severity to that reported in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

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

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow

Card Scheme at www.mhra.gov.uk/yellowcard.

4.9.

Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g,

although lactic acidosis has occurred in such circumstances. High overdose of

metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a

medical emergency and must be treated in hospital. The most effective method to

remove lactate and metformin is haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides; ATC code:

A10BA02

Mechanism of action

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and

postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not

produce hypoglycaemia.

Metformin may act via 3 mechanisms:

reduction of hepatic glucose production by inhibiting gluconeogenesis and

glycogenolysis.

in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and

utilization.

and delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all types of membrane glucose transporters

(GLUTs) known to date.

Pharmacodynamic effects

In clinical studies, use of metformin was associated with either a stable body weight or

modest weight loss.

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 total cholesterol, LDL cholesterol and

triglyceride levels.

Clinical efficacy

The prospective randomised study (UKPDS) has established the long-term benefit of

intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with metformin after failure of diet

alone showed:

a significant reduction of the absolute risk of any diabetes-related complication in the

metformin group (29.8 events/1000 patient-years) versus diet alone

(43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and

insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034;

a significant reduction of the absolute risk of diabetes-related mortality: metformin

7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

a significant reduction of the absolute risk of overall mortality: metformin

13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years

(p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups

18.9 events/1000 patient-years (p=0.021);

a significant reduction in the absolute risk of myocardial infarction: metformin

11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).

Benefit regarding clinical outcome has not been shown for metformin used as second-line

therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of metformin and insulin has been used in selected

patients, but the clinical benefit of this combination has not been formally established.

Paediatric population

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1

year demonstrated a similar response in glycaemic control to that seen in adults.

5.2

Pharmacokinetic properties

Absorption

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

is reached in approximately 2.5 hours (t

). Absolute bioavailability of a 500 mg or 850 mg

metformin hydrochloride 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 is non-linear.

At the recommended metformin doses and dosing schedules, steady state plasma

concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml.

In controlled clinical trials, maximum metformin plasma levels (C

) did not exceed

5 microgram/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following oral

administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in

AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma

concentration were observed. The clinical relevance of these findings is unknown.

Distribution

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak

is lower than the plasma peak and appears at approximately the same time. The red blood

cells most likely represent a secondary compartment of distribution. The mean volume of

distribution (Vd) ranged between 63-276 l.

Metabolism

Metformin is excreted unchanged in the urine. No metabolites have been identified in

humans.

Elimination

Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by

glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal

elimination half-life is approximately 6.5 hours.

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.

Characteristics in specific groups of patients

Renal impairment

The available data in subjects with moderate renal insufficiency are scarce and no

reliable estimation of the systemic exposure to metformin in this subgroup as

compared to subjects with normal renal function could be made. Therefore, the dose

adaptation should be made upon clinical efficacy/tolerability considerations (see

section 4.2).

Paediatric population

Single dose study: After single doses of metformin hydrochloride 500 mg paediatric patients

have shown similar pharmacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice

daily for 7 days in paediatric patients the peak plasma concentration (C

) and systemic

exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to

diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is

individually titrated based on glycaemic control, this is of limited clinical relevance.

5.3

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on

safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and

reproductive toxicity

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Povidone K 30

Magnesium stearate

Film-coating

Hypromellose.

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