Metformin Pinewood 1000 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Metformin Hydrochloride
Available from:
Juta Pharma GmbH
ATC code:
A10BA02
INN (International Name):
Metformin Hydrochloride
Dosage:
1000 milligram(s)
Pharmaceutical form:
Film-coated tablet
Therapeutic area:
metformin
Authorization number:
PA22716/001/003
Authorization date:
2019-07-19

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729 mm

FRONT

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 or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their sign of illness

are the same as yours.

If you get any of the side effects, talk to your doctor or pharmacist or nurse. This includes any side effects not listed in this

leaflet. See section 4.

What is in this leaflet:

1. What Metformin Pinewood tablets are and what they are used for

2. What you need to know before you take Metformin Pinewood tablets

3. How to take Metformin Pinewood tablets

4. Possible side effects

5. How to store Metformin Pinewood tablets

6. Contents of the pack and other information

1. What Metformin Pinewood tablets are and what they are used for

Metformin Pinewood tablets contain the active ingredient metformin hydrochloride. Metformin hydrochloride belongs to a group

of medicines called biguanides used for the treatment of non-insulin-dependent diabetes mellitus (type 2 diabetes) in adults and

children from 10 years of age.

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.

Metformin helps to lower your blood glucose to as normal a level as possible.

If you are an overweight adult, taking Metformin Pinewood tablets over a long period of time also helps to lower the risk of

complications associated with diabetes. Metformin Pinewood tablets are associated with either a stable body weight or modest

weight loss.

Metformin Pinewood tablets are a medicine used to lower high blood sugar levels in patients with diabetes mellitus

(type 2 diabetes); particularly in overweight patients when dietary management and exercise alone does not result in control of

blood sugar.

Adults

Your doctor can prescribe Metformin Pinewood tablets on their own (monotherapy) or in combination with other oral antidiabetic

agents, or with insulin.

Children and adolescents

For children from 10 years of age and for adolescents the doctor can prescribe Metformin Pinewood tablets alone

(monotherapy) or in combination with insulin.

2. What you need to know before you take Metformin Pinewood tablets

Do not take Metformin Pinewood tablets

if you are allergic (hypersensitive) to metformin hydrochloride or any of the other ingredients of this medicine (listed in

section 6).

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 have severely reduced kidney function.

if your kidney function worsens as a consequence of e.g. loss of too much water (dehydration) due to long-lasting vomiting

or severe diarrhoea. Dehydration may lead to kidney problems, which can put you at risk for lactic acidosis (see ‘Warnings

and precautions’ below)

If you have a severe infection, such as infection affecting your lung or bronchial system or your kidney. Severe infection may

lead to kidney problems, which can put you at risk for lactic acidosis (see ‘Warnings and precautions’ below)

if you have acute or chronic diseases which may lead to reduced amount of oxygen in body tissues (tissue hypoxia) such as

- heart failure, or difficulties breathing

- recent heart attack (myocardial infarction)

- collapse or trauma (shock)

if you have liver problems, drink a lot of alcohol or suffer from alcoholism

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 Metformin Pinewood tablets 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 instruction

precisely.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Metformin Pinewood tablets.

Risk of lactic acidosis

Metformin Pinewood tablets 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 Metformin Pinewood tablets 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 Metformin Pinewood tablets 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 Metformin Pinewood tablets during and for some time after the

procedure. Your doctor will decide when you must stop and when to restart your treatment with Metformin Pinewood tablets.

Metformin Pinewood tablets on its own do not cause hypoglycaemia (a blood glucose level which is too low). However, if you

take Metformin Pinewood tablets 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 of difficulty in concentration, it usually helps to eat

or drink something containing sugar.

During treatment with Metformin Pinewood tablets, 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 Metformin tablets

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

If you need to have an injection of contrast medium that contains iodine into your bloodstream, for example in the context of an

X-ray or scan, you must stop taking Metformin Pinewood tablets before or at the time of the injection. Your doctor will decide

when you must stop and when to restart your treatment with Metformin Pinewood tablets.

You may need more frequent blood glucose and kidney function tests, or your doctor may need to adjust the dosage of

Metformin Pinewood tablets. It is especially important to mention the following:

corticosteroids (used to treat a variety of conditions, such as severe inflammation of the skin or in asthma).

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)

specific medicines for the treatment of bronchial asthma (β2-agonists, e.g. salbutamol)

medicines that may change the amount of Metformin 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.

Metformin Pinewood tablets with alcohol

Avoid excessive alcohol intake while taking Metformin Pinewood tablets since this may increase the risk of lactic acidosis (see

section “Warnings and precautions”).

Pregnancy, breast-feeding and fertility

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

for advice before taking this medicine.

Diabetic women who are pregnant or planning to become pregnant, should not be treated with Metformin Pinewood tablets.

Instead, insulin should be used to maintain blood glucose levels as close to normal as possible. Inform your doctor if you are

pregnant or thinking of becoming pregnant so that he or she can change you to insulin therapy.

This medicinal product should not be used while breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Taking metformin alone (monotherapy) does not cause low blood sugar levels (hypoglycaemia) and therefore has no effect on

your ability to drive or use machines. Taking metformin in combination with other antidiabetic agents (e.g. sulphonylureas,

Insulin or meglitinides) may cause low blood sugar levels (with symptoms, such as sweating, fainting, dizziness or weakness)

and thus affecting your ability to drive and use machines or work safely. Symptoms of hypoglycaemia include weakness,

dizziness, increased sweating, fast heart beat, vision disorders or difficulty in concentration. Do not drive or use machines if you

start to feel these symptoms.

3. How to take Metformin Pinewood tablets

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

not sure.

Metformin Pinewood tablets 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.

The dose of Metformin Pinewood tablets should be determined by the doctor according to your blood sugar levels.

Unless prescribed differently by your doctor, the recommended dose is:

Dosage for adults

The usual starting dose is 500 mg or 850 mg metformin hydrochloride two or three times a day. The maximum daily dose is

3000 mg metformin hydrochloride, taken as 3 divided doses.

Package leaflet: Information for the user

Metformin Pinewood 500 mg, 850 mg and 1000 mg film-coated tablets

Metformin hydrochloride

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Dosage for children from 10 years of age and adolescents:

The usual starting dose is 500 mg or 850 mg metformin hydrochloride once a day.

The dosage can be increased up to the maximum recommended daily dose of 2000 mg metformin hydrochloride per day, 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.

If you take insulin too, your doctor will tell you how to start Metformin Pinewood tablets.

Monitoring

Your doctor will adapt your dose of Metformin Pinewood tablets 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.

If you have reduced kidney function, your doctor may prescribe a lower dose. Your dose may be adjusted if you are elderly.

How to take Metformin Pinewood tablets

Take Metformin Pinewood tablets 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 evening (dinner)

If, after some time, you think that the effect of Metformin Pinewood tablets is too strong or too weak, talk to your doctor or

pharmacist.

If you take more Metformin Pinewood tablets than you should

Inform your doctor immediately if you have taken more tablets than you should have. An overdose of Metformin Pinewood

tablets does not lead to hypoglycaemia but increases the risk of hyperacidity of the blood caused by lactic acid (lactic acidosis).

Symptoms of early hyperacidity are similar to the side effects of metformin on the gastrointestinal tract: sickness, vomiting,

diarrhoea and abdominal pain. In severe cases you could also get muscle pain and muscle cramps, very fast breathing which

you cannot stop, as well as a clouding of consciousness and coma. This may develop within hours and requires immediate

emergency treatment in a hospital.

If you forget to take Metformin Pinewood tablets

If you forget to take Metformin Pinewood tablets, take the prescribed amount of Metformin Pinewood tablets at the next

prescribed time and try to keep to the prescription in future. Do not take a double dose to make up for a forgotten dose.

If you stop taking Metformin Pinewood tablets

If you stop treatment with Metformin Pinewood tablets you have to be aware of the risk of uncontrolled blood sugar and of the

long-term effects of diabetes mellitus such as damage on eyes, kidneys and blood vessels.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

4. Possible side effects

Like all medicines, Metformin Pinewood tablets can cause side effects, although not everybody gets them. The following side

effects may occur:

Metformin Pinewood tablets 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 Metformin Pinewood tablets and

contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma.

Very common side effects (may affect 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 Metformin Pinewood tablets. It helps

if you spread the doses over the day and if you take Metformin Pinewood tablets with or straight after a meal.

If symptoms continue, stop taking Metformin Pinewood tablets and talk to your doctor.

Common side effects (may affect up to 1 in 10 people)

changes in taste.

Very rare side effects (may affect up to 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 ‘Warnings and precautions’)

abnormalities 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 Metformin Pinewood

tablets and talk to your doctor.

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

low vitamin B₁₂ levels in the blood. Over time this may lead to anaemia, a sore mouth or tongue or possibly numbness or

tingling in the limbs.

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 or nurse. This includes any possible side effects not listed in this

leaflet.

You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie. By reporting side effects you can help provide more

information on the safety of this medicine.

5. How to store Metformin Pinewood tablets

Keep this medicine out of the sight and reach of children. If a child is treated with Metformin Pinewood tablets, parents and

caregivers are advised to oversee how this medicine is used.

Do not use Metformin Pinewood tablets after the expiry date stated on the blister or the bottle or the carton after "EXP". The

expiry date refers to the last day of that month.

Storage conditions

This medicine does not require any special storage conditions.

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.

6. Contents of the pack and other information

What Metformin Pinewood tablets contain

The active substance is metformin hydrochloride.

Each film-coated tablet contains 500 mg, 850 mg or 1000 mg metformin hydrochloride equivalent to 390 mg, 663 mg, and

780 mg of metformin respectively.

The other ingredients are:

Sodium Starch Glycolate (Type A), Povidone K-30, Maize Starch, Colloidal Anhydrous Silica, Magnesium Stearate,

Hypromellose 15cP, Talc, Titanium Dioxide (E 171), Macrogol 6000, Propylene Glycol.

What Metformin Pinewood tablets looks like and contents of the pack

Metformin Pinewood 500 mg film-coated tablets are supplied as white to off white round, biconvex, film-coated tablets which are

plain on both sides.

Metformin Pinewood 850 mg film-coated tablets are supplied as white to off white capsule shaped, biconvex, film-coated tablets

with scoreline on one side and plain on other side.

Metformin Pinewood 1000 mg film-coated tablets are supplied as white to off white oval shaped, biconvex, film-coated tablets,

with a deep breakline on one side and breakline on other side.

Metformin Pinewood 500 mg, 850 mg and 1000 mg film-coated tablets are available in blisters containing 1 (x100), 9, 10, 20,

21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 180, 200, 300, 500, 600 or 1000 film-coated tablets or in plastic bottles containing 10,

20, 21, 30, 40, 50, 56, 60, 90, 100, 120, 180, 200, 300, 400, 500, 600 or 1000 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Juta Pharma GmbH

Gutenbergstr. 13

24941 Flensburg

Germany

Manufacturers

The manufacturer is Accord Healthcare Limited, Sage house, 319 Pinner Road, north Harrow, Middlesex HA1 4HF,

United Kingdom.

Distributed by:

Pinewood Laboratories Ltd.,

Ballymacarbry,

Clonmel,

Co. Tipperary,

Ireland.

This medicinal product is authorised in the Member States of the EEA under the following names:

Denmark

Metformin Orifarm

The Netherlands

Metformine HCL USV Europe 500 mg, 850 mg en 1000 mg filmomhulde tabletten

Norway

Metformin Orifarm

Sweden

Metformin Orifarm

United Kingdom

Metformin hydrochloride 500 mg, 850 mg and 1000 mg film coated tablets

Ireland

Metformin Pinewood 500 mg, 850 mg, 1000 mg film-coated tablets

Bulgaria

Metformin Juta

Germany

Juformin 500/850/1000 mg film-coated tablets

Spain

Metformina Juta 500 mg / 850 mg / 1000 mg comprimidos recubiertos con pelicula EFG

Poland

Metformin hydrochloride Juta pharma

This leaflet was last revised in Sep 2018

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Metformin Pinewood 1000 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains metformin hydrochloride 1000 mg corresponding to metformin base 780 mg.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White to off white oval shaped, biconvex, film-coated tablets, with a deep breakline on one side and breakline on other side.

The tablet can be divided into equal halves.

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, Metformin Pinewood film-coated tablets 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, Metformin Pinewood film-coated tablets 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. In patients

receiving a high metformin dose (2 to 3 grams per day), it is possible to replace two Metformin Pinewood 500 mg

film-coated tablets with one Metformin Pinewood 1000 mg film-coated tablet.

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

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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.

GFR (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

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.

30-44

1000 mg

<30

Metformin is contraindicated.

Paediatric population

Monotherapy and combination with insulin

Metformin Pinewood film-coated tablets 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.

Method of administration:

To be taken orally.

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 (sever diarrhoea or vomiting, fever or reduced fluid intake), Metformin should be temporarily

discontinued and contact with health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensive, diuretics and NSAIDs) should be initiated

with caution in Metformin treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic

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insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any condition associated with hypoxia, as well as

concomitant use of medicinal products that may cause lactic acidosis (see section 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

dysponea, 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 regular thereafter, see section 4.2. Metformin is contraindicated in

patients with GFR<30mL/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 agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin

accumulation and an increased risk for 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 4.2 and 4.5.

Surgery

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

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. sulphonylureas or meglitinides).

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 pre-pubescent 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.

4.5 Interaction with other medicinal products and other forms of interactions

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.

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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 route) 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 post-natal 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, breastfeeding is not recommended during metformin treatment. A decision on whether to

discontinue breast-feeding should be made, taken 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).

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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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517;

Website: www.hpra.ie; e-mail: medsafety@hpra.ie..

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

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Mechanism of action

Metformin hydrochloride 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 hydrochloride 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 utilisation

and delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin hydrochloride

increases the transport capacity of all types of membrane glucose transporters (GLUT) 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 hydrochloride has favourable effects on lipid metabolism. This

has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride

reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy:

The prospective randomised (UKPDS) 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 hydrochloride after failure of diet alone showed:

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

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 hydrochloride 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 hydrochloride 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 hydrochloride 11 events/1000

patient-years, diet alone 18 events/1000 patient-years (p=0.01)For metformin hydrochloride used as second-line

therapy, in combination with a sulfonylurea, benefit regarding clinical outcome has not been shown. In type 1

diabetes, the combination of metformin hydrochloride 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 micrograms/ml. In controlled clinical trials, maximum metformin plasma levels (C

) did

not exceed 5 micrograms/ml, even at maximum doses.

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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.

Biotransformation

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 a 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

Sodium Starch Glycolate (Type A)

Povidone K-30

Maize starch

Colloidal Anhydrous Silica

Magnesium Stearate

Tablet coating

Opadry White 04G58897 containing:

Hypromellose 15cP, Talc, Titanium Dioxide (E 171), Macrogol 6000, Propylene Glycol

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The tablets are packed in PVC/aluminium blister packs or in white opaque HDPE container and closure with foil seal induction.

Blister packs: 1 (x100), 9, 10, 20, 21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 180, 200, 300, 500, 600 or 1000 film-coated tablets.

HDPE containers: 10, 20, 21, 30, 40, 50, 56, 60, 90, 100, 120, 180, 200, 300, 400, 500, 600 or 1000 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Juta Pharma GmbH

Gutenbergstr 13

24941 Flensburg

Germany

8 MARKETING AUTHORISATION NUMBER

PA22716/001/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 19

July 2019

10 DATE OF REVISION OF THE TEXT

October 2019

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