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GLUCOPHAGE 850MG TABLETS

Active substance(s): METFORMIN HYDROCHLORIDE / METFORMIN HYDROCHLORIDE / METFORMIN HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
GLUCOPHAGE 850 mg film-coated tablet.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 850 mg metformin hydrochloride corresponding to 662.9 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 13.5 mm in diameter and 6.6 mm high
engraved with GL 850.

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
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).
Patients with renal impairment
Metformin may be used in patients with moderate renal impairment, stage 3a (creatinine
clearance [CrCl] 45– 59 mL/min or estimated glomerular filtration rate [eGFR] 45 -59
mL/min/1.73m2) only in the absence of other conditions that may increase the risk of lactic
acidosis and with the following dose adjustments:
The starting dose is 500 mg or 850 mg metformin hydrochloride, once daily. The maximum
dose is 1000 mg daily, given as 2 divided doses. The renal function should be closely
monitored (every 3-6 months).
If CrCl or eGFR fall <45 ml/min or <45 ml/min/1.73m2 respectively, metformin must be
discontinued immediately.
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.
Diabetic ketoacidosis, diabetic pre-coma.
Moderate (stage 3b) and severe renal failure or renal dysfunction (CrCl < 45 ml/min or
eGFR < 45 ml/min/1.73m2).





4.4

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.

Special warnings and precautions for use

Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality rate in the absence of prompt
treatment), metabolic complication that can occur due to metformin accumulation. Reported
cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients
with impaired renal failure or acute worsening of renal function. Special caution should be
paid to situations where renal function may become impaired, for example in case of
dehydration (severe diarrhoea or vomiting), or when initiating antihypertensive therapy or
diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug
(NSAID). In the acute conditions listed, metformin should be temporarily discontinued.
Other associated risk factors should be considered to avoid lactic acidosis such as poorly
controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency
and any condition associated with hypoxia (such as decompensated cardiac failure, acute
myocardial infarction) (see also section 4.3).
The risk of lactic acidosis must be considered in the event of non-specific signs such as
muscle cramps, digestive disorders as abdominal pain and severe asthenia. Patients should be
instructed to notify these signs immediately to their physicians if they occur, notably if
patients had a good tolerance to metformin before. Metformin should be discontinued, at least
temporarily, until the situation is clarified. Reintroduction of metformin should then be
discussed taking into account the benefit/risk ratio in an individual basis as well as renal
function.
Diagnosis:
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia
followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate
levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. In case of lactic
acidosis, the patient should be hospitalised immediately (see section 4.9).
Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.
Renal function
As metformin is excreted by the kidney, creatinine clearance (this can be estimated from
serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined
before initiating treatment and regularly thereafter:

at least annually in patients with normal renal function,

at least two to four times a year in patients with creatinine clearance at the lower limit
of normal and in elderly subjects.

In case CrCl is <45 ml/min (eGFR < 45 ml/min/1.73m2), metformin is contraindicated (see
section 4.3).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution
should be exercised in situations where renal function may become impaired, for example in
case of dehydration, or when initiating antihypertensive therapy or diuretic therapy and when
starting therapy with a non-steroidal anti-inflammatory drug (NSAID).
In these cases, it is also recommended to check renal function before initiating treatment with
metformin.
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 media
The intravascular administration of iodinated contrast media in radiologic studies can lead to
renal failure. This may induce metformin accumulation and may increase the risk for lactic
acidosis. In patients with eGFR > 60 ml/min/1.73 m2, metformin must be discontinued prior
to, or at the time of the test and not be reinstituted until at least 48 hours afterwards, and only
after renal function has been re-evaluated and has not deteriorated further (see section 4.5.).
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m2),
metformin must be discontinued 48 hours before administration of iodinated contrast media
and not be reinstituted until at least 48 hours afterwards and only after renal function has been
re-evaluated and has not deteriorated further (see section 4.5).
Surgery
Metformin must be discontinued 48 hours before elective surgery under general, spinal or
peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or
resumption of oral nutrition and only if normal renal function has been established.
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 metformintreated 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
Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly
in case of fasting or malnutrition, hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medicinal product.
Iodinated contrast media
Intravascular administration of iodinated contrast media may lead to renal failure, resulting in
metformin accumulation and an increased risk of lactic acidosis.
In patients with eGFR > 60 ml/min/1.73m2, metformin must be discontinued prior to, or at the
time of the test and not be reinstituted until at least 48 hours afterwards, and only after renal
function has been re-evaluated and has not deteriorated further (see section 4.4).
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m2),
metformin must be discontinued 48 hours before administration of iodinated contrast media
and not be reinstituted until at least 48 hours afterwards and only after renal function has been
re-evaluated and has not deteriorated further.
Combinations requiring precautions for use
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.

Diuretics, especially loop diuretics
They may increase the risk of lactic acidosis due to their potential to decrease renal function.
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 breastfeeding 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 (Cmax)
is reached in approximately 2.5 hours (tmax). 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 (Cmax) 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 (Cmax) 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.

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
1 (x100), 8, 9, 10, 14, 20, 21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 300, 600 or 1000
tablets in blister packs (PVC-aluminium).

30, 60, 200, 300 or 600 tablets in plastic bottles (high-density polyethylene) with
child-resistant caps (polypropylene).
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
MERCK SERONO LIMITED
BEDFONT CROSS
STANWELL ROAD
FELTHAM
MIDDLESEX
TW14 8NX
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 11648/0086

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/10/2007

10

DATE OF REVISION OF THE TEXT
09/02/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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