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20110108_fr362_metformine mylan 850mg dispersible_spc.pdf

SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

METFORMINE MYLAN 850 mg dispersible tablet.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Metformin 850 mg dispersible tablets: Each tablet contains 850mg Metformin, as Metformin
hydrochloride corresponding to 662,90 mg metformin base.
Excipients: sulphurous anhydride (E220), maltodextrin
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM

Dispersible tablet
A white, marbled and round dispersible tablets.
4.
CLINICAL PARTICULARS
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 MYLAN 850 mg dispersible tablet 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 MYLAN 850mg dispersible
tablet 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 hydrochloride 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 one tablet of METFORMINE MYLAN 500 mg or 850 mg, dispersible
tablet 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 hydrochloride at the dose indicated above. Combination with insulin: Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control.
Metformin hydrochloride is given at the usual starting dose of METFORMINE MYLAN 500 mg or
850 mg dispersible tablet 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 hydrochloride
dosage should be adjusted based on renal function. Regular assessment of renal function is necessary
(see section 4.4).

Children and adolescents:

Monotherapy or in combination with insulin:
METFORMIN MYLAN 850mg dispersible tablet can be used in children from 10 years of age and
adolescents.
The usual starting dose is METFORMINE MYLAN 500mg or 850mg dispersible tablet once daily,
given during meals 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.
In patients receiving a high metformin dose (2 to 3 grams per day), it is possible to replace two METFORMINE MYLAN 500 mg dispersible tablets with one METFORMINE MYLAN 1000 mg dispersible tablet.
Method of administration:
Oral use.
The tablet should be swallowed with water. Alternatively, in patients experiencing difficulty
swallowing, especially in children and elderly, the tablet could be dispersed in water prior to
ingestion.
4.3
Contraindications

• Hypersensitivity to metformin hydrochloride or to any of the excipients.
• Diabetic ketoacidosis, diabetic pre-coma. • Renal failure or renal dysfunction (creatinine clearance < 60 mL/min). • Acute conditions with the potential to alter renal function such as: o dehydration, o severe infection, o shock, o intravascular administration of iodinated contrast agents (see section 4.4); • Acute or chronic disease which may cause tissue hypoxia such as: o cardiac or respiratory failure, o recent myocardial infarction, o shock. • Hepatic insufficiency, acute alcohol intoxication, alcoholism. Special warnings and precautions for use

Lactic acidosis:
Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic
complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic
acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with
significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also
other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive
alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis:
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle
cramps with digestive disorders as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, 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. If metabolic acidosis is suspected, metformin
hydrochloride should be discontinued and the patient should be hospitalised immediately (see section
4.9).
Renal function:

As metformin hydrochloride is excreted by the kidney, serum creatinine levels 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 serum creatinine levels at the upper limit of
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 when initiating
antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.
Administration of iodinated contrast agent:

As the intravascular administration of iodinated contrast materials in radiologic studies can lead to
renal failure, metformin hydrochloride should be discontinued prior to, or at the time of the test and
not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and
found to be normal (see section 4.5).
Metformin hydrochloride 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.
Children and adolescents:

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin
hydrochloride is initiated.
No effect of metformin hydrochloride 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 hydrochloride on these parameters in
metformin hydrochloride-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 metformin hydrochloride efficacy and safety in
children below 12 did not differ from efficacy and safety in older children, 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 hydrochloride alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas.
Excipients: because of maltodextrin (source of glucose), patients with rare malabsorption of the
glucose/galactose should not take this medicinal product.
4.5
Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended:

Alcohol:

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
• fasting or malnutrition,
• hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medicinal product.
Iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in
metformin hydrochloride accumulation and a risk of lactic acidosis.
Metformin hydrochloride should be discontinued prior to, or at the time of the test and not reinstituted
until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal
(see section 4.4).
Combinations requiring precautions for use:

Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring,
especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic medicinal
product during therapy with the other medicinal product and upon its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin
hydrochloride may be necessary during and after addition or discontinuation of such medicinal
products.
Pregnancy and lactation

To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects
with respect to pregnancy, embryonal or fœtal development, parturition or postnatal development (see
section 5.3).
When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with
metformin hydrochloride but insulin should be used to maintain blood glucose levels as close to
normal as possible in order to lower the risk of foetal malformations associated with abnormal blood
glucose levels.
Metformin hydrochloride is excreted into milk in lactating rats. Similar data is not available in
humans and a decision should be made whether to discontinue nursing or to discontinue metformin
hydrochloride, taking into account the importance of the medicinal product to the mother.
4.7
Effects on ability to drive and use machines

METFORMINE MYLAN 850mg dispersible tablet 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 hydrochloride is
used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).
4.8
Undesirable effects

The following undesirable effects may occur under treatment with METFORMINE MYLAN 850 mg
dispersible tablet. 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, not known (cannot be
estimated from the available data).
Metabolism and nutrition disorders:

Very rare: decrease of vitamin B12 absorption with decrease of serum levels during long-term use of
metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents with
megaloblastic anaemia.
Very rare: Lactic acidosis (see section 4.4).
Nervous system disorders:

Common: Taste disturbance
Hepatobiliary disorders:

Not known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin
hydrochloride discontinuation.
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
hydrochloride be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may
also improve gastrointestinal tolerability.
Skin and subcutaneous tissue disorders:

very rare: Skin reactions such as erythema, pruritus, urticaria
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.
Excipients:

Sulphurous anhydride may cause hypersensitivity reactions, including anaphylactic reactions and
bronchospasms.
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 hydrochloride 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 hydrochloride is
haemodialysis.
5.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties

Pharmacotherapeutic group: ORAL ANTI-DIABETICS, ATC code: A10BA02
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:
(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.
(3) 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).
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 adult patients with 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.
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, Tmax is reached in 2.5 hours.
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 hydrochloride absorption is saturable and incomplete. It is
assumed that the pharmacokinetics of metformin hydrochloride absorption is non-linear.
At the usual metformin hydrochloride 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 hydrochloride plasma levels (Cmax) did not exceed 4 microgram/ml, even
at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following
administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC
(area under the curve) and a 35 minute prolongation of time to peak plasma concentration were
observed. The clinical relevance of these decreases is unknown.

Distribution:

Plasma protein binding is negligible. Metformin hydrochloride 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 and 276 l.
Metabolism:

Metformin hydrochloride is excreted unchanged in the urine. No metabolite has been identified in
humans.
Elimination:

Renal clearance of metformin hydrochloride is > 400 ml/min, indicating that metformin hydrochloride
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 hydrochloride in
plasma.
Paediatrics:

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 BID 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 BID 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, toxicity reproduction.

6.

PHARMACEUTICAL PARTICULARS
List of excipients

Povidone K 30, microcrystalline cellulose, saccharin sodium, sodium benzoate, pregelatinised maize
starch, lemon flavour (alpha-pinene, beta-pinene, myrcene, limonene, gamma-terpinene, neral,
geranial, maltodextrin, acacia, butylhydroxyanisole, sulphurous anhydride (E220)).
6.2
Incompatibilities

Not applicable.
6.3
Shelf life
Special precautions for storage

Store in the original package
6.5
Nature and contents of container

30, 50, 60, 90, 150, 180 or 270 tablets in blister packs (PVC/PVDC/Aluminium) or
(Aluminium/Aluminium)
Not all pack sizes may be marketed
6.6
Special precautions for disposal

Any unused product or waste materials should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER

[To be completed nationally]
8.
MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.
DATE OF REVISION OF THE TEXT

[To be completed nationally]

Source: http://agence-prd.ansm.sante.fr/html/par_eu/20110108_fr362_metformine%20mylan%20850mg%20dispersible_spc.pdf

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