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• Metformin Actavis 500 mg 850 mg film-coated tablet SmPC
• Metformin Actavis 500 mg film-coated tablet ENG SmPC

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summary of the product characteristics

Metformin Actavis 500 mg film-coated tablet.

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

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, circular, biconvex, film-coated tablets, impressed "MF" on one face.

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control. Metformin may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic patients treated with metformin as first-line therapy after diet failure (see section 5.1).

Posology

Monotherapy and combination with other oral antidiabetic agents

• The usual starting dose is 500mg or 850mg 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 is 3g 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 is given at the usual starting dose of 500mg or 850mg 2 or3 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/1.73m²respectively, metformin must be discontinued immediately.

Paediatric population

In the absence of data, Metformin Actavis should not be used in children.

• dehydration

• severe infection

• shock

• Decompensated cardiac failure

• respiratory failure

• recent myocardial infarction

• shock

Lactic acidosis:

Lactic acidosis is a very rare, but serious (high mortality 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 or 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 reneal function.

Diagnosis:

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. In case of lactic acidosis, the patient should be hospitalised immediately (see section 4.9).

Physicians should alert the patients on risk and on the symptoms of lactic acidosis.

Renal function

As metformin is excreted by the kidney, serum 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 level 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-steriodal 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 agent

The intravascular administration of iodinated contrast agent in radiologic studies can lead to renal failure. This may induce metformin accumulation which may increase the risk for lactic acidosis. In patients with eGFR > 60ml/min/1.73m³, metformin must 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 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.

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).

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.

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 medications.

Iodinated contrast agents

Intravascular administration of iodinated contrast agents 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 withintrinsic hyperglycaemic activity as glucocorticoids (systemic or by 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 other drug and upon its discontinuation.

Diuretics especially loop diuretics

They may increase the risk of lactic acidosis due to their potential to decrease renal function.

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, embryonal or foetal development, parturition or postnatal development (see also section 5.3)

When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin, instead 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.

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 breastfeeding 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.

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 (sulfonylureas, insulin, or meglitinides).

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 undesirable effects 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, not known (cannot be estimated from the available data)

Metabolism and nutrition disorders:

Very rare:

- Lactic acidosis (see section 4.4).

- Decrease of vitamin Bl2 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 to 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 national reporting system listed in Appendix V.

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.

Pharmacotherapeutic group: Blood glucose lowering drugs, excluding insulins. Biguanides.

ATC code: A10AB02

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:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation

(3) 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 (GLUT).

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 (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 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 alone12.7 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 formetformin 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.

Absorption

After an oral dose of metformin hydrochloride tablet, maximum plasma (Cmax) is reached in approximately 2.5 hours (t_max). Absolute bioavailability of a 500mg or 850mg metformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30 %.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.

At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 mircograms/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 micrograms/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850mg, 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 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 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.

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.

Tablet core:

Hydroxypropylcellulose

Stearic acid

Silica, colloidal anhydrous

Film-coat:

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Not applicable

3 years

No special precautions for storage.

Polypropylene container or Polyethylene container

Pack sizes: 30, 50, 100, 300, 400

Blister (PVC/aluminium)

Pack sizes: 30, 50, 100

Not all pack sizes may be marketed.

No special requirements

Actavis Group PTC ehf.

Reykjavikurvegi 76-78

IS-220 Hafnarfjordur

12785

Date of first authorisation: 1996-09-27

Date of latest renewal: 2006-07-10

2016-05-04