SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Metformin Hydrochloride 500 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg of metformin hydrochloride

Excipient with known effect: Each film-coated tablet contains 14.40 mg lactose monohydrate

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Film-coated tablet.

White, oblong, biconvex film-coated tablets with both sided score notch and M 500 on one side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metformin Hydrochloride 500 mg Tablets are indicated for:

Non-insulin dependent diabetes when dietary management and exercise alone has failed and especially if the patient is overweight. Metformin Hydrochloride 500 mg Tablets can be given alone as initial therapy, or can be administered in combination with other oral antidiabetic agents or with insulin.

In children from 10 years of age and adolescents, Metformin 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).

In insulin-dependent diabetes, Metformin Hydrochloride 500 mg Tablets may be given as an adjuvant to patients whose symptoms are poorly controlled.

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 patients 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:

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

The ususal starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meal.

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

Metformin Hydrochloride 500 mg Tablets are contraindicated in the following cases:

-    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

-    Diabetic coma, diabetic pre-coma, ketoacidosis or a history of ketoacidosis

-    Moderate (stage 3b) and severe renal failure or renal dysfunction (CrCl < 45 ml/min or eGFR < 45 ml/min/1.73m2) including protenuria - if this is suspected metformin should be withdrawn

-    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.

-    Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock

-    Severe peripheral vascular disease.

-    Hepatic insufficiency, acute alcohol intoxication, alcoholism

4.4 Special warnings and precautions for use

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 at the time of, or prior to, the procedure and not be reinstituted until at least 48 hours afterwards, and only after renal function has been reevaluated 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 metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

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

Metformin alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

Annual measurements of vitamin Bi₂ in patient on continuous therapy since reduced Bi₂ has been reported.

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.

Sulfonylurea

Blood glucose should be monitored during concomitant therapy with a sulfonylurea because combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with metformin hydrochloride and insulin should be carried out in hospital because of the possibility of hypoglycaemia, until the correct ratio of the two drugs has been obtained.

Cimetidine

Reduced renal clearance of metformin hydrochloride has been reported during cimetidine therapy, so a dose reduction should be considered.

Anticoagulants

As with a number of drugs, an interaction between metformin hydrochloride and anticoagulants is a possibility and dosage of the latter may need adjustment.

Monotherapy

Metformin hydrochloride does not lower blood glucose levels in non-diabetics, and does not cause hypoglycaemia in diabetics when used as monotherapy. Weight loss often occurs during therapy and levels of plasma cholesterol, triglycerides and prebeta-lipoproteins may be lowered. Metformin hydrochloride has been shown to improve peripheral glucose metabolism.

ACE inhibitors

Possibly enhance the hypoglycaemic effect.

Anti-depressants

MAOIs enhance the hypoglycaemic effect.

Antihypertensives

Diazoxide may antagonise the hypoglycaemic effect. Beta blockers enhance the hypoglycaemic effect and can mask warning signs such as tremors.

Oral contraceptives

Antagonise the hypoglycaemic effect.

Diuretics, especially loop diuretics

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

Clofibrates

May improve glucose tolerance and have an additive effect.

Other antidiabetics

Combined therapy with sulfonylureas may cause hypoglycaemia and blood glucose levels should be monitored.

4.6 Fertility, pregnancy and lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).

When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Breast-feeding

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

However, as only limited data are available, breast-feeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effects on the child.

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

4.7 Effects on ability to drive and use machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulfonylureas, insulin or meglitinides).

4.8 Undesirable effects

Metformin hydrochloride is normally well tolerated but gastro-intestinal disturbances such as 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).

-    Decreased vitamin B₁₂ absorption with decrease of serum levels during longterm 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

Pharmacodynamic properties

Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides ATC code: A10BA Mechanism of action

Metformin hydrochloride is a biguanide oral anti-hyperglycaemic agent,

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:

Microcrystalline cellulose Sodium starch glycollate (type A) Povidone k-28 Colloidal anhydrous silica Magnesium stearate Ethanol 96%

Purified water

Film coating:

Opadry White OY-L-28900 Consisting of:

Lactose monohydrate Methylhydroxypropylcellulose (viscosity: 15cP)

Titanium dioxide (E171) Polyethylene glycol 4000 Purified water

6.2 Incompatibilities

None known.

6.3 Shelf life 3 years.

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

Blister packs of 250 pm white opaque PVC/PVDC welded onto 20 pm internally film-coated aluminium semi-rigid support, or 300 pm white opaque PP welded onto 15 pm internally film-coated aluminium semi-rigid support, packed into lithographed cardboard cartons.

28, 30, 56, 84 or 120 tablets per pack.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd. 3 Howard Road Eaton Socon St. Neots

Cambs. PE19 8ET

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0466

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22/08/2002 Date of latest renewal: 18/03/2009

10    DATE OF REVISION OF THE TEXT

22/09/2016