Metformin 100 Mg/Ml Oral Solution

Document: spc-doc_PL 35574-0012 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Metformin 100 mg / ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 100 mg of metformin hydrochloride.

Excipients: Sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217) and maltilol liquid (E965).

Sodium = 7.0mg/5ml Potassium = 14.5mg/5ml

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral Solution

Clear brown solution with characteristic odour

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 hydrochloride 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 hydrochloride 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 Adults:

Monotherapy and combination with other oral antidiabetic agents:

• The usual starting dose is 500mg (5 ml) or 850 mg (8.5 ml) 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 (30ml) 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 500mg (5 ml) or 850 mg (8.5 ml) 2-3 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).

Children and adolescents:

Monotherapy and combination with insulin

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

• The usual starting dose is 500mg (5 ml) 850 mg (8.5 ml) once daily, given during meals or after meals.

4.3 Contraindications

• Hypersensitivity to metformin or any of the excipients.

• Diabetic ketoacidosis, diabetic pre-coma.

• Renal failure or renal dysfunction (creatinine clearance < 60mL/min).

• Acute conditions with the potential to alter renal function such as:

o dehydration o severe infection o shock

• 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

4.4 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 accumulation. Reported cases of lactic acidosis in patients on metformin 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 dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see section 4.9).

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) 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 lower limit of normal and in elderly subjects.

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, diuretic therapy or when starting therapy with a non-steroidal antiinflammatory drug (NSAID).

Administration of iodinated contrast media

As the intravascular administration of iodinated contrast media in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Metformin 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).

Surgery

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

Excipient warnings

This product contains:

• Parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

• Liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

• Sodium - 7.0 mg per 5ml dose. This should be taken into consideration for patients on a controlled sodium diet.

• Potassium - 14.5 mg per 5ml dose. This should be taken into consideration for patients with reduced kidney function or patients on controlled potassium diets.

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

Consumption of alcohol or alcohol-containing medicinal productsshould be avoided.

Iodinated contrast media

Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin hydrochloride accumulation and a risk of lactic acidosis.

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 found to be normal (see section 4.4).

Combinations requiring precautions for use

Medicinal products with intrinsic hyperglycaemic activity as 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 also increase the risk of lactic acidosis due to their potential to decrease renal function.

4.6 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.

Lactation

Metformin hydrochloride 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. sulphonylureas, insulin, 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; not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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.

Skin and subcutaneous tissue disorders:

Very rare : Skin reactions such as erythema, pruritus, urticaria

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 megaloplastic anaemia.

Hepatobiliary disorders:

Very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

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.

4.9 Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85g, 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: A10B A02

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 utilisation (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) known to date.

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 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 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 sulphonylurea 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 sulphonylurea 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 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, Tmax is reached approximately 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 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 pg/ml. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5 pg/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. 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 findings 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 63-276 L.

Metabolism:

Metformin hydrochloride 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.

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, toxicity reproduction.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium methyl parahydroxybenzoate (E219) Sodium propyl parahydroxybenzoate (E217) Sodium dihydrogen phosphate dihydrate Di-sodium hydrogen phosphate anhydrous (E339)

Liquid Maltitol (75%) (E965) Acesulfame potassium (E950) Caramel colour (E150b) Peppermint flavour Peach flavour Purified Water

6.2 Incompatibilities

None known

6.3 Shelf life

18 months unopened 28 days opened

6.4 Special precautions for storage

Do not store above 25°C.

Once opened, use within 28 days.

6.5 Nature and contents of container

Amber (Type III) glass bottle, with tamper evident and child resistant screw-cap with a PEBD seal, along with a 10ml oral syringe.

Pack size: 150 ml

6.6 Special precautions for disposal and other handling

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

7 MARKETING AUTHORISATION HOLDER

Alapis S.A.

2, Aftokratoros Nikolaou str.

17671, Athens, Greece

8 MARKETING AUTHORISATION NUMBER(S)

PL 35574/0012

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/04/2011

10 DATE OF REVISION OF THE TEXT

06/04/2011