Document: spc-doc_PL 25258-0146 change

• spc-doc_PL 04917-0094
• spc-doc_PL 17780-0543
• spc-doc_PL 25258-0146

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Metformin hydrochloride 500 mg/5 ml oral solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of oral solution contains 500 mg metformin hydrochloride

Also contains: Sodium - 5.3 mg per 5 ml dose and Potassium - 14.5 mg per 5 ml dose

Excipients: Sodium methyl hydroxybenzoate (E219), sodium propyl hydroxybenzoate (E217), maltitol liquid (E965), acesulfame potassium (E950) Sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous (E339).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Oral Solution.

Clear brown liquid.

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 oral solution may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.

•    In children from 10 years of age and adolescents, Metformin hydrochloride oral solution 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 (5ml) or 850mg (8.5ml) 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 3000mg (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 is given at the usual starting dose of 500mg (5ml) or 850mg (8.5ml) 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 oral solution can be used in children from 10 years of age and adolescents.

The usual starting dose is 500mg (5ml) or 850mg (8.5ml) 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 is 2000mg (20ml) daily, taken as 2 or 3 divided doses.

The required volume for each dose can be achieved with the dosing pipette.

4.3 Contraindications

•    Hypersensitivity to metformin hydrochloride or 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:

-    dehydration

-    severe infection

-    shock

•    Acute or chronic disease which may cause tissue hypoxia such as:

-    cardiac or respiratory failure

-    recent myocardial infarction

-    shock.

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) 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 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 anti-inflammatory drug (NSAID).

Administration of iodinated contrast agents

As the intravascular administration of iodinated contrast agents in radiologic studies can lead to renal failure, metformin must be discontinued prior to, or at the time of the test and not be 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 must be discontinued 48 hours before elective surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function is 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 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, although caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g sulphonylureas or meglitinides).

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

Potassium - 14.5 mg per 5 ml 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 cases of fasting or malnutrition or hepatic insufficiency. Consumption of alcohol and alcohol-containing medications should be avoided.

Iodinated contrast agents (see section 4.4)

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and an increased 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 such 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 respective medicinal product and upon its discontinuation.

Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function.

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, embryonal 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.

Lactation:

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 taking into account the benefit of breast-feeding and the potential risk of 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 hydrochloride oral solution 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 (sulphonylureas, insulin or meglitinides).

4.8 Undesirable effects

The following undesirable effects may occur under treatment with metformin hydrochloride.

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, undesirable effects 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 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

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 hydrochloride. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Hepatobiliary disorders:

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

Overdose

Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin 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, excluding insulins

ATC code: A10B A02

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; and

(3)    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) known to date.

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 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 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 (C_max) is reached in approximately 2.5 hours (t_max).. 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 2030%.

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

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.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium methyl hydroxybenzoate (E219)

Sodium propyl hydroxybenzoate (E217)

Sodium dihydrogen phosphate dihydrate Disodium hydrogen phosphate anhydrous (E339) Maltitol, liquid (E965)

Acesulfame potassium (E950)

Caramel (E150)

Peppermint flavour Peach flavour Purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

18 months

28 days once opened.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Nature and contents of container

Amber (Type III) glass bottles.

Closures: HDPE, EPE wadded, tamper evident, child resistant closure.

One 5ml oral medication syringe (plastic dosing pipette) with 0.1ml graduation and the corresponding neck fitted syringe adaptor for the bottle

Pack size: 100 ml and 150 ml.

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

Glenmark Pharmaceuticals Europe Limited, Laxmi House, 2-B Draycott Avenue, Kenton, Harrow, Middlesex, HA3 0BU. United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL: 25258/0146

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 20/01/2012

10 DATE OF REVISION OF THE TEXT

20/11/2014