This information is intended for use by health professionals

1. Name of the medicinal product

Metformin 100mg/ml Oral Solution

2. Qualitative and quantitative composition

Each 1ml of solution contains 100mg of metformin hydrochloride.

Excipient(s) with known effect

Sodium methyl parahydroxybenzoate (E219): contains 2.07mg sodium methyl parahydroxybenzoate per ml,

Sodium propyl parahydroxybenzoate (E217): contains 0.22mg sodium propyl parahydroxybenzoate per ml,

Liquid maltitol (E965): contains 463.0 mg liquid maltitol per ml,

Sodium: contains 7.0mg sodium per 5ml

Potassium: contains 14.5mg potassium per 5ml

It also contains sodium sulphite (E221), ethanol and sucrose.

For the 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.

Adults

• In adults, metformin hydrochloride may be used as monotherapy or in combination with other oral anti-diabetic agents or 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.).

Paediatric population

• In children from 10 years of age and adolescents, metformin hydrochloride may be used as monotherapy or in combination with insulin.

4.2 Posology and method of administration

Posology

Adults (with normal renal function, GFR≥ 90 mL/min):

Monotherapy and combination with other oral antidiabetic agents:

• The usual starting dose is 500mg (5ml) or 850mg (8.5ml) 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. In patients receiving a high metformin hydrochloride dose (2 to 3 grams per day), it is possible to replace two metformin hydrochloride 500mg doses (5ml) with one metformin hydrochloride 1000mg (10ml) dose. 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 (5ml) or 850mg (8.5ml) 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Patients with renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

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:

GFR mL/min

Total maximum daily dose

(to be divided into 2-3 daily doses)

Additional considerations

60-89

3000 mg

Dose reduction may be considered in relation to declining renal function.

45-59

2000 mg

Factors that may increase the risk of lactic acidosis (see 4.4) should be reviewed before considering initiation of metformin.

The starting dose is at most half of the maximum dose.

30-44

1000 mg

<30

-

Metformin is contraindicated.

Metformin is contraindicated in patients with severe renal failure (GFR <30 mL/min).

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).

Paediatric population

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 (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 2g (20ml) daily, taken as 2 or 3 divided doses.

Method of administration

Metformin oral solution is for oral administration.

4.3 Contraindications

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

• Diabetic pre-coma

• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis.)

• Severe renal failure (GFR <30 mL/min)

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

i) dehydration

ii) severe infection

iii) shock

• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as:

iv) Decompensated heart failure

v) respiratory failure

vi) recent myocardial infarction

vii) shock

• Hepatic insufficiency, acute alcohol intoxication, alcoholism.

4.4 Special warnings and precautions for use

Lactic acidosis

Lactic acidosis, a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with impaired renal failure or acute worsening of 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, fever or reduced fluid intake), 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 and contact with a health care professional is recommended.

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 heart failure, acute myocardial infarction) (see 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 renal function.

Diagnosis:

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis.

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>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 the risk and on the symptoms of lactic acidosis.

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 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 anti-inflammatory drug (NSAID).

In these cases, it is also recommended to check renal function before initiating treatment with metformin.

-- Metformin is contraindicated in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function, see section 4.3.

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

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, 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 imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and has not deteriorated further, see section 4.2 and 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 at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

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 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 cause 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:

• Sodium methyl and propyl parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

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

• Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Sucrose may also be harmful to teeth.

• Sodium – 7mg per 5ml dose. To be taken into consideration by patients on a controlled sodium diet.

• Potassium – 14.5mg per 5ml dose. To be taken into consideration by patients with reduced kidney function or patients on controlled potassium diets.

• Sodium sulphite. This may rarely cause severe hypersensitivity (allergic) reactions and bronchospasm.

• Ethanol. This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per 10ml.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Consumption of alcohol or alcohol-containing medicinal products should 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.

In patients with eGFR >60 ml/min/1.73m2, metformin must be discontinued prior to, or at the time of the imaging procedure, and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see section 4.2 and 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

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Medicinal products with intrinsic hyperglycaemic activity such 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.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.

• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.

• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

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 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.

Breast-feeding

Metformin hydrochloride is excreted into human breast milk. No adverse effects were observed in breast-fed new-borns/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 600mg/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 has no influence on the 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 the doses slowly.

Adverse events are which have been associated with Metformin are given below, listed by system organ class and frequency. Undesirable effects are especially likely to occur at treatment onset or at dose increase.

The following adverse reactions may occur under treatment with metformin. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

very common (≥1/10),

common (≥1/100 to <1/10),

uncommon (≥1/1000 to<1/100),

rare (≥1/10000 to<1/1000),

very rare (<1/10000),

not known (cannot be estimated from the available data).

System organ class

Frequency

Undesirable effects

Metabolism and nutrition disorders

Very rare

Lactic acidosis ( serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis)

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformini.

Nervous system disorders

Common

Taste disturbance

Gastrointestinal disorders

Very common

nausea, vomiting, diarrhoea, abdominal pain and loss of appetiteii

Hepatobiliary disorders

Very rare

liver function test abnormalities or hepatitisiii

Skin and subcutaneous tissue disorders

Very rare

Skin reactions such as erythema, pruritus, urticaria

i) Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia

ii) 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.

iii) Isolated reports of liver function test 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.

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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Symptoms

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.

Management

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

Mechanism of action

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.

Pharmacodynamic effect

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) 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 and safety:

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 500mg or 850mg 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 1μg/ml. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5μg/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 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 63-276L.

Biotransformation:

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin is >400ml/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 500mg, paediatric patients have shown similar pharmacokinetic profiles to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500mg 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 500mg 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

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

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) (containing sucrose and sodium sulphite (E221))

Peppermint flavour

Peach flavour (containing ethanol)

Purified Water

Hydrochloric acid 2N (for pH adjustment)

6.2 Incompatibilities

Not applicable.

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 either a LDPE or HDPE seal, along with a 10ml oral syringe.

Pack size: 150ml

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

Focus Pharmaceuticals Ltd

Capital House,

85 King William Street,

London EC4N 7BL,

United Kingdom.

8. Marketing authorisation number(s)

PL 20046/0255

9. Date of first authorisation/renewal of the authorisation

11/07/2013

10. Date of revision of the text

16/08/2018