Metformin Hydrochloride 500mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin Hydrochloride 500mg/5ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml oral solution contains 500mg Metformin Hydrochloride.
1ml of oral solution contains 100mg Metformin Hydrochloride.
Excipients: Sodium methyl parahydroxybenzoate (E219), sodium propyl parahydroxybenzoate (E217) and maltitol liquid (E965).
Sodium = 5.3mg/5ml
Potassium = 14.5mg/5ml
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 anti-diabetic 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 5.1. Pharmacodynamic properties).
4.2 Posology and method of administration Adults:
Monotherapy and combination with other oral antidiabetic agents:
■ The usual starting dose is one 5ml spoonful (500mg) 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 3g (six 5ml spoonfuls) daily, taken as 3 divided doses.
■ If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin hydrochloride at the dose indicated above.
Combination with insulin:
Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of one 5ml spoonful (500mg) 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 hydrochloride 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 3 a (creatinine clearance [CrCl 45- 59 mL/min or estimated glomerular filtration rate [eGFR] 45-59 mL/min/1.73m ) 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.
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 one 5ml spoonful (500mg) 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 hydrochloride is 2g (four 5ml spoonfuls) daily, taken as 2 or 3 divided doses.
4.3 Contraindications
■ Hypersensitivity to metformin hydrochloride or any of the excipients listed in section 6.1.
■ Diabetic ketoacidosis, diabetic pre-coma.
■ Moderate (stage 3b) and severe renal failure or renal dysfunction (CrCl < 45 ml/min or eGFR < 45 ml/min/1.73m2).
■ Acute conditions with the potential to alter renal function such as:
- dehydration
- severe infection
- shock
- Intravascular administration of iodinated contrast agents (see 4.4 Warnings and special precautions for use).
■ 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
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride 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), 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 hydrochloride should be temporarily discontinued. Other associated risk factors should be considered to avoid lactic acidosis such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia (such as decompensated cardiac failure, acute myocardial infarction) (see also section 4.3).
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps, digestive disorders as abdominal pain and severe asthenia. Patients should be instructed to notify these signs immediately to their physicians if they occur, notably if patients had a good tolerance to metformin hydrochloride before. Metformin hydrochloride should be discontinued, at least temporarily, until the situation is clarified.
Reintroduction of metformin hydrochloride should then be discussed taking into account the benefit/risk ratio in an individual basis as well as renal function.
Diagnosis:
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 hydrochloride should be discontinued and 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 hydrochloride is excreted by the kidney, serum creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined before initiating treatment and regularly thereafter:
■ at least annually in patients with normal renal function.
■ at least two to four times a year in patients with serum creatinine levels at the upper 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 when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.
In these cases, it is also recommended to check renal function before initiating treatment with metformin.
Cardiac function
Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, metformin is contraindicated (see section 4.3).
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast 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 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 4.5.).
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 hydrochloride must be discontinued 48 hours before elective surgery under general, spinal or epidural anaesthesia and should not be usually resumed earlier than 48 hours afterwards and only after 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 hydrochloride is initiated.
No effect of metformin hydrochloride on growth and puberty has been detected during controlled clinical studies of one year duration but no long term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children is recommended.
Children aged between 10 and 12 years:
Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, 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 never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas 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. This may have a mild laxative effect. The calorific value is 2.3kcal per gram of maltitol (31.5kcal in maximum daily dose)
■ Sodium - 5.3mg per 5ml dose. This should be taken into consideration for patients on a controlled sodium diet.
■ Potassium - 14.5mg per 5ml dose. This should be taken into consideration for patients with reduced kidney function or patients on controlled potassium diets.
4.5 Interactions with other medicinal products and other forms of interaction
Concomitant use not recommended Alcohol
Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
- fasting or malnutrition
- hepatic insufficiency
Avoid consumption of alcohol and alcohol-containing medications.
Iodinated contrast agents (see section 4.4)
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin hydrochloride accumulation and a risk of lactic acidosis.
In patients with eGFR > 60 ml/min/1.73m , 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)
Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Diuretics, especially loop diuretics
They may increase the risk of lactic acidosis due to their potential to decrease renal function.
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 also section 5.3). When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with metformin hydrochloride but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.
Breast-feeding
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants.
However, as only limited data are available, 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 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 hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin or 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 hydrochloride in 2 or 3 daily doses and to increase slowly the doses.
The following adverse reactions 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. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Metabolism and nutrition disorders:
Very rare:
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.
Very rare: Lactic acidosis (see 4.4. Special warnings and precautions for use).
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.
Hepatobiliary disorders:
Very rare
Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride 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 professional are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V- to be completed nationally.
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 or concomitant risks of metformin hydrochloride 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 hydrochloride is haemodialysis.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Oral 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.
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.
Pharmacodynamic effects
In clinical studies, use of metformin hydrochloride was associated with either a stable body weight or modest weight loss.
In humans, independently of its action on glycaemia, metformin hydrochloride 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 type 2 diabetes.
Analysis of the results for overweight patients treated with metformin hydrochloride 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)
For metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea, benefit regarding clinical outcome has not been shown.
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, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500mg dose 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 hydrochloride absorption are non-linear.
At the usual metformin hydrochloride 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 4 pg/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. 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 decreases 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 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 hydrochloride is > 400 ml/min, indicating that metformin hydrochloride 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 hydrochloride 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 BID 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 BID 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 (E965)
Acesulfame Potassium (E950)
Ammonia Caramel (E150c)
Peppermint Flavour (containing propylene glycol, isopropyl alcohol and pulegone)
Peach Flavour (containing propylene glycol and isopropyl alcohol)
Purified Water
6.2 Incompatibilities
None known.
6.3 Shelf life
1 year unopened 28 days opened
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
Amber (Type III) glass bottles
Closures: HDPE, EPE wadded, tamper evident, child resistant closure Dosing Device: 5ml polypropylene spoon
Pack Size: 100ml, 150ml or 4 x 150ml - 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
Rosemont Pharmaceuticals Ltd
Rosemont House
Yorkdale Industrial Park
Braithwaite Street
Leeds
LS11 9XE
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00427/0139 PA 312/011/001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/07/2007
10 DATE OF REVISION OF THE TEXT
14/10/2016
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF
RADIOPHARMACEUTICALS (IF APPLICABLE)