Summary of medicine characteristics - METFORMIN TABLETS 850 MG
Metformin Tablets 850mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains metformin hydrochloride Ph Eur 850mg.
Film-coated tablet.
4.1 Therapeutic indications
Metformin Tablets are indicated for treatment of non-insulin dependent diabetes mellitus (Type II/maturity onset-type diabetes) when dietary measures are inadequate to control the diabetes, especially if the patient is overweight, or if attempts to achieve control with sulphonylureas and exercise have been unsuccessful. Metformin may be used in conjunction with sulphonylureas, but close medical supervision is required.
4.2 Posology and method of administration
Adults with normal renal function (GFR > 90 mL/min):
The usual initial dose of metformin is 500mg 3 times daily, or 850mg twice daily, with meals. Adequate diabetic control may occur in a few days, but can often take up to 2 weeks. The dose may be cautiously increased, if necessary, to a maximum dose of 3,000mg (3g) daily. Once control is obtained it may be possible to reduce the dosage.
Metformin Tablets may be given to elderly patients if there is no renal impairment.
Renal impairment
A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an 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.
| 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 section 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. |
Children:
Not recommended for children.
4.3 Contraindications
Metformin Tablets are contra-indicated in any of the following circumstances:
– hypersensitivity to metformin, or any of the other ingredients;
– any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
– severe renal failure (GFR <30 mL/min);
– diabetic coma and ketoacidosis;
– renal impairment;
– chronic liver disease;
– cardiac failure or recent myocardial infarction;
– lactic acidosis, shock or pulmonary insufficiency;
– conditions associated with hypoxaemia; and
– alcoholism (acute or chronic).
intravascular administration of iodinated contrast agents (see section 4.4 special warnings and precautions for use)
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.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
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 of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. 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.
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should 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 sections 4.2 and 4.5.
Renal function
GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. 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.
Surgery
Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia. 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.
Other precautions
Blood glucose levels must be regularly monitored.
An annual estimation of vitamin B12 levels should be made as there have been reports of decreased vitamin B12 absorption.
Caution is advised when metformin is used in combination with insulin or sulphonylureas as hypoglycaemia may occur.All patients should continue their diet with 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.
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.
Iodinated contrast agents
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 sections 4.2 and 4.4.
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.
Blood glucose should be monitored if metformin is given with a sulphonylurea because the combination may cause hypoglycaemia.
If insulin is to be given with metformin, the patient should be stabilised in hospital because of possible hypoglycaemia until the correctly balanced ratio between insulin and metformin is achieved.
Concomitant administration of cimetidine and metformin may lead to reduced renal clearance of the latter, so a dose reduction should be considered.
Anticoagulants may interact with metformin, therefore dosage adjustment may be required for the anticoagulant.
Co-administration of metformin with ACE inhibitors may result in an enhanced hypoglycaemic effect.
Ketotifen and metfornin co-administration could cause depressed thrombocyte count.
MAOIs are thought to enhance the hypoglycaemic effect of metformin.
Octreotide may reduce the requirements of oral hypoglycaemic drugs like metformin in diabetes mellitus.
4.6 Fertility, pregnancy and lactation
Metformin Tablets are not recommended for use during pregnancy or lactation.
4.7 Effects on ability to drive and use machines
Patients’ ability to drive and use machines is not usually impaired when they are being treated with metformin alone but diabetics who experience dizziness or hypoglycaemia should be warned about the risks and their obligations to notify the UK vehicle licensing centre.
4.8 Undesirable effects
Gastrointestinal disturbances such as diarrhoea, abdominal pain, nausea and vomiting sometimes occur. These are usually minor and can often be avoided by taking metformin with or after meals. Sometimes, a temporary lowering of the dose may be required. Initial intolerance has been found to often resolve on its own. Also there are reports of a metallic taste in the mouth as relatively common side effect.
Megaloblastic anaemia may occur as a result of decreased vitamin B12 absorption and therefore vitamin B12 deficiency which may be caused by taking metformin.
Hypoglycaemia may occur, particularly in association with sulphonylurea therapy, but is less commonly associated with biguanides alone.
Reports of the occurrence of lactic acidosis have been made, most often in patients with contra-indications to metformin treatment. Lactic acidosis should be suspected in patients with a metabolic acidosis without evidence of ketoacidosis (ketonuria and ketonaemia), and metformin treatment must be stopped. Lactic acidosis must be treated in hospital immediately as a medical emergency.
Additionally there have been reports of skin rashes.
Other undesirable effects include anorexia, erythema, urticaria, pruritus and hepatitis.
4.9 Overdose
4.9 OverdoseLactic acidosis may develop if too many tablets have been taken.
Hypoglycaemia may occur if metformin has been taken with alcohol, insulin or a sulphonylurea. Intensive supportive treatment should be undertaken directed at correcting fluid loss and metabolic disturbance in particular.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Metformin is a biguanide antihyperglycaemic. It reduces high blood glucose concentrations in patients with diabetes only without increasing insulin secretion. It also encourages the muscles to take up glucose, reduces gluconeogenesis and slows intestinal glucose absorption.
5.2 Pharmacokinetic properties
Oral doses of metformin are absorbed via the gastrointestinal tract within 6 hours to give a bioavailability of 50–60%. Higher doses (over 1,500mg) are less bioavailable than lower doses.
Metformin is quickly distributed in the tissues and does not bind to plasma proteins. There is a slowly increasing binding to blood cells. The mean plasma elimination half-life is between 1.5 and 4.5 hours. This is prolonged in patients with renal impairment. Metformin does not appear to be metabolised and is excreted via the kidneys.
5.3 Preclinical safety data
5.3 Preclinical safety dataThere are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6.1 List of excipients
Sodium starch glycollate, maize starch, povidone, colloidal anhydrous silica, magnesium stearate, methylhydroxypropylcellulose, titanium dioxide (E171), propylene glycol, polyethylene glycol 6000 and purified talc.
6.2 Incompatibilities
None known
6.3
36 months
6.4 Special precautions for storage
Store below 25°C in a dry place.
6.5 Nature and contents of container
Blister packs comprised of PVC/PVDC/aluminium strips enclosed in an outer carton containing* 28, 30, 56, 60, 84, 90, 100 or 112 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
6.6 Special precautions for disposalNot applicable.
Ennogen Healthcare Limited Unit G2-G4
Riverside Industrial Estate
Riverside Way
Dartford, DA1 5BS
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 40739/0252