Metformin Tablets 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin Tablets 500 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains metformin hydrochloride 500 mg
For excipients see 6.1
3 PHARMACEUTICAL FORM
Film-coated tablets
White coloured, round shaped, biconvex tablets engraved with “C” on one side and “323” on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Non-insulin-dependent diabetes (NIDDM, type II) and, in particular, in overweight patients, when adequate dietary treatment and exercise has failed.
In adults metformin hydrochloride 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 may be used as monotherapy or in combination with insulin.
4.2 Posology and method of administration Dosage
Usual dosage:
Adults:
Monotherapy and combination with other oral antidiabetics
Therapy should be initiated with one 850mg tablet twice a day or one 500mg
tablet three times a day. In order to minimise the gastro-intestinal side-effects the daily dose should be divided and taken with or after meals. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements.
If diabetic control is incomplete a cautious increase in dosage to a maximum of 3g daily is justified. Once control has been achieved it may be possible to reduce the daily dose.
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 tablet 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, the metformin hydrochloride dosage should be adjusted based on renal function. Regular assessment of renal function is necessary, stopping metformin hydrochloride if renal impairment develops.
Children and adolescents:
Monotherapy and combination with insulin
Metformin hydrochloride can be used in children from 10 years of age and in adolescents.
The usual starting dose is one tablet of 500 mg or 850 mg once 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 GI tolerability. The maximum recommended dose of metformin hydrochloride is 2g daily taken as 2 or 3 divided doses.
Method of administration
Metformin Tablets 500 mg should be taken whole with a glass of water during or after meals. They should not be chewed.
Monitoring advice
See special warnings and special precautions for use.
4.3 Contraindications
- Diabetic precoma, coma and ketoacidosis.
- Hypersensitivity to metformin hydrochloride or to any of the excipients.
- Renal failure or renal dysfunction (creatinine clearance <60 ml/min).
- Hepatic insufficiency, acute alcohol intoxication, alcoholism.
- 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, severe peripheral vascular disease.
- Pregnancy.
- IV administration of iodinated contrast agents (see section 4.4).
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 hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride 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 dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/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).
Renal function:
As metformin hydrochloride is excreted by the kidney, serum creatinine levels 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.
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 a non-steroidal antiinflammatory drug.
Administration of iodinated contrast agent:
As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin hydrochloride should 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 hydrochloride must be discontinued 48 hours before elective surgery with 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 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 longterm 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 hydrochloride 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 sulfonylureas.
Vitamin B12 levels:
Patients receiving continuous metformin hydrochloride therapy should have an annual estimation of Vitamin B12 levels because of reports of decreased Vitamin B12 levels.
4.5 Interaction with other medicinal products and other forms of interaction Contra-indicated
During treatment with Metformin Tablets 500 mg alcohol should be strictly avoided. Alcohol may enhance the hypoglycaemic effect and produce an increased risk of lactic acidosis.
IV administration of iodinated contrast agents may lead to renal failure (see section 4.4), metformin hydrochloride should therefore be discontinued prior to such procedures.
Precaution for use
An increase of the antihyperglycaemic effect of metformin hydrochloride is possible in the event of concomitant administration with medicinal products for the same indication, for example:
- insulin
- oral antidiabetic drugs of the sulphonylurea type
An increase of the antihyperglycaemic effect of metformin is also possible in the event of concomitant administration with medicinal products for other indications which possess blood glucose-lowering effects of their own, for example:
- NSAIDs, e.g. salicylates or pyrazolones
- MAO inhibitors
- Oxytetracycline
- ACE inhibitors
- Fibrates
- Cyclophosphamide and its derivatives
The combination of metformin hydrochloride and the above mentioned drugs can induce hypoglycaemia, if necessary the dose of metformin hydrochloride should be adjusted.
Moreover, during permanent therapy, beta-blockers may decrease blood glucose levels and may mask the warning signs of hypoglycaemia (such as tremor).
A decrease of the antihyperglycaemic effect of metformin hydrochloride in combination with the following drugs may also occur:
- Glucocorticoids
- Oestrogen-progestagen-combinations
- Adrenaline and other Sympathomimetics
- Glucagon
- Thyroid hormones
- Thiazides and loop diuretics
- Diazoxide
- Phenothiazines
- Nicotinic acid derivatives
Guar: A decrease of the absorption of metformin may lead to an attenuation of metformin effects.
Cimetidine: Substances which delay the elimination of metformin
hydrochloride, e.g. cimetidine, may increase the risk of lactic acidosis.
Coumarins: Elimination of coumarins may be accelerated during metformin therapy. Therefore the blood coagulation inhibiting effect may be decreased and frequent controls of blood coagulation are necessary.
To be taken into account
During maintenance therapy the onset or termination of any other additional therapy can disturb the control of diabetes.
4.6 Fertility, Pregnancy and lactation
Pregnancy
During pregnancy the administration of Metformin Tablets 500 mg is contraindicated. Diabetes mellitus should be treated with insulin during pregnancy or when pregnancy is desired. Animal studies have shown no particular effects with respect to reproduction and fertility. In man insufficient experience with metformin hydrochloride during pregnancy has been obtained.
Use during lactation
The use of Metformin Tablets 500 mg should be avoided in women who are breast-feeding.
Three studies in a total of fifteen lactating females have shown that very small amounts of metformin hydrochloride are excreted in human breast milk. Metformin hydrochloride concentration in milk remained constant across the maternal dosing interval. Metformin hydrochloride was present in very low or undetectable concentrations in the plasma of six of the nine infants exposed during suckling. No immediate adverse experiences were detected in these nine infants, but these studies did not investigate potential long-term effects.
4.7 Effects on ability to drive and use machines
When used as monotherapy metformin hydrochloride does not influence the ability to drive or operate machinery. In cases of combined therapy with sulphonylureas or other drugs with blood glucose lowering effects, hypoglycaemia may occur and, hence, such combinations may produce minor or moderate adverse effects. Patients undergoing such combination therapy should be warned about the possible adverse effects of hypoglycaemia.
4.8 Undesirable effects
Frequencies are defined as follows:
Very common : > 1 in 10. Common : >1 in 100, <1 in 10. Uncommon : >1 in 1,000, <1 in 100. Rare : >1 in 10,000, < 1 in 1,000. Very rare : <1 in 10,000 and not known (cannot be estimated from available data).
Metabolism and nutrition disorders Very rare:
- Lactic acidosis (with coma and death is possible) (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.
Nervous system disorders Common: Metallic taste.
Gastro-intestinal disorders
Very common: nausea, vomiting, abdominal pain, diarrhoea, loss of appetite.
These gastro-intestinal disturbances are generally of minor importance and frequently do not require termination of metformin hydrochloride therapy. The frequency and severity of these gastro-intestinal disturbances can be reduced markedly by starting with low and gradually increasing metformin hydrochloride doses and by administration of metformin hydrochloride with or after meals. Persisting gastro-intestinal disturbances may require the termination of metformin hydrochloride therapy.
Hepatobiliary disorders
Frequency not known: There have been reports of liver function test abnormalities or cholestatic hepatitis, reversible after discontinuation of metformin hydrochloride.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritis, urticaria.
4.9 Overdose
Human experience
Intoxication with metformin hydrochloride does not lead to hypoglycaemia but lactic acidosis may develop.
Management of overdosage in man
In cases of metformin hydrochloride overdosage, for example in attempted suicide, or if signs of lactic acidosis are shown, patients must be admitted to a hospital as an emergency. The diagnosis of lactic acidosis should be confirmed by determination of lactate and metformin hydrochloride concentrations. Haemodialysis is the most effective measure to eliminate lactate and metformin hydrochloride. Symptomatic treatment includes circulatory stabilisation, compensation of acidosis and elimination of hypoxia. The metformin hydrochloride concentration in erythrocytes is a good indicator for accumulation and can be used to decide whether repeated haemodialysis is indicated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Metformin hydrochloride is a biguanide oral antihyperglycaemic agent (ATC Code A10B A02) and reduces elevated blood glucose levels only in patients with noninsulin-dependent diabetes (NIDDM), but does not increase insulin secretion and does not cause hypoglycaemia or increased weight gain. Its mode of action is multifactorial and not yet completely understood. However, the augmentation of glucose uptake into peripheral tissues may influence glucose utilisation. Furthermore, the effects of metformin hydrochloride include reduced hepatic gluconeogenesis and delayed intestinal glucose absorption which may explain the blood glucose-lowering effect. The efficacy of metformin hydrochloride is dependent on a minimum concentration of insulin. A slight influence of the insulin secretion by metformin hydrochloride is possible but a clinical relevance is not very likely. Metformin hydrochloride seems to potentiate insulin action by enhancing insulin binding to its receptors and by facilitating steps in the post-receptor pathways of insulin-action. Apart from the glucose-lowering effect, metformin hydrochloride reduces the serum triglyceride level and possesses antithrombotic properties
5.2 Pharmacokinetic properties
After oral administration metformin hydrochloride is incompletely absorbed from the gastro-intestinal tract. The oral bioavailability of usual doses is 50 -60 %. The maximum plasma concentration is achieved after about 2 hours. Gastrointestinal absorption is complete within 6 hours of ingestion. The volume of distribution lies between 63 and 276 litres. Metformin hydrochloride is rapidly distributed but a slow transfer to a deep compartment seems to occur. Metformin hydrochloride does not bind to plasma proteins but accumulates in the salivary glands, duodenum, kidneys and liver. No metabolites or conjugates of metformin hydrochloride have been identified. Metformin hydrochloride is completely eliminated by renal excretion and the mean plasma elimination half-life ranges between 1.5 and 4.5 hours. A quantitatively minor terminal elimination phase, probably out of the deep compartment, with a longer mean half-life ranging from 8.9 to 19 hours, has been observed. The renal clearance of metformin hydrochloride ranges between 350 and 550 ml/min and correlates with the creatinine clearance, indicating that metformin hydrochloride is excreted by active tubular secretion. In patients with impaired renal function accumulation of metformin hydrochloride is probable.
5.3 Preclinical safety data
Acute toxicity:
Acute toxicity after different routes of administration and in different animals was investigated. The data indicate the highest toxicity of metformin hydrochloride after subcutaneous administration to guinea pigs and rabbits (LD50 = 150 mg/kg) and intravenous administration to mice (LD50 = 180 mg/kg). The toxicity after oral ingestion of metformin hydrochloride seems to be several times lower, rabbits and guinea pigs (LD50 3 5 0 and 500 mg/kg, respectively) being more sensitive than mice or rats (LD50 1 45 0 mg/kg and 1000 mg, respectively). Hence, in various animal species studied, after different routes of administration the LD50 values are considerably higher than the therapeutic dose range in humans (maximum approximately 40 mg/kg/day). The data indicate a low potential of acute toxicity.
Chronic toxicity:
Studies with repeated administration of metformin hydrochloride to rats (up to 18 months), dogs (up to 18 months) and monkeys (up to 2 years) revealed no specific toxic effects.
Mutagenic and carcinogenic effects:
Bacterial tests for mutagenicity of metformin hydrochloride were negative but chromosomal alterations were observed in vitro in mammalian cells. The relevance of these effects remains obscure. Long-term animal studies failed to detect any oncogenic properties of metformin hydrochloride.
Reproductive toxicity:
No teratogenic properties of metformin hydrochloride have been found in rats. The no adverse-effect level (NOAEL) of metformin hydrochloride in rats was estimated to be 300 mg/kg/day for embryotoxicity and female reproduction and up to 600 mg/kg/day for male fertility. No teratogenic effects were observed in rabbits with doses up to 140 mg/kg/day (p.o.). In rats doses up to 600 mg/kg/day administered p.o. pre- and postnatally showed no effects.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Sodium starch glycollate Maize starch Povidone
Colloidal anhydrous silica Magnesium stearate
Film-coating:
Methylhydroxypropylcellulose Titanium dioxide E 171 Propylene glycol Macrogol 6000 Purified talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
PVC/PE-PVDC/Aluminium or PVC/PVDC/Aluminium blisters, packs of 28, 56 or 84 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special precautions are required.
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
3&4 Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20416/0323
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/05/2006
10 DATE OF REVISION OF THE TEXT
24/10/2016