Metformin 850 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin 850 mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains:
Metformin hydrochloride 850mg
3 PHARMACEUTICAL FORM
Film-coated tablets
White coloured, film coated, round biconvex tablets with MET 850 on one side and CP on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
- Non-insulin-dependent diabetes (NIDDM, type II) and, in particular, in obese patients, when adequate dietary treatment has failed.
- Metformin 850 mg Tablets can be given alone as initial therapy, or can be administered in combination with sulphonylureas after careful assessment of the contra-indications.
4.2 Posology and Method of Administration
Dosage Usual dosage:
The required daily dose ranges from 500mg to 3 g. Therapy should be initiated with a low dose of 500mg or 850mg daily. Depending on the metabolic state the dose can be increased stepwise at intervals of a few days up to two weeks until the therapeutically required dose has been reached. In order to minimise the gastro-intestinal side-effects the daily dose should be divided and taken with or after meals. Generally, daily doses of 1000mg to 1700mg are sufficient. If diabetic control is incomplete a cautious increase in dosage to a maximum of 2 to 3g daily is justified. No additional benefit can usually be achieved by use of doses exceeding 3g daily. Once control has been achieved it may be possible to reduce the daily dose.’
In cases of metabolic decompensation:
The metformin dosage may be reduced in cases of metabolic decompensation. If only small daily doses are administered an omission of one metformin dose should be tried. This is of importance in elderly patients to reduce the risk of lactic acidosis.
Children and juveniles:
Metformin 850 mg Tablets are not recommended for use in children Elderly patients:
Metformin 850 mg Tablets are indicated for use in the elderly.
Further dosage information Combination with sulphonylureas:
Metformin 850 mg Tablets may be used in combination with sulphonylureas if monotherapy with metformin does not lead to a satisfactory response. However, it should be noted that metformin and sulphonylureas have a different mode of action and therefore an additive or potentiating effect of these drugs might cause hypoglycaemic shock.
Substitution for sulphonylureas:
Metformin 850 mg Tablets may be used instead of sulphonylureas in patients who formerly have been treated with sulphonylureas.
Method of administration
Metformin 850 mg Tablets 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
- In patients with non-insulin-dependent diabetes (NIDDM, type II), if sulphonylurea therapy has completely failed
- Diabetic precoma, coma and ketoacidosis
- Hypersensitivity to metformin.
- Impaired renal function of any degree
_ Hepatic impairment or disease. In patients with impaired liver function, lactate clearance may be restricted
- Severe cardiovascular impairment.
- Cardiac failure and recent myocardial infarction.
- Severe peripheral vascular disease
- Acute severe disorders, for example infections with fever, pancreatitis or trauma.
- Dehydration.
- History of or conditions associated with lactic acidosis such as shock or
pulmonary insufficiency, alcoholism (acute or chronic), and conditions associated with hypoxaemia.
Reduced diet (< 1000 kcal or 4200 kJ per day).
4.4 Special warnings and precautions for use
Warnings
- The risks of lactic acidosis and accumulation are determined by renal function. Therefore,
metformin therapy requires a normal renal function which should be monitored continuously, particularly in the elderly.
- In elderly patients (approximately over the age of 65 years) metabolism is reduced and therefore a risk/benefit assessment should be carried out.
-Risk/benefit should be considered in patients with debilitated physical condition.
- During concomitant therapy with sulphonylureas or insulin, blood glucose levels should be monitored because combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with metformin and insulin should be carried out in a hospital until the correct ratio of the two drugs has been obtained.
- Metformin hydrochloride must be discontinued 48 hours before elective surgery under 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.
- Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such studies are planned, metformin should be discontinued at the time of, or prior to, the procedure and withheld for 48 hours subsequent to the procedure and re-instituted only after renal function has been re-evaluated and found to be normal.
- Patients receiving continuous metformin therapy should have an annual estimation of Vitamin B ^ levels because of reports of decreased Vitamin B12 absorption.
Precautions for use
- Patients should be warned to consult a physician immediately if they suddenly suffer from muscle spasms, dyspepsia, abdominal pain and fatigue, since these symptoms may indicate lactic acidosis. Lactic acidosis is accompanied by acidotic dyspnoea, abdominal pain, hyperthermia, comatose state, decrease of blood pH value and increase of lactate value.
- Serum creatinine levels should be determined before and four weeks after metformin therapy has been started. Regular measurements should take place once or twice a year unless required earlier due to intercurrent disorders. In elderly patients serum creatinine values often are not meaningful. Therefore, creatinine clearance should be tested before the onset of metformin therapy.
4.5 Interaction with Other Medicinal Products and Other Forms of Interaction
Contra-indicated
During treatment with Metformin 850 mg Tablets alcohol should be strictly avoided. Alcohol may enhance the hypoglycaemic effect and produce an increased risk of
lactic acidosis.
Precaution for Use Contrast Media
‘Intravascular administration of iodinated contrast media may cause renal failure which could result in lactic acidosis in patients taking metformin. Refer to section 4.4, Special Warnings and Special Precautions for Use.’
An increase of the antihyperglycaemic effect of metformin is possible in the event of concomitant administration with medicinal products for the same indication, for example:
- Insulin
- Oral antidiabetic drugs, of the sulphonylurea and acarbose type (see section 4.2 Posology and Method of Administration)
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
- MAO inhibitors
- ACE inhibitors
- Clofibrate derivatives
The combination of metformin and the above mentioned drugs can induce hypoglycaemia.
Moreover, during permanent therapy, beta-blockers and antisympathotonic drugs, such as clonidine, reserpine or guanethidine, may decrease blood glucose levels. However, of particular clinical relevance is their reducing action on the hormonal and neural counterregulation during hyperglycaemia, which in turn also impairs the subjective perception of hypoglycaemic warning signs.
A decrease of the antihyperglycaemic effect of metformin in combination with one of the following drugs may occur:
- Glucocorticoids
- Oestrogen-progestagen-Combinations
- Adrenaline and other Sympathomimetics
- Thyroid hormones
- Thiazides and loop diuretics
- Diazoxide
- Phenothiazines
Cimetidine: Substances which delay the elimination of metformin, e.g. cimetidine, may increase the risk of lactic acidosis.
Phenprocoumone: Elimination of phenprocoumone and other coumarins may be accelerated during metformin therapy. Therefore the blood coagulation inhibiting effect may be decreased and frequent controls of blood coagulation are necessary.
Disopyramide may enhance the hypoglycaemic effect of metformin.
During maintenance therapy the onset or termination of any other additional therapy can disturb the control of diabetes.
4.6 Pregnancy and Lactation
Pregnancy
During pregnancy the administration of Metformin 850 mg Tablets is contraindicated. The treatment of diabetes mellitus should be adjusted with insulin during pregnancy or when pregnancy is desired. Animal studies have shown no particular effects with respect to reproduction and fertility. In humans insufficient experience with metformin during pregnancy has been obtained.
Use during lactation
The use of Metformin 850 mg Tablets should be avoided in women who are breastfeeding.
Metformin hydrochloride is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin hydrochloride, taking into account the importance of the medicinal product to the mother.
4.7. Effects on Ability to Drive and Use Machines
When used as monotherapy metformin 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
Frequently arising undesirable effects are: Gastro-intestinal disturbances
- Metformin 850 mg Tablets are normally well tolerated, but at the beginning of metformin therapy gastro-intestinal disturbances, such as nausea, vomiting, abdominal pain, diarrhoea, anorexia and metallic taste occur in 5 - 20% of patients. These gastro-intestinal disturbances are generally of minor importance and require no termination of metformin therapy. The frequency and severity of these gastro-intestinal disturbances can be reduced markedly by starting with low and gradually increasing metformin doses and by administration of metformin with or after meals.
Chronic diarrhoea may occur as a late onset adverse effect (some patients had been on stable metformin therapy for several years before the onset of diarrhoea).
- About 5 % of all patients do not tolerate metformin therapy.
Rarely arising undesirable effects are:
-Hypoglycaemia occurs rarely, usually only with toxic doses, other antidiabetic agents or fasting.
Rare side effects are:
-Hepatitis
-Haemolytic anaemia
Very rarely arising undesirable effects are:
- Lactic acidosis.
Under metformin therapy lactic acidosis with coma and death is possible. Lactic acidosis induced by metformin is an indicator for a general cell toxicity and is accompanied by impaired hepatic lactate clearance and increased muscular lactate release. Although metformin-induced lactic acidosis occurs very rarely the lethality reaches 50 %.
Causes of lactic acidosis: Apart from overdosage other causes of lactic acidosis may be renal insufficiency, impaired liver function, alcohol consumption, other diseases with effects on oxidative metabolism, for example cardiac decompensation or severe infections and catabolic conditions as well as interactions with other drugs.
Symptoms of lactic acidosis: At first lactic acidosis resembles the gastrointestinal side-effects of metformin, for example nausea, vomiting, diarrhoea and abdominal pain. However, within a few hours the complete clinical picture of lactic acidosis with muscle pains, hyperventilation, clouding of consciousness and coma may develop. Hypotension and Hypothermia may also be experienced. On suspicion of lactic acidosis metformin therapy must be immediately stopped and the patient must be treated at once as an emergency in hospital.
Reported single cases:
- Inhibition of the absorption of Vitamin B12 or folic acid may cause megaloblastic anaemia. Therefore, patients receiving continuous metformin therapy should have an annual estimation of Vitamin B12 levels and, if necessary, Vitamin B12 has to be given parenterally.
- Persisting gastro-intestinal disturbances require the termination of metformin therapy.
Unknown frequency:
-Flatulence
-Bloating
-Liver function test abnormalities -Weight Loss
-Hypersensitivity reactions of the skin including urticaria.
-Erythema and pruritus
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9. Overdose
Human experience
Intoxication with metformin does not lead to hypoglycaemia but lactic acidosis may develop. Hypoglycaemia can occur when metformin is given concomitantly with sulphonylureas, alcohol or insulin.
Management of overdosage in man
In cases of metformin 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 concentrations. Haemodialysis is the most effective measure to eliminate lactate and metformin. Symptomatic treatment includes circulatory stabilisation, compensation of acidosis and elimination of hypoxia. Glucose or glucagon may be required for hypoglycaemia. The metformin 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 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 include reduced hepatic gluconeogenesis and delayed intestinal glucose absorption which may explain the blood glucose-lowering effect. The efficacy of metformin is dependent on a minimum concentration of insulin. A slight influence of the insulin secretion by metformin is possible but a clinical relevance is not very likely. Metformin 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 reduces the serum triglyceride level and possesses antithrombotic properties.
5.2. Pharmacokinetic Properties
After oral administration metformin is incompletely absorbed from the gastrointestinal 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 is rapidly distributed but a slow transfer to a deep compartment seems to occur. Metformin does not bind to plasma proteins but accumulates in the salivary glands, duodenum, kidneys and liver. No metabolites or conjugates of metformin have been identified. Metformin 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 ranges between 350 and 550 ml/min and correlates with the creatinine clearance, indicating that metformin is excreted by active tubular secretion. In patients with impaired renal function accumulation of metformin 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 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 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.
Reproductive toxicity:
No teratogenic properties of metformin have been found in rats. The no adverse-effect level (NOAEL) of metformin 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 (Type A)
- Maize starch
- Povidone K30
- Colloidal anhydrous silica
- Magnesium stearate
Film-coating
- Methylhydroxypropylcellulose
- Titanium dioxide E 171
- Propylene glycol
- Polyethylene glycol 6000
- Purified talc
6.2. Incompatibilities
None known.
6.3. Shelf Life
3 years
6.4. Special Precautions for Storage
Do not store above 25 °C.
Nature and Contents of Container
6.5.
Blister pack of 56 film-coated tablets
6.6. Instruction for Use/Handling
No special precautions are required.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0134
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/05/2007
10 DATE OF REVISION OF THE TEXT
24/05/2016