Metformin Hydrochloride Tablets 850mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Metformin Hydrochloride 850mg Tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 850mg of Metformin hydrochloride. For a full list of excipients see section 6.1
3 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Approximately 22mm x 8.7mm, white, oblong with score notch on one side and marked “M850” on the other.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Metformin Hydrochloride 850mg tablets are indicated for:
Non-insulin dependent diabetes when diet management and exercise alone has failed and especially if the patient is
overweight. Metformin Hydrochloride Tablets 850mg can be given alone as monotherapy, or can be administered in combination with other oral antidiabetic agents or with insulin.
In children from 10 years of age and adolescents, Metformin 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 section 5.1).
In insulin-dependent diabetes, Metformin Hydrochloride Tablets 850mg may be given as an adjuvant to patients whose symptoms are poorly controlled.
4.2 Posology and method of administration
Adults:
Initially, one 850mg tablet twice a day, with or after food. Good diabetic control may be achieved within a few days, but it is not unusual for the full extent to be delayed for up to two weeks. A slow increase of dose may improve gastrointestinal tolerability. If control is incomplete, a cautious increase in dosage to a maximum of 3g daily taken as 3 divided doses is justified. Once control has been obtained, it may be possible to reduce the dosage of Metformin Hydrochloride Tablets 850mg.
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 500 mg or 850 mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.
Elderly:
Metformin should be used with caution in elderly patients whose renal function may be reduced. Regular assessment of renal function is necessary (see section 4.4).
Children and adolescent:
Monotherapy and combination with insulin: Metformin can be used in children from 10 years of age and adolescents. The ususal starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meal. 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 2 g daily, taken as 2 or 3 divided doses.
4.3 Contraindications
Metformin hydrochloride Tablets 850mg are contraindicated in the following cases:
- Hypersensitivity to any of the components of the formulation
- Diabetic pre-coma and diabetic ketoacidosis
- Severe infection or trauma
Severe peripheral vascular disease
- Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).
- 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.
- Hepatic insufficiency, acute alcohol intoxication, alcoholism.
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 accumulation. Reported cases of lactic acidosis in patients on metformin 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 should be discontinued and the patient should be hospitalised immediately (see section 4.9).
Physicians should alert the patient 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) 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 creatinine clearance level 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 antiinflammatory drug (NSAID).
Administration of iodinated contrast agent:
The intravascular administration of iodinated contrast agents in radiologic studies can lead to renal failure. This may induce metformin accumulation and may increase the risk for lactic acidosis. Metformin must be discontinued prior to, or a 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 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.
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 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).
Children and adolescents :
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 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 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.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use not recommended:
- Alcohol
• Acute alcohol intoxication is associated with an increased risk of lactic
acidosis, particularly in case of fasting or malnutrition, hepatic insufficiency
Avoid consumption of alcohol or alcohol-containing medicinal products.
Intravascular administration of iodinated contrast agent may lead to renal failure resulting in metformin accumulation and an increased risk of lactic acidosis.
Metformin must 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 reevaluated and found to be normal (see section 4.4).
Combinations requiring precautions for use: • Diuretics especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function • Medicinal products with intrinsic hyperglycaemic activity as glucocorticoids (systemic or by local route) and sympathomimetics: more frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during the therapy with the respective medicinal products and upon its discontinuation.
Stabilisation of diabetic patients with metformin hydrochloride and insulin should be carried out in hospital because of the possibility of hypoglycaemia, until the correct ratio of the two drugs has been obtained.
Antihypertensives: diazoxide may antagonise the hypoglycaemic effect. Beta-blockers enhance the hypoglycaemic effect and can mask warning signs such as tremors.
ACE inhibitors: possibly enhance the hypoglycaemic effect.
Diuretics: loop diuretics antagonise the hypoglycaemic effect.
Clofibrates: may improve glucose tolerance and have an additive effect Anti-depressants: MAOIs enhance the hypoglycaemic effect.
Corticosteroids: antagonise the hypoglycaemic effect.
Oral contraceptives: antagonise the hypoglycaemic effect.
Reduced renal clearance of metformin hydrochloride has been reported during cimetidine therapy, so a dose reduction should be considered.
As with a number of drugs, an interaction between metformin hydrochloride and anticoagulants is a possibility and dosage of the latter may need adjustment.
Metformin hydrochloride does not lower blood glucose levels in non-diabetics, and does not cause hypoglycaemia in diabetics when used as monotherapy. Weight loss
often occurs during therapy and levels of plasma cholesterol, triglycerides and prebeta-lipoproteins may be lowered. Metformin hydrochloride has been shown to improve peripheral glucose metabolism.
4.6 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. 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.
Lactation:
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants.
However, as only limited data are available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breastfeeding should be made, taken into account the benefit of breastfeeding and the potential risk to adverse effects on the child.
Fertility:
Fertility of male or female rats were unaffected by metformin when administered at doses as high as 600mg/kg/day, which is approximately three times the maximum recommended human daily dose on body surface area comparisons.
4.7 Effects on 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 (sulphonylureas, insulin or meglitinides).
4.8 Undesirable effects
The following undesirable effects may occur under treatment with metformin.
Frequencies are defined as follows: very common: >1/1 0; common > 1/100, < 1/1 0; uncommon > 1 /1 ,000, <1/100; rare > 1/10,000, <1/1,000; very rare <1/10,000, not known (cannot be estimated from the available data)
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 be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Skin and subcutaneous tissue disorders:
Very rare: Skin reactions such as erythema, pruritus, urticaria
Metabolism and nutrition disorders:
Very rare: Lactic acidosis (see section 4.4), decrease of vitamin B 12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
Hepatobiliary disorders:
Very rare: Isolated reports of liver function tests 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 to 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 the internet at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks 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 is haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmaceutical group: Blood glucose lowering drug. Biguanides; ATC code: A1OBA02
Metformin 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 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
Metfomin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) 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 reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy:
The prospective randomised study (UKPDS) 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 sulfonyurea 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 montherapy 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 and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Children and adolescents:
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 tablet, maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the nonabsorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin 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 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution:
Plasma protein binding is negligible. Metformin 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 63-276 l.
Metabolism:
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of metformin is> 400 ml/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.
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 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 500 mg 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
Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic, potential and reproductive toxicity.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet Core:
Microcrystalline cellulose Copovidone
Colloidal anhydrous silica Magnesium stearate Film Coating:
Talc
Opadry white OY-L-28900 consisting of: Lactose monohydrate
Hypromellose (viscosity: 15cp) Titanium dioxide, E171 Macrogol 4000
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
No special precautions are necessary.
6.5 Nature and contents of container
Blister packs of 250pm white opaque PVC/PVDC and 20pm aluminium.
Pack sizes of 28, 30, 56, 84 or 120 tablets per pack.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots Cambs PE19 8ET United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0096
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 16 May 2000 Date of latest renewal: 13 March 2009
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DATE OF REVISION OF THE TEXT
07/05/2014