Aurobindo Metformin Hydrochloride Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

Metformin Tablets BP 500 mg, 850 mg and 1000 mg

Rx Only

 

NAME OF DRUG PRODUCT

Metformin Tablets BP 500 mg, 850 mg and 1000 mg.

 

(TRADE) NAME OF PRODUCT

Metformin Tablets BP 500 mg.

Metformin Tablets BP 850 mg.

Metformin Tablets BP 1000 mg.

 

STRENGTH

500 mg,  850 mg and 1000 mg.

 

PHARMACEUTICAL DOSAGE FORM

Tablet

 

QUALITATIVE AND QUANTITATIVE COMPOSITIONS

Metformin Tablets BP 500 mg

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 500 mg.

 

Metformin Tablets BP 850 mg.

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 850 mg

 

Metformin Tablets BP 1000 mg.

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 1000 mg.

 

PHARMACEUTICAL FORM

Metformin Tablets BP 500 mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘60’ debossed on the other side.

Metformin Tablets BP 85O mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘61’ debossed on the other side.

Metformin Tablets BP 1000 mg: White, biconvex, oval shaped film coated tablets with a scoreline in between ‘6’ and’2’ on one side and ‘A’ debossed on the other side.

 

CLINICAL PARTICULARS

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 film-coated tablets 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 film-coated tablets 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 (Pharmacodynamic properties).

 

Posology and method of administration

The maximum recommended daily dose of Metformin is 3000 mg in adults and 2000 mg in pediatric patients (10-16 years of age). Metformin is not recommended in patients below the age of 10 years. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

 

Adults

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin may be given to a maximum daily dose of 3000 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.

Monotherapy and combination with other oral antidiabetic agents:

The usual starting dose is one tablet 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 is 3000 mg daily.

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 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 in elderly, the Metformin dosage should be djusted based on renal function. Regular assessment of renal function is necessary.

 

Children and adolescents

The usual starting dose of Metformin is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Monotherapy and combination with insulin:

Metformin film-coated tablets can be used in children from 10 years of age and adolescents. Metformin is not recommended in patients below the age of 10 years.
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 dose of Metformin is 2 g daily, taken as 2 or 3 divided doses.

 

Pregnancy

Metformin is not recommended for use in pregnancy.

 

Contraindications

– Hypersensitivity to Metformin hydrochloride or to any of the excipients.

– Diabetic ketoacidosis, diabetic pre-coma.

– Renal failure or renal dysfunction (creatinine clearance < 60 ml / min).

– Acute conditions with the potential to function such as dehydration, severe shock, intravascular administration of contrast agents.

– 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.

– Lactation.

 

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. Lactic acidosis on Metformin may occur 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:

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.

 

Renal function

As Metformin 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.

Decreased renal function in elderly 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.

Administration of iodinated contrast agent:

As the intravascular administration of iodinated contrast materials may lead to renal failure, Metformin should be discontinued prior to or at the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Surgery:

Metformin hydrochloride should be discontinued 46 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.

 

Children and adolescents

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with Metformin is initiated. A careful follow-up of the effect of Metformin in metformin-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

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 alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas.

 

Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended:

Alcohol

Increased risk of lactic acidiosis in acute alcohol intoxication, particularly in case of:

– fasting or malnutrition

– hepatic insufficiency

Avoid consumption of alcohol and alcohol-containing medications.

 

Iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in Metformin accumulation and a risk of lactic acidosis.

Metformin should be discontinued prior to or at the time of the test and not reinstituted until 48 hours afterwards and only after renal function has been evaluated and found to be normal.

 

Combinations requiring precautions for use

Glucocorticoids (systemic and local routes), beta-2-agonists and diuretics have intrinsic hyperglycaemic activity. 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.
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

 

Pregnancy and lactation

When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with Metformin 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.

 

Effects on ability to drive and use machines

Metformin monotherapy does not cause hpoglycaemia 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, repaglinide).

 

Undesirable effects

The following undesirable effects may occur under treatment with Metformin.

Frequencies are defined as as follows: very common: >1/10; common >1/100, <1/10; uncommon >1/1000, <1/100; rare >1/10000, <1/1000; very rare <1/10000.

Metabolism and nutritional disorders:

Very rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of Metformin. Consideration of such aetiology is recommended if a patient presents with megaloplastic anaemia.

Very rare: Lactic acidosis

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.

 

Overdosage

Hypoglycaemia may not be seen with Metformin doses of up to 85 g, although lactic acidosis may occur in such circumstances. High overdose or concomitant risks of Metformin 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.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

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 utilization.

(3) Delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).

In humans, independently of its action on glycaemia, Metformin has favourable effects on lipid metabolism. Metformin reduces total cholesterol, LDL, chlesterol and triglyceride level.

 

Pharmacokinetic properties

Absorption:

After an oral dose of Metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg Metformin tablet is approximately 50-60%. After an oral dose, the non absorbed 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 usual Metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 mg/ml.

Food decreases the extent and slightly delays the absorption of Metformin. 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 occurs.

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 Vd ranged between 63-276l.

Metabolism:

Metformin is excreted unchanged in the urine.

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.

 

PHARMACEUTICAL PARTICULARS

List of excipients

Povidone, Magnesium stearate, Opadry, and Purified water.

 

Incompatibilities

None known.

 

Shelf life

48 months.

 

Special precautions for storage

Do not store above 30°C.

 

Nature and contents of container

Blister pack:

Metformin Tablets BP 500 mg and 850 mg : Blister of 14 tablets.

Metformin Tablets BP 1000 mg: Blister of 10 tablets.

 

HDPE container pack:

Metformin Tablet BP 500 mg and 850 mg: 100; 400 & 1000 tablets.

Metformin Tablets BP 1000mg : 60, 100 & 500 tablets.

 

MARKETING AUHORISATION HOLDER

Aurobindo Pharma Limited,

Plot NO.: 2, Maitrivihar,

Ameerpet, Hyderabad-500 038

Andhra Pradesh, India.

 

DATE OF PREPARATION OF THIS LEAFLET

February 2009.