Each film-coated tablet contains 500 mg Metformin hydrochloride.
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via 3 mechanisms: (1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, (2) increasing insulin sensitivity in muscles, improving peripheral glucose uptake and utilization and (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 clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
In humans, independently of its action on glycemia, metformin has favorable 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.
Pharmacokinetics: Absorption: After an oral dose of metformin, maximum plasma concentration (Cmax) is reached in 2.5 hours (Tmax). Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces 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 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/mL, even at maximum doses.
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 in the time to peak plasma concentration were observed. The clinical relevance of these decreases 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 from 63 to 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.
A randomized, open-label bioequivalence study in 16 healthy volunteers showed, on the basis of Cmax and AUC determinations, that one tablet of metformin 1 gram can replace two tablets of metformin 500 mg.
The relative bioavailability of metformin 1 gram compared to metformin 500 mg tablets is 92.6% for AUC and 88% for Cmax.
Toxicology: Preclinical Safety Data: Preclinical safety data revealed no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, on carcinogenic potential, toxicity in reproduction.
Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control. Metformin may be used as as monotherapy or in combination with other oral antidiabetic agents, or with insulin.
Intensive glucose control with metformin as first line therapy in overweight type 2 diabetic patients has been shown to reduce diabetes complications.
Impaired Glucose Tolerance (IGT) for patients in whom lifestyle interventions (diet and exercise) have failed.
Treatment of type 2 diabetes mellitus in children and adolescents from 10 years of age and older.
Unless otherwise prescribed, the dosage and administration is as follows: Adults: Monotherapy and combination with other oral antidiabetic agents: The usual starting dose is one tablet of metformin 500 mg or metformin 850 mg 2 - 3 times daily with or after meals. Metformin must be taken daily without interruption, except if specifically indicated by the doctor. If the patient has forgotten to take metformin, the next dose should be taken at the usual time. Do not double the dose of metformin. If the patient has taken more metformin tablets than indicated, the doctor or pharmacist must be consulted immediately.
After 10 to 15 days the dose may be slowly increased by an increment of one tablet depending on blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.
In patients receiving a high metformin dose (2 to 3 grams per day), it is possible to replace two metformin 500 mg tablets with one metformin 1 gram tablet. The maximum recommended dose of metformin is 3 g daily, taken as 3 divided doses.
If transfer from another oral antidiabetic 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. Unless otherwise prescribed, metformin is given at the usual starting dose of one tablet of metformin 500 mg or metformin 850 mg 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 subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see Precautions).
Children and adolescents: Monotherapy and combination with insulin: Metformin 500 mg, 850 mg and 1 gram tablet can be used in children from 10 years of age and adolescents. Unless otherwise prescribed, the usual starting dose is one tablet of 500 mg or 850 mg once daily, given during meals or after meals. After 10 to 15 days the dose may be slowly increased by an increment of one tablet depending on the basis of blood glucose measurements.
A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin is 2 g daily, taken as 2 or 3 divided doses.
Hypoglycemia has not been seen with metformin 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 a hospital. The most effective way to remove lactate and metformin from the blood is hemodialysis.
Metformin must not be used in the following cases: Known hypersensitivity to metformin hyrdrochloride or to any of the excipients.
Severe destabilization of diabetes with either pre-coma or ketoacidosis (a condition caused by substances called 'ketone bodies' accumulating in the blood; symptoms include stomach pain, fast and deep breathing, sleepiness or unusual fruity odor of the breath.
Renal insufficiency, even if moderate (impairment of kidney function with increased blood creatinine levels or decreased creatinine clearance <60 mL/min).
Acute conditions with the potential to alter renal functions such as: Dehydration due to persistent or severe diarrhea, recurrent vomiting; Severe infection (for example, respiratory tract infection, urinary tract infection); Following an X-ray examination involving the use of iodinated contrast media (for example, intravenous urography, angiography).
Elective major surgery, see Precautions.
Acute or chronic disease which may cause tissue hypoxia such as cardiac failure, recent myocardial infarction, respiratory insufficiency, shock.
Hepatic insufficiency (impaired liver function).
Acute alcohol intoxication, alcoholism (excessive consumption of alcoholic beverages).
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: This risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramp with digestive disorders as abdominal pain and severe asthenia.
This can be followed by acidotic dyspnea, abdominal pain, hypothermia and 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 hospitalized immediately (see Overdosage).
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 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 or diuretic therapy and when starting with a non-steroidal anti-inflammatory drug (NSAID).
Administration of iodinated contrast media: The intravascular administration of iodinated contrast media in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Therefore metformin must be discontinued 48 hours before the test 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 Interactions).
Surgery: Metformin must be discontinued 48 hours before elective major surgery. 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: Avoid consumption of alcoholic beverages.
Patients have to inform their doctor of any other treatment they are receiving and of any infectious diseases such as influenza, respiratory tract infection or urinary tract infection.
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 hypogylcemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).
Effect on ability to drive and use machines: Metformin monotherapy does not cause hypoglycemia and therefore has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents (e.g. sulfonylureas, insulin or meglitinides).
Use in 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 on the effect on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.
Use in 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 hepatic children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children particular caution is recommended when prescribing to children aged between 10 and 12 years.
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 fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical and Safety Data under Actions). However, 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 risk of malformations of the fetus.
Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborn/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, taking into account the benefit of breastfeeding and potential risk to adverse effects on the child.
Treatment with metformin. Frequencies are defined as follows: very common ≥1/10; common ≥1/100, <1/10; uncommon ≥1/1,000, <1/100; rare ≥1/10,000, <1/1,000; very rare <1/10,000.
Metabolism and nutrition disorders:
Very rare: Lactic acidosis (see Precautions). Decrease of vitamin B12
absorption with decrease of serum levels during long-term use of metformin. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia.
Nervous system disorders:
Common: Taste disturbance.
Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhea, 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.
Very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
Skin and subcutaneous tissue disorders:
Very rare: Skin reactions such as erythema, pruritus, urticaria.
Patients must report any undesirable or distressing effect to their doctor or pharmacist. To prevent serious reactions, they must consult their doctor immediately, if an undesirable effect is severe, occurred suddenly or gets worse rapidly.
Contraindicated combinations: Iodinated contrast materials: Depending on the renal function, metformin must be discontinued 48 hours before the test or from the time of the test and may not be reinstituted until 48 hours afterwards (see Contraindications and Precautions).
Concomitant use not recommended: Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication particularly in case of: fasting or malnutrition; hepatic insufficiency.
Avoid consumption of alcohol and alcohol-containing medications.
Combinations requiring precautions for use: Medicinal products with intrinsic hyperglycemic activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics): More frequent blood glucose monitoring may be required especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.
Diuretics, especially loop diuretics: They may increase the risk of lactic acidosis due to their potential to decrease renal function.
Store at temperatures not exceeding 30°C.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.