Metformin is a biguanide with antihyperglycemic effect. Decreases baseline plasma glucose and plasma glucose after meal. Does not stimulate insulin secretion, and has no hypoglycemic effect.
Metformin acts in 3 ways:
– decreases the production of glucose in the liver by inhibiting gluconeogenesis and glycogenolysis;
– increase insulin sensitivity in muscles by improving the capture and utilization of peripheral glucose;
– slows down the intestinal absorption of glucose.
Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthetase.
Increases transport capacity of all types of membrane glucose transporters (GLUT).
Regardless of its effect on glycemia, metformin shows positive effect on lipid metabolism: reduces total cholesterol, low density lipoproteins and triglycerides.
During clinical studies, body weight of individuals on metformin tended to remain stable or even decrease somewhat. Besides action on glycemia, metformin has a positive effect on lipid metabolism. controlled, medium-and long-term clinical studies indicated that metformin at therapeutic doses total cholesterol, low density lipoproteins and triglycerides.
Absorption. After oral administration, metformin is almost completely absorbed in gastrointestinal tract; 20-30 % is excreted in faeces. Time to reach maximum concentration (Тmax) is 2.5 hours. Absolute bioavailability is around 50-60%.
When used along with meal, the rate of metformin absorption is reduced and slowed.
Distribution. Blood plasma protein binding is negligible. Metformin penetrates into erythrocytes. Cmax in blood is lower than Cmax in plasma, and is reached approximately in the same time. Erythrocytes 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 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.
Type 2 diabetes mellitus (insulin-independent) in case of ineffective diet therapy,
– in adults as monotherapy or in combination with other oral hypoglycemic drugs or with insulin in adults;
– in children older than 10 years 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.
– Hypersensitivity to metformin or any other component of the drug;
Drug interactions and other kinds of interactions.
Combinations that are not recommended to use.
Acute alcohol intoxication is associated with increased risk of lactic acidosis, especially in case of fasting or hypocaloric diet, and hepatic failure. During Metamin® therapy, avoid using alcohol or any alcohol containing drugs.
Radiocontrast iodine-containing products may provoke lactic acidosis in patients with diabetes mellitus at the background of functional renal failure. Metamin® should be stopped before the examination, and restarted not earlier than in 48 hours, after the examination with radiocontrast iodine-containing products.
Combinations requiring precaution.
Medications which may induce hyperglycemia (glucocorticoids of systemic and local routes, sympathomimetics,chlorpromazine). Perform more frequent blood glucose monitoring, especially at the beginning of treatment. Adjust the dosage of the Metamin® during therapy with the other medicinal product and upon its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary during combination therapy.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis.
Peculiarities of use.
Lactic acidosis is a rare and severe metabolic complication, which may be caused by accumulation of metformin hydrochloride. There are cases of lactic acidosis in patients with diabetes mellitus and severe hepatic failure. Risk factors for lactic acidosis are: uncontrolled diabetes, ketose, continuous fast, alcohol abuse, hepatic failure and hypoxia-related conditions.
Lactic acidosis is characterized by muscle convulsions with abdominal pain and severe asthenia. Later acidotic dyspnea, abdominal pain, hypothermia and coma are possible. Diagnostic laboratory findings are decreased blood pH, serum lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, the drug should be discontinued and the patient should be hospitalized immediately.
Hepatic failure. As metformin is renally excreted, serum creatinine levels should be determined before initiating treatment and during Metamin® therapy:
- at least annually in patients with normal renal function;
- at least two or four times a year in patients with impaired renal function and in elderly subjects.
Caution should be exercised in case of possible impairment of renal function, e.g. at the beginning of treatment with antihypertensive agents, diuretics, during therapy with nonsteroidal anti-inflammatory drugs.
Radiocontrast iodine-containing products. The intravascular administration of radiocontrast materials can lead to renal failure, and as a result, lead to accumulation of metformin and the development of lactic acidosis.Therefore, depending on the kidneys function, metformin should be discontinued 48 hours 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.
Surgical interventions. Metamin® should be discontinued 48 hours before the planned surgical intervention, performed with general, spinal or epidural anesthesia, and restarted not earlier than in 48 hours, after performing the surgery and evaluation of renal function.
Children. No effect of metformin on growth and puberty has been detected in children. But no long-term data on effect of metformin on growth and puberty are available, therefore, special caution should be exercised when using the drug in children during puberty, especially in children aged 10 to 12 years.
Other precautions. All patients should continue their diet with a regular distribution of carbohydrate intake during the day and control the laboratory parameters. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for blood glucose levels should be performed regularly. In co-administration of Metamin® with insulin or other oral hypoglycemic agents (e.g. sulfonylurea or meglitinide), hypoglycemic action may increase.
The presence of tablet coating fragments in feces is possible. This is normal and has no clinical significance.
In case of intolerance of some sugars one should consult a doctor before administration of this drug, because it contains lactose.
Pregnancy and lactation.
Uncontrolled diabetes during pregnancy (gestational or chronic) increases the risk of congenital anomalies and perinatal mortality. There is limited data about administration of metformin in pregnant women, which do not indicate an increased risk of congenital abnormalities. Preclinical studies do not indicate harmful effects with respect to pregnancy, embryonic development, parturition or postnatal development. When planning pregnancy or in case of becoming pregnant, the metformin therapy should be stopped, one should inform the physician and insulin therapy is recommended to maintain blood glucose levels.
Lactation. Metformin is excreted into breast milk. No adverse effects were observed in newborns/infants. However, as only limited data of safety drug administration are available, breastfeeding is not recommended during Metamin® treatment. A decision on whether to discontinue breast-feeding should be made taking into account the necessity of administering the drug for mother and the potential risk for the child.
Fertility. Fertility of male or female was unaffected by metformin when administered at doses of 600 mg/kg/day, that is approximately three times higher than the maximum recommended human daily dose based on body surface area calculation.
Effects on ability to drive and operate machinery.
Metamin® has no effect on the ability to drive or to use machines since monotherapy does not cause hypoglycaemia.
Metformin should be administered carefully in combination with other hypoglycemic agents (sulfonylurea derivatives, insulin, repaglinide) due to the risk of hypoglycemia.
Dosage and administration.
Monotherapy and combined therapy with other oral hypoglycemic agents.
Adults. The usual initial dose is 500 mg or 850 mg (Metamin®, coated tablets, 500 mg or 850 mg) 2-3 times per day during or after meal.
After 10-15 days of treatment, the dose should be adjusted according to the results of measuring serum glucose level.
Slow increase of the dosage helps minimize adverse effects on the gastrointestinal tract.
Maximum recommended dose is 3000 mg per day, divided in 3 doses.
For treatment with high doses, Metamin® coated tablets 1000 mg are used.
When changing to Metamin®other antidiabetic drug should be stopped.
Combination with insulin.
To achieve a better glucose level control, metformin and insulin should be used as a combined therapy. The usual initial dose is 500 mg or 850 mg of Metamin® 2-3 times per day, while the dose of insulin is adjusted individually according to serum glucose level.
Monotherapy or combined therapy with insulin.
Children. The drug Metamin® is used in children older than 10 years. The usual initial dose is 500 mg or 850 mg of Metamin® 1 time per day after meal. After 10-15 days of treatment, the dose should be adjusted according to serum glucose level.
Slow increase of the dosage helps minimize adverse effects on the gastrointestinal tract.
Maximum recommended dose is 2000 mg per day, divided in 2-3 doses.
In elderly patients renal function impairment is possible, therefore, the dose of metformin should be adjusted according to assessment of renal function, which should be held regularly (see “Peculiarities of use”).
Children. The drug Metamin® is used in children older than 10 years.
Hypoglycemia was not observed when using metformin at a dose of 85 g. But in this case lactic acidosis was observed. In case of lactic acidosis, Metamin® therapy should be stopped and the patient should be hospitalized immediately. The most effective method to remove lactate and metformin from the organism is hemodialysis.
Metabolism and nutrition disorders: lactic acidosis.
Long-term drug administration in patients with megaloblastic anemia may decrease the absorption of vitamin B12, which is accompanied by reducing its level in the blood serum.
Nervous system: dysgeusia.
Gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, anorexia. Most of these side effects occur at the beginning of treatment and usually disappear spontaneously. To avoid gastrointestinal adverse effects, it is recommended to increase the dose slowly and use the drug during or after meal 2-3 times per day.
Hepatobiliary system: impaired liver functions or hepatitis, which completely disappear after withdrawal of metformin
Skin and subcutaneous tissue: allergic skin reactions, including rash, erythema, itching, urticaria.
Store below 25°С in a dry place. Protect from sunlight.
Keep out of reach of children.
Tablets 500 mg, 850 mg: 10 tablets in a blister. 3 or 10 blisters in a carton.
Tablets 1000 mg: 15 tablets in a blister. 2 or 6 blisters in a carton.
Conditions of supply. On prescription.
LLC “KUSUM PHARM”.
54 Skryabina St., Sumy 40030, Ukraine.
Last revision date.
No. 67 of 23.01.14
type 2 diabetes mellitus (insulin-independent) in case of ineffective diet therapy,
in adults as monotherapy or in combination with other oral hypoglycemic drugs or insulin;
in children older than 10 years as monotherapy or in combination with insulin.