for medical use
active substance: metformin hydrochloride;
1 tablet containsmetformin hydrochloride 500 mg;
excipients: microcrystalline cellulose, ethyl cellulose, hypromellose, magnesium stearate, colloidal anhydrous silica.
Pharmaceutical form. Sustained-release tablets.
Main physico-chemical properties: white oval tablets, smooth on both sides
Pharmacotherapeutic group. Code АТС А10В А02
Oral hypoglycemic agents, except insulins. Biguanides.
Metformin – is a biguanide with the antihyperglycemic effect. Decreases both baseline and postprandial blood plasma glucose levels. Does not stimulate insulin secretion and has no hypoglycemic effect.
Metformin acts in 3 ways:
1) decreases the glucose production in liver by inhibiting gluconeogenesis and glycogenolysis;
2) improves the capture and utilization of peripheral glucose in muscles by increasing insulin sensitivity;
3) reduces the intestinal absorption of glucose.
Metformin stimulates intracellular glycogen synthesis, affecting on glycogen synthase.
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.
Increases insulin sensitivity of peripheral receptors and glucose utilization by cells.
Inhibits gluconeogenesis in the liver. Inhibits intestinal glucose absorption.
Absorption. After oral administration of the drug as sustained-release tablet time to peak concentration (Тmax) is 7 hours, whereas for immediate-release tablet is - 2.5 hours.
In steady condition the maximum plasma concentration (Cmax) and area under the curve “concentration-time” (AUC) are increased disproportionately to the administered oral dose. After a single 2000 mg oral dose of metformin sustained-release tablets AUC was similar to that, observed after administration of metformin 1000 mg immediate-release tablets 2 times per day.
In administration of metformin sustained-release tablets some people showed Cmax and AUC fluctuation comparable with that of metformin immediate-release tablets.
In administration of sustained-release tablet under fasting conditionAUC is reduced by 30%, but Cmax and Tmax remain unchanged.
Food composition does not affect the absorption of metformin sustained-release tablets. At a multiple dose up to 2000 mg of metformin sustained-release tablets no accumulation was observed.
Distribution. Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood maximum concentration is lower than the plasma maximum concentration and appears at approximately 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. This indicates 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 metformin plasma levels.
Type 2 diabetes mellitus (insulin-independent) in adults (especially in obese patents) in case of ineffective diet therapy and physical activity, as monotherapy or in combination with other oral antidiabetic drugs, or with insulin.
Hypersensitivity to metformin or any other component of the excipients;
diabetic ketoacidosis, diabetic pre-coma;
renal insufficiency or impaired renal function (creatinine clearance < 60 mL/min);
acute conditions, which increase the risk of impaired renal function, such as:
dehydration, severe infectious diseases, shock;
acute and chronic diseases which may cause hypoxia development:
cardiac or respiratory failure, recent myocardial infarction, shock;
impaired hepatic function, acute alcohol intoxication, alcoholism.
Drug interactions and other kinds of interactions.
Combinations that are not recommended for use.
Acute alcohol intoxication is associated with increased risk of lactic acidosis, especially in case of fasting or hypocaloric diet, and impaired hepatic function. During the Metamin SR therapy, avoid consumption of alcohol and alcohol-containing medicinal products.
Radiopaque iodine-containing substances can cause the development of lactic acidosis in patients with diabetes mellitus because of functional renal failure. Metamin® SR must be discontinued prior to the test and not be reinstituted until 48 hours afterwards, using radio-opaque substances and the renal function estimation.
Combinations, requiring precautions for use:
Drugs that have a hyperglycemic activity (glucocorticosteroids of systemic and local routes, sympathomimetics, chlorpromazine). More frequent blood glucose monitoring may be required, especially at the beginning of treatment. During and after the discontinuation of such co-therapy is necessary to adjust the dose of Metamin® SR under the control of glycemic level.
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the drug dosage during co-therapy.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis.
Lactic acidosis is a rare, but serious metabolic complication, that can occur due to metformin hydrochloride accumulation. Cases of lactic acidosis in diabetic patients with significant renal failure were reported. Lactic acidosis associated risk factors: poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition, associated with hypoxia.
Lactic acidosis may occur as the muscle cramps with abdominal pain and severe asthenia. Development of acidotic dyspnea, abdominal pain, hypothermia and coma is possible in future. Diagnostic findings: laboratory decreased blood pH, plasma lactate levels more than 5 mol/l, increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately.
Renal insufficiency. As metformin is excreted by the kidneys, before initiating treatment and during the treatment with Metamin® SR creatinine clearance should be determined in blood plasma:
NLT once a year in patients with normal renal function;
NLT 2-4 times a year in patients with impaired renal function and in elderly subjects.
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 anti-inflammatory drug.
Radiopaque iodine-containing agents. The intravascular administration of radiopaque iodine-containing agents can lead to renal failure, followed by metformin accumulation and development of lactic acidosis. Thus, metformin must be discontinued for 48 hours before or during the test and not be reinstituted until 48 after the test and renal function evaluation.
Surgery. Metformin should be discontinued 48 hours before elective surgery under general, spinal or peridural anesthesia, and therapy should not be resumed earlier than 48 hours after surgery and renal function evaluation.
Other precautions. All patients should keep their diet, a regular distribution of carbohydrate intake during the day and control laboratory parameters. Overweight patients should continue their energy-restricted diet. Laboratory parameters of blood glucose should be controlled regularly.
Metamin® SR in combination with insulin or other oral hypoglycemic agents (e.g. sulphonylureas or meglitinides) may cause strengthening of hypoglycemic action.
Such inactive ingredients as a soft mass in a tablet shape may be presented in feces.This is normal and has no clinical significance.
Administration during pregnancy and lactation.
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality. The limited data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Preclinical studies did not indicate any negative effects on pregnancy, embryonic development, parturition or post-natal development. When planning for pregnancy and during pregnancy, it is recommended to discontinue a therapy with metformin, inform a doctor and prescribe the insulin therapy to maintain the 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® SR treatment. A decision on whether to discontinue breast-feeding should be made, taken into account the necessity of administering the preparation for mother and the potential risk for the child.
Fertility. Fertility of male or female rats was unaffected by metformin when administered at doses of 600 mg/kg/day, that is approximately three times the maximum recommended human daily dose based on body surface area calculation.
Effects on ability to drive and operate machinery.
Metamin® SR does not affect the ability to drive transport and operate other mechanisms, as a drug monotherapy does not provoke hypoglycemia.
However, metformin in combination with other hypoglycemic agents (sulfonylurea derivatives, insulin, repaglinide) should be used carefully due to the risk of hypoglycemia.
Dosage and administration.
Monotherapy or combined therapy with other oral hypoglycemic drugs.
The recommended initial dose is - 1 tablet per day.
After 10-15 days of treatment, the dose should be adjusted according to measurement results of serum glucose level. Slow increasing of dosage helps minimize the adverse effects on the gastrointestinal tract. Maximum recommended dose is 4 tablets per day.
Take a drug dose once per day with meal, increasing it by 500 mg every 10-15 days up to 2000 mg. If necessary level of glycemia cannot be reached by using Metamin® SR at a maximum dose of 2000 mg, taken 1 time per day, this dose may be divided into 2 doses per day (1 in the morning and 1 in the evening, with the meal). If the desired level of glycemia is not reached, you can use Metamin®, coated tablets, at maximum recommended dose of 3000 mg per day.
For patients already treated with metformin, the initial dose of Metamin®SR, sustained-release tablets should be equivalent to the daily dose of immediate release tablets.
When changing the treatment to Metamin® SR sustained-release tablets, 500 mg the administration of other antidiabetic drug should be discontinued.
Combined therapy with insulin.
To achieve a better glucose blood level control, metformin and insulin should be used as a combined therapy. Usually, the initial dose of Metamin®SR is 1 tablet per day with the evening meal, and then the dose of insulin should be adjusted according to the measurement results of serum glucose level.
In elderly patients renal function impairment is possible, therefore, the dose of metformin should be adjusted according to the renal function evaluation, which should be held regularly (see "Peculiarities of use").
Do not use the drug in children, as there are no clinical data for patients of this age group.
Hypoglycaemia was not observed with the drug doses of up to 85 g. Although lactic acidosis was occurred in such circumstances. In the case of lactic acidosis development, Metamin® SR therapy should be discontinued 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 administration of the drug in patients with megaloblastic anemia may decrease the absorption of vitamin B12, followed by decreasing of its serum level.
Nervous system disorders: taste disorders.
Gastrointestinal tract disorders: nausea, vomiting, diarrhea, abdominal pain, anorexy. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the drug dose is recommended to avoid the adverse effects from gastrointestinal tract.
Hepatobiliary system disorders: impaired liver functions or hepatitis, which totally disappear after metformin discontinuation.
Skin and subcutaneous tissue disorders: skin allergic reactions, including rash, erythema, itching, urticaria.
Store at a temperature MNT 25 °С in a dry place, protected from sunlight.
Keep out of reach of children.
7 tablets in a blister; 4 blisters in a carton.
15 tablets in a blister, 2 or 6 blisters in a carton.
Conditions of supply.
“KUSUM PHARM” LTD.
54 Skryabina St., Sumy 40030, Ukraine.
Last revision date.
№67 dated 23.01.14