Instructions for Metformin-Astrapharm film-coated tablets 500 mg No. 90
Composition
active ingredient: metformin;
1 tablet contains metformin hydrochloride 500 mg or 850 mg or 1000 mg;
excipients: povidone, magnesium stearate; coating: hypromellose 2910, 5sPz; PEG 6000;
titanium dioxide.
Dosage form
Film-coated tablets.
Main physicochemical properties:
500 mg tablets: round tablets with a biconvex surface, coated with a white film coating;
850 mg tablets: oval-shaped tablets with a biconvex surface, coated with a white film coating;
1000 mg tablets: oval-shaped tablets with a biconvex surface, film-coated in white, with a score on one side.
Pharmacotherapeutic group
Hypoglycemic agents, except insulins. Biguanides. ATC code A10B A02.
Pharmacological properties
Pharmacodynamics.
Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after a meal. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.
Metformin works in three ways:
– leads to a decrease in glucose production in the liver due to inhibition of gluconeogenesis and glycogenolysis;
– improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization;
– delays the absorption of glucose in the intestine.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).
Independently of its effect on glycemia, metformin has a positive effect on lipid metabolism. Metformin reduces total cholesterol, low-density lipoproteins, and triglycerides.
During the studies, patients' body weight remained stable or moderately decreased while taking metformin.
Pharmacokinetics.
Absorption. After oral administration of metformin, the time to peak concentration is approximately 2.5 hours. The absolute bioavailability of metformin as a 500 mg or 850 mg tablet is approximately 50-60% in healthy volunteers. After oral administration, the fraction that is not absorbed and is excreted in the feces is 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete.
The pharmacokinetics of metformin absorption are assumed to be non-linear. At recommended metformin doses and dosing regimens, steady-state plasma concentrations are achieved within 24-48 hours and are less than 1 μg/mL. In studies, maximum metformin plasma levels did not exceed 5 μg/mL even at maximum doses.
When taken with food, the absorption of metformin is reduced and slightly delayed.
Following oral administration of an 850 mg dose, there was a 40% decrease in peak plasma concentration, a 25% decrease in area under the concentration-time curve, and a 35-minute increase in time to peak plasma concentration. The clinical significance of these changes is unknown.
Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and are reached at approximately the same time. Erythrocytes are likely to represent a second distribution compartment. The mean volume of distribution ranges 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. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.
Indication
Type 2 diabetes mellitus, with ineffective diet therapy and exercise regimen, especially in patients with excess body weight:
– as monotherapy or combination therapy in combination with other oral hypoglycemic agents or in combination with insulin for the treatment of adults.
– as monotherapy or combination therapy with insulin for the treatment of children aged 10 years and older.
To reduce the complications of diabetes in adult patients with type 2 diabetes mellitus and overweight, as a first-line drug after ineffective diet therapy.
Contraindication
– Hypersensitivity to metformin or any other component of the drug;
– diabetic ketoacidosis, diabetic precoma;
– moderate (stage IIIb) and severe renal failure or impaired renal function (creatinine clearance (CC) 45 ml/min, or glomerular filtration rate (GFR) 2);
– diseases that can lead to the development of tissue hypoxia (especially acute diseases or exacerbation of a chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
– liver failure, acute alcohol poisoning, alcoholism.
Interaction with other medicinal products and other types of interactions
Combinations that are not recommended for use.
Alcohol: Acute alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or low-calorie diet, and in patients with hepatic insufficiency. Alcohol and alcohol-containing medications should be avoided during metformin treatment.
Iodinated radiocontrast agents: Intravenous use of iodinated radiocontrast agents may lead to renal failure and, as a result, metformin accumulation and an increased risk of lactic acidosis.
In patients with a GFR > 60 mL/min/1.73 m2, metformin should be discontinued prior to or at the time of the test and not resumed until 48 hours after the test and only after re-evaluation of renal function and confirmation of no further deterioration in renal status.
In patients with moderate renal impairment (GFR 45-60 mL/min/1.73 m2), metformin should be discontinued 48 hours prior to the administration of iodinated radiocontrast agents and not resumed until 48 hours after the examination, only after re-evaluation of renal function and confirmation of no further deterioration of renal function.
Combinations that should be used with caution.
Drugs that have a hyperglycemic effect (glucocorticosteroids of systemic and local action, sympathomimetics). It is necessary to monitor the blood glucose level more often, especially at the beginning of treatment. During and after discontinuation of such concomitant therapy, it is necessary to adjust the dose of Metformin-Astrapharm.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to possible decreased renal function.
Application features
Lactic acidosis is a very rare but serious metabolic complication (high mortality rate in the absence of urgent treatment) that may occur as a result of metformin hydrochloride accumulation. Cases of lactic acidosis have been reported in diabetic patients with renal failure or acute deterioration in renal function. Caution should be exercised in cases where renal function may be impaired, for example in cases of dehydration (severe diarrhea or vomiting), or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). In the event of these exacerbations, metformin should be temporarily discontinued.
Other risk factors should be considered to avoid the development of lactic acidosis: poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction).
Lactic acidosis may present with muscle cramps, indigestion, abdominal pain and severe asthenia. Patients should immediately inform their doctor of the occurrence of such reactions, especially if they have previously tolerated metformin well. In such cases, metformin should be temporarily discontinued until the situation is clarified. Metformin therapy should be resumed after assessing the benefit/risk ratio in each individual case and assessing renal function.
Diagnostics. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, and coma may develop later. Diagnostic indicators: laboratory decrease in blood pH, increase in serum lactate concentration above 5 mmol/L, increase in anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be hospitalized immediately. The doctor should warn patients about the risk of developing and symptoms of lactic acidosis.
Renal insufficiency. Since metformin is excreted by the kidneys, creatinine clearance (estimated by plasma creatinine using the Cockcroft-Gault formula) or GFR should be checked before starting and regularly during metformin treatment:
– patients with normal kidney function – at least once a year;
– patients with creatinine clearance at the lower limit of normal and elderly patients – at least 2-4 times a year.
In the case of CC 2), the use of metformin is contraindicated.
Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure.
Iodinated radiocontrast agents. Intravenous administration of radiocontrast agents for radiological examinations may cause renal failure, and consequently lead to metformin accumulation and an increased risk of lactic acidosis. In patients with a GFR > 60 mL/min/1.73 m2, metformin should be discontinued prior to or at the time of the examination and not resumed until 48 hours after the examination and only after re-evaluation of renal function and confirmation of no further deterioration of renal function.
In patients with moderate renal impairment (GFR 45-60 ml/min/1.73 m2), metformin should be discontinued 48 hours before the administration of iodinated radiocontrast agents and not resumed earlier than 48 hours after the examination and only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal status.
Surgery: Metformin should be discontinued 48 hours before elective surgery under general, spinal or epidural anaesthesia and should not be restarted until 48 hours after surgery or resumption of oral nutrition and only if renal function has returned to normal.
Children. Type 2 diabetes mellitus should be confirmed before starting metformin treatment. Studies have not shown an effect of metformin on growth and puberty in children. However, there is no data on the effect of metformin on growth and puberty with longer-term use of metformin, so careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.
Children aged 10 to 12 years. Studies have shown that the efficacy and safety of metformin in children aged 10 to 12 years do not differ from that in older children. The drug should be prescribed with particular caution in children aged 10 to 12 years.
Other precautions: Patients should follow a diet with a balanced carbohydrate intake throughout the day. Overweight patients should continue to follow a low-calorie diet. Patients' carbohydrate metabolism should be monitored regularly.
Metformin monotherapy does not cause hypoglycemia, but caution should be exercised when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g. sulfonylureas or meglitinides).
Use during pregnancy or breastfeeding
Pregnancy.
Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. Limited data on the use of metformin in pregnant women do not indicate an increased risk of congenital anomalies. Preclinical studies have not revealed any adverse effects on pregnancy, embryonal or foetal development, labour and postnatal development. In cases of planning pregnancy and in cases of pregnancy, it is recommended to use insulin, not metformin, to maintain blood glucose levels as close to normal as possible in order to reduce the risk of foetal malformations.
Breast-feeding.
Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. A decision on whether to discontinue breastfeeding should be made taking into account the benefit of breastfeeding and the potential risk of adverse effects to the child.
Fertility.
Metformin did not affect animal fertility at doses of 600 mg/kg body weight per day, which is almost 3 times the maximum recommended daily human dose based on body surface area.
Ability to influence reaction speed when driving vehicles or other mechanisms
Metformin monotherapy does not affect the reaction speed when driving or using other mechanisms, since the drug does not cause hypoglycemia. However, caution should be exercised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin or meglitinides) due to the risk of hypoglycemia.
Method of administration and doses
Adults.
Monotherapy or combination therapy compatible with other oral hypoglycemic agents.
Usually the starting dose is 500 mg or 850 mg 2-3 times a day during or after meals.
After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
The maximum recommended dose is 3000 mg per day in 3 divided doses.
If switching from another antidiabetic agent, this agent should be discontinued and metformin should be prescribed as described above.
Combination therapy is compatible with insulin.
To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2-3 times daily, while the insulin dose should be adjusted according to blood glucose measurements.
Children.
Monotherapy or combination therapy compatible with insulin.
Metformin-Astrapharm is used in children aged 10 years and older. The usual starting dose is 500 mg or 850 mg of metformin once daily with or after meals. After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
The maximum recommended dose is 2000 mg per day in 2-3 doses.
Elderly patients may have decreased renal function, so the dose of metformin should be selected based on assessment of renal function, which should be performed regularly.
Patients with renal failure.
Metformin can be used in patients with moderate renal insufficiency, stage IIIa (CC 45-59 ml/min or GFR 45-59 ml/min/1.73 m2), only in the absence of other factors increasing the risk of lactic acidosis, with subsequent dose adjustment. The initial dose is 500 mg or 850 mg of metformin hydrochloride once a day. The maximum dose is 1000 mg per day and should be divided into 2 doses. Careful monitoring of renal function (every 3-6 months) is necessary.
If CK or GFR decreases to 2, respectively, metformin should be discontinued immediately.
Children.
Metformin-Astrapharm is used in children aged 10 years and older.
Overdose
When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can cause lactic acidosis. Lactic acidosis is an emergency condition that requires treatment in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.
Adverse reactions
The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms in most cases resolve on their own. To prevent the occurrence of these side effects, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses.
Metabolic: lactic acidosis. With prolonged use of the drug, absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood serum. It is recommended to consider this possible cause of hypovitaminosis B12 if the patient has megaloblastic anemia.
From the nervous system: taste disturbance.
From the digestive tract: nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and in most cases disappear spontaneously. To prevent the occurrence of side effects from the digestive tract, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses during or after meals.
On the part of the hepatobiliary system: liver function tests or hepatitis, which completely disappear after metformin withdrawal.
Skin: skin reactions including erythema, pruritus, urticaria.
Expiration date
Film-coated tablets, 500 mg, 850 mg – 5 years.
Film-coated tablets, 1000 mg – 3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister made of polyvinyl chloride film and printed lacquered aluminum foil; 3 or 6 or 9 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"ASTRAPHARM" LLC.
Location of the manufacturer and address of its place of business
08132, Ukraine, Kyiv region, Kyiv-Svyatoshynskyi district, Vyshneve, Kyivska st., 6.
