Metformin-Astrapharm film-coated tablets 1000 mg No. 90

Instructions for Metformin-Astrapharm film-coated tablets 1000 mg No. 90

Composition

active ingredient: metformin hydrochloride;

1 tablet contains metformin hydrochloride 1000 mg;

excipients: core: povidone K-30, silicon dioxide colloidal anhydrous, magnesium stearate; film coating*: hypromellose (2910/5), titanium dioxide (E 171), macrogol (type 400).

*Opadry Y-1-7000H White or Aquarius™ Prime BAP318014 White or a film coating of the same qualitative and quantitative composition but under a different trade name may be used.

Dosage form

Film-coated tablets.

Main physicochemical properties: white or almost white oval tablets, film-coated, with scores on both sides, embossed with "9" to the left and "3" to the right of the score on one side, "72" to the left and "14" to the right of the score on the other side.

The score is intended solely for ease of swallowing and not for dividing the tablet into two equal doses.

Pharmacotherapeutic group

Oral hypoglycemic agents, excluding insulins. ATX code A10B A02.

Pharmacological properties

Pharmacodynamics.

Metformin hydrochloride is an antidiabetic drug of the biguanide group that lowers fasting and postprandial blood glucose levels. It does not stimulate insulin secretion and does not cause hypoglycemic effects mediated by this mechanism.

Metformin hydrochloride has three mechanisms of antidiabetic action.

1. Reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis.

2. Increases insulin sensitivity in muscles, enhancing glucose uptake and utilization in peripheral tissues.

3. Reduces glucose absorption in the intestines.

Metformin hydrochloride stimulates intracellular glycogen synthesis; increases the transport capacity of all types of transport systems that carry glucose across the cell membrane; has a positive effect on lipid metabolism. It has been proven that metformin in therapeutic doses reduces the concentration of total cholesterol, low-density lipoproteins and triglycerides.

It has been reported that patients' body weight remained stable or decreased moderately while taking metformin.

Pharmacokinetics.

Absorption. After oral administration of metformin, the time to maximum concentration (Tmax) is approximately 2.5 hours. The absolute bioavailability of 500 mg or 850 mg tablets is approximately 50-60%. 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. When using the recommended doses of metformin and following the dosing regimen, steady-state plasma concentrations are achieved within 24-48 hours and are less than 1 μg/ml. The maximum plasma concentration of metformin (Cmax) did not exceed 5 μg/ml even when using maximum doses.

With simultaneous use of food, the absorption of metformin is reduced and slightly slowed down.

Following oral administration of an 850 mg dose, there was a 40% decrease in peak plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to peak plasma concentration. The clinical significance of these changes is unknown.

Distribution. Metformin is poorly bound to plasma proteins. Metformin penetrates into erythrocytes. The maximum concentration in the blood is lower than the maximum concentration in plasma and is reached after approximately the same time. Erythrocytes are most likely to represent a second distribution chamber. The mean volume of distribution (Vd) is 63-276 l.

Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination. Renal clearance of metformin is over 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 renal impairment, renal clearance decreases in proportion to creatinine clearance, resulting in a prolonged half-life. This results in increased plasma metformin concentrations.

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 and adolescents.

Reduction of diabetic complications in overweight adult patients with type 2 diabetes mellitus who used metformin as first-line therapy after ineffective diet therapy.

Contraindication

Hypersensitivity to metformin or any other component of the drug.

Any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis).

Diabetic precoma.

Severe renal failure (GFR

Acute conditions that occur with the risk of developing kidney dysfunction:

− dehydration of the body;

− severe infectious diseases;

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 intoxication, alcoholism.

Interaction with other medicinal products and other types of interactions

Not recommended combinations.

Alcohol: Acute alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or low-calorie dieting, and in cases of impaired liver function. Alcohol and alcohol-containing medications should be avoided during treatment with metformin.

Iodinated radiocontrast agents: Intravenous administration of iodinated radiocontrast agents may lead to renal failure and, as a result, metformin accumulation and an increased risk of lactic acidosis.

Metformin should be discontinued prior to or during the examination and should not be resumed until 48 hours after the examination, and only after renal function has been re-evaluated and determined to be stable (see section 4.4).

Combinations that should be used with caution.

Some medicinal products may adversely affect renal function, increasing the risk of lactic acidosis, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase II (COX) inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. At the beginning of therapy, the concomitant use of these medicinal products in combination with metformin requires careful monitoring of renal function.

Medicinal products with hyperglycaemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the start of treatment. Metformin dose should be adjusted during and after discontinuation of such concomitant therapy.

Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to possible decreased renal function.

Application features

Lactic acidosis. Lactic acidosis is rare but is a serious metabolic complication (high mortality rate if not treated promptly), most commonly occurring as a result of acute renal failure, cardiorespiratory disease or sepsis. Acute renal failure leads to metformin accumulation, thereby increasing the risk of lactic acidosis. Cases of lactic acidosis have been reported mainly in diabetic patients with significant renal impairment. The incidence of lactic acidosis can be reduced by controlling and continuously reassessing risk factors such as poor diabetic control, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency and any conditions associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see section "Contraindications").

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), metformin should be temporarily discontinued and a doctor consulted.

Patients taking metformin should be cautious when using medications that may cause acute renal impairment (such as antihypertensives, diuretics, NSAIDs).

The physician should warn patients and caregivers about the risk of lactic acidosis, which may manifest as the following signs: acidotic breathing (Kussmaul breathing), abdominal pain, muscle cramps, asthenia and hypothermia with subsequent development of coma. If the above signs occur, metformin should be discontinued and medical attention should be sought immediately.

Laboratory markers of lactic acidosis include: decreased blood pH (below 7.35), increased serum lactate concentration (above 5 mmol/L), increased anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be hospitalized immediately (see section "Overdose").

Lactic acidosis may present with non-specific symptoms such as 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 these cases, metformin should be temporarily discontinued until the situation is clarified. Metformin therapy should only be resumed after an assessment of the benefit/risk ratio in each individual case and after assessment of renal function.

Decreased renal function is common in the elderly and is asymptomatic. Caution should be exercised in situations where renal function may be impaired, such as dehydration or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with non-steroidal anti-inflammatory drugs (NSAIDs). In such cases, it is also recommended to check renal function before starting treatment with metformin.

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 radiopaque agents. Intravenous administration of iodinated radiopaque agents may cause contrast-induced nephropathy and lead to metformin accumulation and, as a result, an increased risk of lactic acidosis. Metformin should be discontinued prior to or during the examination and should not be restarted until 48 hours after the examination, and only after renal function has been re-evaluated and found to be stable (see section 4.4).

Surgery: Metformin should be discontinued for elective surgery under general, spinal or epidural anaesthesia. Metformin therapy should not be resumed until 48 hours after surgery or resumption of oral nutrition and after renal function has been re-evaluated and found to be stable.

Children and adolescents. Type 2 diabetes mellitus should be confirmed before starting metformin treatment. Studies of one year duration have not shown any 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, so special caution should be exercised when using the drug in children during puberty, especially between the ages of 10 and 12 years.

Children aged 10 to 12 years. It is known that the efficacy and safety of metformin in this group of patients did not differ from that in older children and adolescents. The drug should be prescribed with particular caution to 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. Animal studies have not shown any adverse effects on pregnancy, embryonal or foetal development, parturition or postnatal development. When planning pregnancy and during pregnancy, insulin is recommended for the treatment of diabetes, rather than metformin, to maintain blood glucose levels as close to normal as possible to reduce the risk of foetal malformations.

Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed infants/newborns. However, as there is insufficient information on the safety of metformin during breast-feeding, its use is not recommended during this period. A decision on whether to discontinue breast-feeding should be made taking into account the benefit of breast-feeding and the potential risk of adverse effects to the infant.

Fertility: Metformin had no effect on animal fertility at doses of 600 mg/kg/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 operating 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.

The usual starting dose is 500 mg or 850 mg (to be administered in the appropriate dosage) of metformin hydrochloride 2-3 times daily during or after meals.

After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements.

When treating with high doses (2000-3000 mg/day), it is possible to replace every 2 tablets of Dianormet® 500 mg or Metformin-Teva 500 mg with 1 tablet of Metformin-Teva 1000 mg.

The maximum recommended dose is 3000 mg/day, divided into 3 doses.

In case of switching from another antidiabetic agent, it is necessary to discontinue this agent and prescribe metformin 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 (to be administered in the appropriate dosage) of 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 hydrochloride is used in children aged 10 years and older and adolescents. The usual starting dose is 500 mg or 850 mg (to be administered in the appropriate dosage) of metformin hydrochloride 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/day, divided into 2-3 doses.

Elderly patients may have decreased renal function, therefore the dose of metformin should be selected based on assessment of renal function, which should be performed regularly (see section "Special instructions").

Patients with renal failure.

Glomerular filtration rate should be assessed before starting metformin or metformin-containing products and at least annually during treatment. In patients at increased risk of further progression of renal function and in elderly patients, renal function should be assessed more frequently, at least every 3-6 months (see table).

Children.

Metformin should be used to treat 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 and should be treated in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.

Adverse reactions

The most common adverse reactions, especially at the beginning of treatment, are nausea, vomiting, diarrhea, abdominal pain, and lack of appetite.

Gastrointestinal: nausea, vomiting, loss of appetite, diarrhea, abdominal pain may occur. Most often, these side effects occur at the beginning of treatment and, as a rule, resolve on their own. To prevent the occurrence of side effects from the gastrointestinal 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.

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.

On the part of the hepatobiliary system: in rare cases - a decrease in liver function tests or hepatitis, which completely disappear after metformin withdrawal.

Skin and subcutaneous tissue disorders: skin reactions including erythema, pruritus, urticaria.

When metformin was used for 1 year in children aged 10 to 16 years, adverse reactions were similar to those in adults.

Expiration date

3 years.

Storage conditions

No special storage conditions are required. Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a box. 15 tablets in a blister: 2 blisters in a box.

Vacation category

According to the recipe.

Producer

1. Teva Pharmaceutical Industries Ltd.

2. TEVA Pharmaceutical Plant JSC.

Address

1. 18 Eli Hurwitz St., Ind. Zone, Kfar Saba, Israel.

2. Precinct 1; H-4042 Debrecen, Pallagi utca 13, Hungary.