Metformin-Teva film-coated tablets 1000 mg blister No. 30

Instructions for use Metformin-Teva film-coated tablets 1000 mg blister No. 30

Composition

active ingredient: metformin hydrochloride;

1 tablet contains metformin hydrochloride 1000 mg;

excipients:

core: povidone K-30, colloidal anhydrous silicon dioxide, 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

Drugs affecting the digestive system and metabolism. Antidiabetic drugs. Oral hypoglycemic agents, except insulins. Biguanides. 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.

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

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

Reduces glucose absorption in the intestine.

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.

Special patient groups

Children. In a single-dose study of 500 mg metformin hydrochloride, the pharmacokinetic profile in pediatric patients was similar to that in healthy adults. Multiple-dose data are limited to one study. After repeated administration of 500 mg metformin twice daily for 7 days in pediatric patients, peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to those in adult diabetic patients receiving repeated doses of 500 mg twice daily for 14 days. Since the dose is titrated individually based on glycemic control, the above information is of limited clinical relevance.

Indication

Type 2 diabetes mellitus with ineffective diet therapy and exercise regimen, especially in patients with excess body weight:

− as monotherapy or as part of combination therapy with other oral hypoglycemic agents or with insulin for the treatment of adults;

− as monotherapy or as part of combination therapy with insulin for the treatment of children aged 10 years and older and adolescents.

To reduce the complications of diabetes in adult patients with type 2 diabetes and overweight as a first-line drug after ineffective diet therapy.

Contraindication

– Hypersensitivity to metformin or to any other component of the drug;

– any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);

– diabetic precoma;

– severe renal failure (glomerular filtration rate (GFR) <30 ml/min);

– acute conditions that occur with a risk of developing kidney dysfunction, such as: dehydration, severe infectious diseases, shock;

– 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: Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in the presence of fasting, malnutrition, or liver failure.

Iodinated radiocontrast agents: Patients should discontinue metformin prior to or at the time of the procedure and not resume treatment until 48 hours after the procedure and only after renal function has been re-evaluated and stable (see sections 4.2 and 4.4).

Combinations to be used with caution

Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase II (COX) inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics, may adversely affect renal function, which may increase the risk of lactic acidosis. At the beginning of therapy, the simultaneous 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.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters – OCT1 and OCT2.

Concomitant use of metformin with:

– OCT1 inhibitors (such as verapamil) may reduce the effectiveness of metformin;

– OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

– OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with a subsequent increase in metformin plasma concentrations;

– OCT1 and OCT2 inhibitors (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.

Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.

Application features

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.

Patients receiving metformin should be cautiously initiated on medicinal products that may acutely impair renal function (e.g. antihypertensives, diuretics and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting and any condition associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections 4.3 and 4.5). Patients and/or their caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia, which may subsequently progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical advice immediately. Lactic acidosis is characterized by diagnostic laboratory parameters: decreased blood pH (<7.35), increased serum lactate concentration (>5 mmol/L), increased anion gap and lactate/pyruvate ratio.

Renal function: GFR should be assessed before initiating and regularly during metformin treatment (see section 4.2). Metformin is contraindicated in patients with a GFR <30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

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. Intravascular administration of iodinated radiocontrast 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 at the time of the examination and should not be resumed until 48 hours after the examination and only after renal function has been re-evaluated and stable (see sections 4.2 and 4.5).

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

Children. Type 2 diabetes mellitus should be confirmed before starting metformin therapy. One-year controlled clinical trials have shown no 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 careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.

Children aged 10 to 12 years. According to the results of controlled clinical studies involving 15 children aged 10 to 12 years, 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 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 may decrease serum vitamin B12 levels. The risk of decreased vitamin B12 levels increases with increasing metformin dose, duration of treatment and/or in patients with risk factors for vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g. anaemia or neuropathy). Periodic monitoring of vitamin B12 levels may be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued as long as tolerated and without contraindications, and appropriate treatment should be given to correct vitamin B12 deficiency in accordance with current clinical guidelines.

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 mellitus 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 case of planning or onset 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.

Breastfeeding. 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 benefits of breastfeeding and the potential risk of adverse effects to the child.

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

Adult patients with normal renal function (GFR ≥90 mL/min)

Monotherapy or combination therapy 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 with or after meals. After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements. A slow increase in dose helps to reduce gastrointestinal side effects.

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

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

If switching from another antidiabetic agent, this agent should be discontinued and metformin should be prescribed as described above.

Combination therapy 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.

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").

Renal impairment: GFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually during treatment. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be monitored closely as frequently as possible, e.g. every 3-6 months.

Children.

Monotherapy or combination therapy with insulin

Metformin 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 once daily with or after meals. After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements. A slow dose increase helps to reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg/day, divided into 2-3 doses.

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 lead to 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 at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms usually 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.

Adverse reactions are classified according to frequency using the following convention: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10000 and <1/1000), very rare (<1/10000). Within each system organ class, adverse reactions are presented in order of decreasing clinical significance.

Metabolic: often - decrease/deficiency of vitamin B12 (see section "Special instructions for use"); very rarely - lactic acidosis (see section "Special instructions for use").

Nervous system: often - taste disturbance.

Gastrointestinal: very often - digestive system disorders, such as nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and, as a rule, disappear 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.

On the part of the hepatobiliary system: very rarely - abnormal liver function tests or hepatitis, which completely disappear after metformin withdrawal.

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

Children.

In published and post-marketing data and controlled clinical trials in a limited pediatric population aged 10-16 years treated with metformin for 1 year, adverse reactions reported in children were similar in nature and severity to those reported in adults.

Reporting of suspected adverse reactions

Once a medicine has been authorised, it is important to report suspected adverse reactions. This allows the benefit-risk balance of the medicine to be monitored. Healthcare professionals should report any adverse reactions via the national reporting system.

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 or 6 blisters in a box.

Vacation category

According to the recipe.

Manufacturers

Teva Pharmaceutical Industries Ltd.

Teva Pharmaceutical Plant JSC.

Location of the manufacturer and address of its place of business

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

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