Metformin-teva

INSTRUCTION for medical use of the medicinal product Metformin-Teva (Metformin-Teva)

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet contains metformin hydrochloride 500 mg, or 850 mg, or 1000 mg;

Excipients:

Core: povidone K30, colloidal silicon dioxide anhydrous, magnesium stearate;

Film coating: hypromellose (2910/5), titanium dioxide (E 171), macrogol (400).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

500 mg film-coated tablets: white or almost white, oval film-coated tablets, with "93" engraved on one side and "48" on the other;

850 mg film-coated tablets: white or almost white, oval film-coated tablets, with "93" engraved on one side and "49" on the other;

1000 mg film-coated tablets: white or almost white, oval film-coated tablets with a score line on both sides, with "9" to the left and "3" to the right of the score on one side, and "72" to the left and "14" to the right of the score on the other side.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Metformin is a biguanide with an antihyperglycemic effect. It reduces glucose levels in blood plasma both in the fasting state and after food intake. It does not stimulate insulin secretion and does not produce a hypoglycemic effect mediated by this mechanism.

Metformin acts via three mechanisms:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscle tissue, leading to enhanced peripheral glucose uptake and utilization;
• delays intestinal absorption of glucose.

Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthase. It increases the transport capacity of all known types of glucose membrane transporters.

Independent of its effects on glycemia, metformin has a beneficial effect on lipid metabolism. This effect has been demonstrated during controlled medium- or long-term clinical trials using therapeutic doses: metformin reduces levels of total cholesterol, low-density lipoproteins, and triglycerides.

During clinical trials, patients' body weight remained stable or decreased slightly when metformin was administered.

Pharmacokinetics.

Absorption. After oral administration of metformin, the time to reach maximum plasma concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin from 500 mg or 800 mg tablets is approximately 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces is 20–30%. After oral administration, absorption of metformin is saturable and incomplete.

It is presumed that the pharmacokinetics of metformin absorption are nonlinear. With recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. In controlled clinical trials, maximum plasma levels of metformin (Cmax) did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption.

After oral administration of an 850 mg dose, a 40% reduction in plasma Cmax, a 25% reduction in AUC, and a 35-minute prolongation in time to reach maximum plasma concentration were observed. The clinical significance of these changes is unknown.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached at approximately the same time. Erythrocytes likely represent a secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism. Metformin is excreted unchanged in 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. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance of metformin decreases proportionally to creatinine clearance, thus prolonging the elimination half-life and resulting in increased plasma metformin levels.

Special patient groups

Renal impairment. Data in patients with moderate renal impairment are limited; therefore, systemic exposure to metformin in this patient group compared to those with normal renal function cannot be precisely assessed. Dose adjustment is therefore required based on clinical efficacy and tolerability (see section "Dosage and administration").

Pediatric population. Following a single 500 mg dose of metformin hydrochloride, the pharmacokinetic profile in pediatric patients was similar to that in healthy adults. Data on multiple dosing 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 adult patients with diabetes receiving repeated 500 mg doses twice daily for 14 days. Since the dose is individually titrated based on glycemic control, the above information has limited clinical significance.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when dietary therapy and physical exercise have failed, particularly in patients with excess body weight:

• as monotherapy or in combination with other oral hypoglycemic agents or insulin for the treatment of adults;
• as monotherapy or in combination with insulin for the treatment of children aged 10 years and adolescents.

For reducing complications of diabetes in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line agent after ineffective dietary therapy.

Contraindications.

• Hypersensitivity to metformin or to any other component of the medicinal product;
• any type of acute metabolic acidosis (e.g., lactate acidosis, diabetic ketoacidosis);
• diabetic precoma;
• severe renal impairment (glomerular filtration rate (GFR) <30 mL/min);
• acute conditions associated with a risk of developing renal dysfunction, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or acute exacerbation of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly during fasting, malnutrition, or hepatic impairment.

Iodinated contrast media. Metformin should be discontinued before or during radiological procedures involving iodinated contrast agents and should not be restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of stable renal function (see sections "Special precautions for use" and "Method of administration and dosage").

Combinations requiring caution

Certain medicinal products, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when using them in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of metformin may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (e.g., verapamil) may reduce metformin efficacy;
• OCT1 inducers (e.g., rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• OCT2 inhibitors (e.g., cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal elimination of metformin, leading to increased plasma metformin concentrations;
• dual OCT1 and OCT2 inhibitors (e.g., crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

Therefore, caution is recommended when co-administering these agents with metformin, particularly in patients with impaired renal function, as plasma metformin concentrations may increase. Dose adjustment of metformin should be considered if necessary, since OCT inhibitors/inducers may influence metformin efficacy.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in the presence of acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute worsening of renal function leads to metformin accumulation, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended, and medical advice should be sought.

Patients receiving metformin should initiate treatment with caution when using medicinal products that may acutely worsen renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

Lactic acidosis is characterized by diagnostic laboratory findings: decreased blood pH (<7.35), elevated serum lactate concentration (>5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Renal function. eGFR should be assessed before initiating treatment and regularly thereafter (see section "Posology and method of administration"). Metformin is contraindicated in patients with eGFR <30 mL/min and should be temporarily discontinued in conditions affecting renal function (see section "Contraindications").

Cardiac function. Patients with heart failure have an increased risk of developing hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Iodinated contrast agents. Intravascular administration of iodinated contrast agents may induce contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and should not be restarted earlier than 48 hours after the procedure, and only after reassessment and confirmation of stable renal function (see sections "Interaction with other medicinal products and other forms of interaction" and "Posology and method of administration").

Surgical procedures. Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia. Metformin therapy should not be resumed earlier than 48 hours after surgery or after resumption of oral nutrition, and only after reassessment and confirmation of stable renal function.

Children. Before initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. Based on results from one-year controlled clinical studies, no effect of metformin on growth and sexual maturation in children was observed. However, there are no data on the long-term effects of metformin on growth and sexual maturation, so careful monitoring of these parameters is recommended in children treated with metformin, particularly during puberty.

Children aged 10 to 12 years. Results from controlled clinical studies involving 15 children aged 10 to 12 years showed that the efficacy and safety of metformin in this patient group were comparable to those in older children and adolescents. The drug should be prescribed with particular caution to children aged 10 to 12 years.

Other warnings. Patients should adhere to a diet with balanced carbohydrate intake throughout the day. Obese patients should continue a low-calorie diet. Regular monitoring of carbohydrate metabolism parameters is necessary.

Metformin may reduce serum vitamin B12 levels. The risk of vitamin B12 deficiency increases with higher metformin doses, longer treatment duration, and/or in patients with risk factors predisposing to vitamin B12 deficiency. In case of suspected vitamin B12 deficiency (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. 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 it is well tolerated and not contraindicated, and appropriate treatment for correcting vitamin B12 deficiency should be administered according to current clinical guidelines.

Metformin monotherapy does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides).

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse outcomes of hyperglycemia for both mother and child.

Metformin crosses the placenta in amounts that may reach concentrations similar to those in the mother.

A large body of data from pregnant women (over 1000 pregnancy outcomes) from cohort studies based on registries, as well as published meta-analyses and clinical trials, indicates no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure in the periconceptional period and/or during pregnancy.

There are some unconfirmed data regarding the long-term effect of metformin on body weight in children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed in utero, although data on long-term outcomes are limited.

If clinically necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct to or as an alternative to insulin.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed neonates/infants. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin did not affect fertility in animals at doses of 600 mg/kg/day, which is nearly three times the maximum recommended human daily dose based on body surface area.

Ability to affect reaction rate when driving or operating machinery.

Metformin monotherapy does not affect reaction speed when driving or operating machinery, as the drug does not cause hypoglycemia. However, caution is required when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Method of Administration and Dosage

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

Monotherapy or combination therapy with other oral hypoglycemic agents

The usual initial dose is 500 mg or 850 mg (Metformin-Teva film-coated tablets, 500 mg or 850 mg) taken 2–3 times daily, with or after meals. After 10–15 days, the dose should be adjusted based on serum glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects.

When treating with high doses (2000–3000 mg per day), each 2 tablets of Metformin-Teva 500 mg may be replaced by 1 tablet of Metformin-Teva 1000 mg. The maximum recommended dose is 3000 mg daily, divided into 3 doses. When switching from another antidiabetic agent, the previous medication should be discontinued and metformin initiated as described above.

Combination therapy with insulin

To achieve better blood glucose control, metformin and insulin can be used together in combination therapy. The usual initial dose is 500 mg or 850 mg of metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring results.

In elderly patients, renal function may be reduced; therefore, the dose of metformin should be selected based on assessment of renal function, which must be performed regularly (see section "Special Warnings and Precautions for Use").

Renal impairment. eGFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually during treatment. In patients at increased risk of progressive renal impairment and in elderly patients, careful monitoring of renal function should be performed as frequently as possible, for example every 3–6 months.

Children.

Monotherapy or combination therapy with insulin

Metformin is used in children aged 10 years and older and in adolescents. The usual starting dose is 500 mg or 850 mg of metformin once daily, taken during or after a meal. After 10–15 days, the dose should be adjusted according to serum glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg per day, given in 2–3 divided doses.

Overdose.

When the drug was administered at a dose of 85 g, hypoglycemia was not observed. However, in this case, lactic acidosis developed. Significant overdose of metformin or concomitant risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital setting. Hemodialysis is the most effective intervention for removing lactate and metformin from the body.

Side effects.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously. To prevent the occurrence of these adverse effects, it is recommended to gradually increase the dosage and administer the daily dose in 2–3 divided doses.

Adverse reactions are classified by frequency of occurrence into the following categories: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1,000 and <1/100), rare (>1/10,000 and <1/1,000), very rare (<1/10,000). Within each organ system class, adverse reactions are listed in order of decreasing clinical significance.

Metabolic disorders: common – vitamin B12 deficiency/low levels (see section "Special precautions"); very rare – lactic acidosis (see section "Special precautions").

Nervous system disorders: common – taste disturbances.

Gastrointestinal disorders: very common – gastrointestinal disturbances such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse effects most frequently occur at the beginning of treatment and usually resolve spontaneously. To prevent gastrointestinal adverse reactions, it is recommended to gradually increase the dosage and take the daily dose in 2–3 divided doses during or after meals.

Hepatobiliary disorders: very rare – liver function test abnormalities or hepatitis, which resolve after discontinuation of metformin.

Skin and subcutaneous tissue disorders: very rare – 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 who received metformin for 1 year, reported adverse effects in children were similar in nature and severity to those observed in adults.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Packaging. 15 tablets in a blister; 2, 4, 6, or 8 blisters in a cardboard box; 100 tablets in a bottle.

Prescription status. Prescription only.

Manufacturers.

Teva Czech Industries s.r.o.

AT Pharma Plant Teva.

Manufacturers' addresses and locations of their business activities.

Ostravska 305/29, Komarov, 747 70 Opava, Czech Republic.

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