Metformin-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFORMIN-TEVA (METFORMIN-TEVA)

Composition:

Active substance: metformin hydrochloride;

1 tablet contains 850 mg of metformin hydrochloride;

Excipients: povidone, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, elongated tablets with a smooth surface, free from spots and damage.

Pharmacotherapeutic group. Medicinal products affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycaemic agents, excluding insulin. Biguanides. ATC code A10B A02.

Pharmacological Properties

Pharmacodynamics

Metformin hydrochloride is an antidiabetic agent of the biguanide class that reduces glucose concentration in blood plasma both in the fasting state and after food intake. It does not stimulate insulin secretion and therefore does not cause hypoglycemia through 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 muscle tissue, enhancing glucose uptake and utilization in peripheral tissues.
3. Decreases glucose absorption in the intestine.

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

It has been reported that during treatment with metformin, patients' body weight remains stable or slightly decreases.

Pharmacokinetics

Absorption. After oral administration, the time to reach maximum concentration (T_max) of metformin is approximately 2.5 hours. The absolute bioavailability of 500 mg tablets is about 50–60%. After oral administration, the fraction not absorbed and excreted in feces is 20–30%.

After oral administration, metformin absorption is saturable and incomplete.

Nonlinear pharmacokinetics of metformin absorption is presumed. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. Maximum plasma concentrations (C_max) of metformin have been reported not to 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 maximum plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to maximum plasma concentration were observed. The clinical significance of these changes is unknown.

Distribution. Metformin is minimally bound to plasma proteins. 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 (V_d) 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 exceeds 400 mL/min, indicating that metformin is eliminated via glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life. This leads to increased metformin plasma concentrations.

Special patient groups

Renal impairment. Data in patients with moderate renal impairment are limited; therefore, it is not possible to precisely assess systemic exposure to metformin in this patient group compared to those with normal renal function. Dose adjustment is therefore necessary according to clinical efficacy/tolerability (see section "Dosage and administration").

Children. 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 (C_max) and systemic exposure (AUC_0–t) were reduced by approximately 33% and 40%, respectively, compared to adult patients with type 2 diabetes receiving repeated 500 mg doses twice daily for 14 days. Since the dose is individually titrated based on glycemic control, the aforementioned information has limited clinical significance.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when dietary therapy and physical exercise are ineffective, 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 older and adolescents.

For reducing complications of type 2 diabetes mellitus in adult patients with type 2 diabetes 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. lactic acidosis, diabetic ketoacidosis);
• diabetic precoma;
• severe renal impairment (glomerular filtration rate (GFR) <30 mL/min);
• acute conditions associated with risk of developing renal dysfunction, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or exacerbations 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, undernutrition, or hepatic impairment.

Iodine-containing radiographic contrast agents. Administration of metformin should be discontinued before or during the procedure 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 "Dosage and administration" and "Special precautions").

Combinations requiring caution

Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (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. At the beginning of therapy, concomitant use of these agents with metformin requires careful monitoring of renal function.

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 transporters – OCT1 and OCT2.

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 excretion 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, particular caution is recommended when co-administering these agents with metformin, especially 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 cases of acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute deterioration 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 attention should be sought.

Patients receiving metformin should initiate treatment cautiously with drugs that may acutely impair renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes, 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 symptom of lactic acidosis occurs, the patient should discontinue metformin immediately and seek medical help without delay. Lactic acidosis is characterized by specific laboratory findings: decreased blood pH (<7.35), increased serum lactate concentration (>5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Renal function. Glomerular filtration rate (GFR) must be assessed before initiating and regularly during metformin treatment (see section "Dosage and administration"). Metformin is contraindicated in patients with GFR <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 impairment. 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.

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

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

Children. A diagnosis of type 2 diabetes mellitus must be confirmed before initiating metformin therapy. Results from one-year controlled clinical trials have shown no effect of metformin on growth and pubertal development in children. However, there are no data on the long-term effects of metformin on growth and pubertal development; therefore, careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.

Children aged 10 to 12 years. Controlled clinical trials involving 15 children aged 10 to 12 years demonstrated that the efficacy and safety of metformin in this age group were comparable to those observed in older children and adolescents. However, metformin should be prescribed with particular caution in children aged 10 to 12 years.

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

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 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 diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital malformations and perinatal mortality. Limited available data on metformin use in pregnant women do not indicate an increased risk of congenital anomalies. Preclinical studies have not revealed adverse effects on pregnancy, embryonic or fetal development, parturition, or postnatal development. However, in planning or during pregnancy, insulin rather than metformin is recommended for the management of diabetes to maintain blood glucose levels as close to normal as possible, thereby reducing the risk of fetal malformations.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. Nevertheless, 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 animal studies at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Metformin monotherapy does not affect reaction speed when driving vehicles 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.

Administration and Dosage

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

Monotherapy or combination therapy with other oral antihyperglycemic agents

The usual initial dose is 500 mg (administered at the appropriate dosage) or 850 mg of metformin hydrochloride (1 tablet) 2–3 times daily, taken during 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. The maximum recommended dose is 3000 mg daily, divided into 3 doses. When switching from another antidiabetic agent, discontinue the previous agent and initiate metformin as described above.

Combination therapy with insulin

To achieve better glycemic control, metformin and insulin can be used together as combination therapy. The usual initial dose is 500 mg (administered at the appropriate dosage) or 850 mg of metformin hydrochloride (1 tablet) 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 metformin dose should be adjusted based on assessment of renal function, which must be performed regularly throughout treatment (see section "Special precautions").

Renal impairment. eGFR should be evaluated before initiating treatment with metformin-containing medicinal products and monitored at least annually during treatment. In patients at increased risk of progressive renal impairment and in elderly patients, renal function should be carefully monitored 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 (administered at the appropriate dosage) or 850 mg of metformin once daily, taken with or after meals. After 10–15 days, the dose should be adjusted according to blood plasma 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 hospital. Hemodialysis is the most effective intervention for removing lactate and metformin from the body.

Adverse Reactions

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 effects 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), and very rare (<1/10,000). Within each organ system class, adverse reactions are listed in decreasing order of clinical significance.

Metabolism and nutrition disorders:
Common – vitamin B12 deficiency/low levels (see section "Special precautions for use");
Very rare – lactic acidosis (see section "Special precautions for use").

Nervous system disorders:
Common – taste disturbances.

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

Children

In published and post-marketing data as well as controlled clinical trials in a limited pediatric population aged 10–16 years treated with 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

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging. 10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Teva Operations Poland Sp. z o.o.

Manufacturer's address and place of business.
80 Mogilska Street, 31-546 Kraków, Poland