Metformin-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Metformin-Teva (Metformin-Teva)

Composition:

active substance: metformin hydrochloride;

1 tablet contains 1000 mg of metformin hydrochloride;

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 another trade name may be used.

Pharmaceutical form. Film-coated tablets.

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

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

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

Pharmacological properties.

Pharmacodynamics.

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

Metformin hydrochloride stimulates intracellular glycogen synthesis; enhances the transport capacity of all types of glucose transport systems responsible for transferring glucose across the cell membrane; and exerts a positive effect on lipid metabolism. It has been demonstrated that metformin, at therapeutic doses, reduces concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

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

Pharmacokinetics.

Absorption. After oral administration, the time to reach maximum plasma concentration (Tmax) of metformin is approximately 2.5 hours. The absolute bioavailability of 500 mg or 850 mg tablets is approximately 50–60%. After oral administration, the fraction not absorbed and excreted in feces ranges from 20% to 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 concentration (Cmax) of metformin does 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 maximum plasma concentration, a 25% decrease in AUC, and a 35-minute prolongation in time to maximum plasma concentration (Tmax) 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 (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 exceeds 400 mL/min, indicating that metformin is eliminated via glomerular filtration and tubular secretion. After oral administration, 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 populations

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 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 type 2 diabetes receiving repeated 500 mg doses twice daily for 14 days. Since dosing is individually titrated based on glycemic control, the clinical relevance of these findings is limited.

Clinical characteristics.

Indications.

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

− as monotherapy or in combination with other oral antihyperglycemic agents or with 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 type 2 diabetes in adult patients with type 2 diabetes and excess body weight, as a first-line agent after failure of dietary management.

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 renal function impairment, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (particularly 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

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

Iodinated contrast media. Metformin should be discontinued before or during the procedure and restarted no earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of stable renal function (see sections "Method of administration and dosage" and "Special instructions").

Combinations requiring caution

Certain medicinal products, such as nonsteroidal 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 medicinal products with metformin requires careful monitoring of renal function.

MEDICINAL PRODUCTS EXERTING HYPERGLYCEMIC EFFECTS (systemic and local glucocorticosteroids, 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 combination therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (such as verapamil) may reduce metformin efficacy;
• 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 renal excretion of metformin, leading to increased plasma metformin concentrations;
• dual OCT1 and OCT2 inhibitors (such as 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 frequently occurring in acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute worsening of renal function leads to accumulation of metformin, increasing the risk of lactic acidosis.

In case of dehydration (severe diarrhoea 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 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 intake, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, any conditions associated with hypoxia, and 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 lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. If any symptom of lactic acidosis occurs, the patient must discontinue metformin and seek immediate medical attention. Lactic acidosis is characterized by diagnostic 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 altering renal function (see section "Contraindications").

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

Iodinated contrast agents. Intravascular administration of iodinated contrast agents may induce contrast-induced nephropathy, leading to metformin accumulation and consequently increasing the risk of lactic acidosis. Metformin should be discontinued before or during the procedure and restarted no earlier than 48 hours after the procedure, and only after re-evaluation 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 should be discontinued during elective surgical procedures under general, spinal, or epidural anesthesia. Metformin therapy should be resumed no earlier than 48 hours after surgery or restoration of oral nutrition, and only after re-evaluation and confirmation of stable renal function.

Children. Prior to initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. One-year controlled clinical studies have not shown any 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 studies involving 15 children aged 10 to 12 years have shown that the efficacy and safety of metformin in this patient group do not differ from those observed in older children and adolescents. However, metformin should be prescribed with particular caution in children aged 10 to 12 years.

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

Metformin may decrease 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. anaemia or neuropathy), serum vitamin B12 levels should be monitored. Periodic monitoring of serum 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 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 hypoglycaemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycaemic 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 shown adverse effects on pregnancy, embryofetal development, parturition, or postnatal development. However, in case of planned or established pregnancy, insulin rather than metformin is recommended for the treatment of diabetes to maintain blood glucose levels as close to normal as possible, thereby minimizing the risk of fetal malformations.

Breastfeeding. Metformin is excreted in breast milk, but adverse effects have not been observed in breastfed newborns/infants. Nevertheless, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. The decision regarding discontinuation of breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility. Metformin did not affect fertility in animals when administered 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 the speed of reactions when driving vehicles or operating machinery, as the drug does not cause hypoglycaemia. However, caution is required when metformin is used in combination with other hypoglycaemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycaemia.

Dosage and Administration.

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 (administered at the corresponding dosage) of metformin hydrochloride 2–3 times daily, taken during or after meals. After 10–15 days, the dose should be adjusted according to serum glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects.

When treating with high doses (2000–3000 mg/day), every 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/day, 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 may be used together as combination therapy. The usual initial dose is 500 mg or 850 mg (administered at the corresponding dosage) of metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring.

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 (see section "Special Warnings and Precautions for Use").

Renal impairment. eGFR should be evaluated before initiating treatment with metformin-containing medications 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 adolescents. The usual starting dose is 500 mg or 850 mg (administered at the appropriate dosage strength) 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 reduces gastrointestinal side effects. The maximum recommended dose is 2000 mg/day, divided into 2–3 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 removal of 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 as follows: 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 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"); 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 administer the daily dose in 2–3 divided doses during or after meals.

Hepatobiliary disorders: very rare – liver function test abnormalities or hepatitis, which completely 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

After marketing authorization, it is important to report suspected adverse reactions. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters in a carton. 15 tablets in a blister; 2 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturers.

1. Teva Pharmaceutical Industries Ltd.
2. AT Pharmaceutical Plant Teva.

Manufacturer's address and location of activity.

1. 18 Hapoel HaMerkazi Street, Industrial Zone, Kfar Saba, Israel.
2. Unit 1; Palagyi Street 13, H-4042 Debrecen, Hungary.