Metformin-teva

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

Composition:

Active substance: metformin hydrochloride;

1 tablet contains metformin hydrochloride 500 mg;

Excipients: povidone, magnesium stearate, talc.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: white, round tablets with a smooth surface, free from spots and damage.

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

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 therefore does not cause hypoglycemia via 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 responsible for glucose transport across the cell membrane; and has 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, patient body weight remains stable or slightly decreases.

Pharmacokinetics.

Absorption. After oral administration, the time to reach maximum 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 amounts to 20–30%.

After oral administration, metformin absorption is saturable and incomplete.

Nonlinear pharmacokinetics of metformin absorption are presumed. With recommended dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. It has been reported that 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 reach 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 compartment of distribution. 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.

Excretion. Renal clearance of metformin exceeds 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 patients with impaired renal function, 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, 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 the dose is individually titrated based on glycemic control, the aforementioned information has limited clinical significance.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when diet therapy and physical exercise regimens are ineffective, especially 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 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 excipient 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 impaired renal function, 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

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

Contrast media containing iodine. 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 "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. Careful monitoring of renal function is required when initiating treatment with these agents or when used concomitantly 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 combination 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 concentrations of metformin;
• 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 concentrations of metformin 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 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 case of dehydration (severe diarrhoea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended and medical advice should be sought.

Patients receiving metformin should start 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, 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 dyspnoea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptom suggestive 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. eGFR should be assessed before initiating and regularly during metformin treatment (see section "Dosage and 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 insufficiency. 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 and unstable heart failure (see section "Contraindications").

Use of iodinated contrast agents. Intravascular administration of iodinated radiological contrast agents may induce contrast-induced nephropathy, leading to metformin accumulation and consequently increasing the risk of lactic acidosis. Metformin administration must 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 "Interaction with other medicinal products and other forms of interaction").

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

Children. Diagnosis of type 2 diabetes mellitus should be confirmed before initiating metformin treatment. Results from one-year controlled clinical studies showed no effect of metformin on growth and sexual maturation in children. However, there are no data on the long-term effects of metformin on growth and sexual maturation; therefore, careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.

Children aged 10 to 12 years. Only 15 individuals aged 10 to 12 years were included in controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children were comparable to those in older children and adolescents, particular caution is recommended when prescribing metformin to children aged 10 to 12 years.

Other warnings. Patients should adhere to a diet with evenly distributed carbohydrate intake throughout the day. Overweight patients should continue a calorie-restricted 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 duration of treatment, and/or in patients with risk factors predisposing to vitamin B12 deficiency. Monitoring of serum vitamin B12 levels is necessary if vitamin B12 deficiency is suspected (e.g., anaemia or neuropathy). Periodic monitoring of vitamin B12 levels may be required 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 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., sulphonylureas 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 malformations. Preclinical studies have not shown any adverse effects on pregnancy, embryonic or foetal 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 reducing the risk of foetal malformations.

Breastfeeding. Metformin is excreted in breast milk, but adverse effects have not been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, 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 had no effect on fertility in animals when administered at a dose of 600 mg/kg/day, which is almost three times higher than the maximum recommended human daily dose based on body surface area.

Ability to affect driving and use of machines.

Metformin monotherapy does not affect the ability to drive or operate machinery, as the drug does not cause hypoglycaemia. However, caution is required when metformin is used in combination with other hypoglycaemic agents (sulphonylurea derivatives, 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 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 daily dose is 3000 mg, divided into 3 doses. When switching from another antidiabetic agent, that agent should be discontinued and metformin initiated as described above.

Combination therapy with insulin

To achieve better glycemic control, metformin and insulin may be used together. The usual initial dose of metformin is 500 mg 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring.

In elderly patients, renal function may be impaired; therefore, metformin dosage must be adjusted based on assessment of renal function, which should be regularly monitored (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, renal function should be closely monitored as frequently as 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 initial dose is 500 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, administered 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 did develop. Significant overdose of metformin or concomitant risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency requiring hospital treatment. Hemodialysis is the most effective procedure 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 as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), 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 disturbances such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse effects most frequently occur at the start of treatment and usually resolve spontaneously. To prevent gastrointestinal adverse effects, it is recommended to gradually increase the dosage and administer 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 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

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 through the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging. 15 tablets in a blister; 2 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