Diformin®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAFORMIN® (DIAFORMIN)

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet containing 1000 mg contains 1000 mg of metformin hydrochloride;

Excipients: sodium starch glycolate (type A), povidone (K-30), maize starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating Opadry White 04 G58897: hypromellose, talc, titanium dioxide (E 171), macrogol 6000, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: oval, biconvex, film-coated tablets, white or almost white, with a deep score line on one side and a line on the other side.

Pharmacotherapeutic group. Oral hypoglycaemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological Properties

Pharmacodynamics

Metformin is a biguanide with an antihyperglycemic effect. It reduces both fasting plasma glucose levels and postprandial glucose levels. It does not stimulate insulin secretion and therefore does not cause hypoglycemia through this mechanism.

Metformin exerts its effects through three main mechanisms:

• Reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• Improves insulin sensitivity in muscle tissue, resulting in enhanced peripheral glucose uptake and utilization;
• Delays intestinal absorption of glucose.

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

In addition to its effects on glycemia, metformin has a beneficial effect on lipid metabolism: it reduces levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

During treatment with metformin, patient body weight remained stable or moderately decreased.

Pharmacokinetics

Absorption. After oral administration of metformin, the time to reach maximum plasma concentration (Tmax) is approximately 2.5 hours. Absolute bioavailability is about 50–60%. After oral administration, the unabsorbed fraction excreted in feces amounts to 20–30%.

Following oral administration, metformin absorption is saturable and incomplete.

Non-linear pharmacokinetics of metformin absorption is presumed. 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 metformin levels (Cmax) did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and delays metformin absorption.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached approximately at the same time. Erythrocytes likely serve as 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.

Excretion. Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by 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 and consequently increased metformin plasma levels.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when dietary therapy and physical exercise regimen are ineffective, particularly in patients with excess body weight;

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

For reducing diabetes complications 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 drug;
• diabetic ketoacidosis, diabetic precoma;
• moderate (stage IIIb) to severe renal impairment or impaired kidney function (creatinine clearance < 45 mL/min or eGFR < 45 mL/min/1.73 m²);
• acute conditions associated with a risk of developing kidney dysfunction, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or exacerbation of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• hepatic insufficiency, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting or adherence to a low-calorie diet, as well as in hepatic insufficiency. During treatment with Diaformin®, alcohol intake and medicinal products containing alcohol should be avoided.

Iodinated contrast agents. Intravenous administration of iodinated contrast agents may lead to renal impairment and, consequently, to metformin accumulation and increased risk of lactic acidosis.

In patients with eGFR > 60 mL/min/1.73 m², metformin should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, only after re-evaluation of kidney function and confirmation of no further deterioration in renal status (see section "Special precautions for use").

In patients with moderate renal impairment (eGFR 45–60 mL/min/1.73 m²), metformin should be discontinued 48 hours prior to administration of iodinated contrast agents and not restarted earlier than 48 hours after the procedure, and only after re-evaluation of kidney function and confirmation of no further deterioration in renal status.

Combinations to be used with caution.

Medicinal products exerting hyperglycemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. During and after discontinuation of such concomitant therapy, the dose of Diaformin® should be adjusted under glycemic control.

Diuretics, particularly loop diuretics, may increase the risk of lactic acidosis due to potential reduction in kidney function.

Special precautions for use.

Lactic acidosis is a rare but serious metabolic complication (with high mortality in the absence of emergency treatment) that may occur due to metformin accumulation. Cases of lactic acidosis have been reported in patients with diabetes mellitus who have renal impairment or a sudden deterioration in renal function. Caution is required in situations where renal function may be impaired, such as in dehydration (severe diarrhea or vomiting) or at the initiation of antihypertensive agents, diuretics, or nonsteroidal anti-inflammatory drugs (NSAIDs). If such conditions occur, metformin should be temporarily discontinued.

Other risk factors for lactic acidosis should also be considered: poorly controlled diabetes, ketosis, prolonged fasting, alcohol abuse, hepatic insufficiency, or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see section "Contraindications").

Lactic acidosis may present as muscle cramps, gastrointestinal disturbances, abdominal pain, and severe asthenia. Patients should immediately inform their physician if such symptoms occur, especially if they previously tolerated metformin well. In such cases, metformin should be temporarily discontinued until the situation is clarified. Metformin therapy should be resumed only after an individual benefit-risk assessment and evaluation of renal function.

Diagnosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, with possible progression to coma. Diagnostic indicators include laboratory-confirmed blood pH reduction, elevated serum lactate concentration above 5 mmol/L, increased anion gap, and elevated lactate/pyruvate ratio. In case of lactic acidosis development, immediate hospitalization is required (see section "Overdose"). The physician must inform patients about the risk of developing symptoms of lactic acidosis.

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) or maternally inherited diabetes and deafness (MIDD), due to the risk of worsening lactic acidosis and neurological complications, which may exacerbate the course of the disease.

If signs or symptoms suggestive of MELAS or MIDD occur after metformin administration, metformin treatment should be immediately discontinued and a rapid diagnostic evaluation initiated.

Renal impairment. Since metformin is excreted by the kidneys, creatinine levels (estimated using plasma creatinine and the Cockcroft-Gault formula) or eGFR should be assessed before initiating and regularly during treatment with DIAFORMIN®:

• in patients with normal renal function – at least once a year;
• in patients with creatinine clearance at the lower limit of normal and in elderly patients – at least 2–4 times a year.

Metformin is contraindicated if creatinine clearance is < 45 mL/min (eGFR < 45 mL/min/1.73 m²) (see section "Contraindications").

Decline in renal function is common and often asymptomatic in elderly patients. Caution is required in situations where renal function may be impaired, such as dehydration or initiation of antihypertensive agents, diuretics, or NSAIDs. In such cases, renal function should also be evaluated before starting metformin therapy.

Cardiac function. Patients with heart failure have a higher risk of developing hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure, provided cardiac and renal function are regularly monitored. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Iodinated contrast agents. Intravenous administration of radiological contrast agents may lead to renal impairment and, consequently, metformin accumulation and increased risk of lactic acidosis. In patients with eGFR > 60 mL/min/1.73 m², metformin should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, and only after re-evaluation of renal function and confirmation of no further deterioration in renal status (see section "Interaction with other medicinal products and other forms of interaction").

In patients with moderate renal impairment (eGFR 45–60 mL/min/1.73 m²), metformin should be discontinued 48 hours before administration of iodinated contrast agents and not restarted earlier than 48 hours after the procedure, and only after re-evaluation of renal function and confirmation of no further deterioration in renal status (see section "Interaction with other medicinal products and other forms of interaction").

Surgical procedures. DIAFORMIN® should be discontinued 48 hours before elective surgical procedures performed under general, spinal, or epidural anesthesia, and not restarted earlier than 48 hours after surgery or restoration of oral nutrition, and only if renal function is normal.

Children. Prior to initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. Clinical studies have not shown any effect of metformin on growth and sexual maturation in children. However, there are no data on the long-term effects of DIAFORMIN® on growth and sexual maturation; therefore, the drug should be used with particular caution in children during puberty, especially those 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. Glycemic parameters should be monitored regularly.

Metformin usually reduces serum vitamin B12 levels, which may lead to deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and in patients with risk factors known to cause vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if deficiency is suspected (e.g., in patients with megaloblastic anemia or newly developed neuropathy), and current clinical guidelines for testing and treating vitamin B12 deficiency should be followed. In patients with risk factors for vitamin B12 deficiency, periodic monitoring of vitamin B12 levels is recommended. Metformin therapy should be continued as long as it is well tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycemia. However, when DIAFORMIN® is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides), the hypoglycemic effect may be enhanced.

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital anomalies, pregnancy loss, pregnancy-induced 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 associated with hyperglycemia for both mother and child.

Metformin crosses the placenta and reaches levels in the fetus that may be as high as maternal concentrations.

A large amount of data from pregnant women (over 1000 outcomes) from cohort registry studies and published data (meta-analyses, clinical trials, and registries) indicate no increased risk of congenital anomalies or fetal/neonatal toxicity following exposure to metformin during the periconceptional period and/or during pregnancy.

There are limited and inconclusive data on the long-term effects of metformin on the weight of 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 long-term outcome data are limited.

Metformin may be considered during pregnancy and in the periconceptional period, if clinically necessary, as an adjunct or alternative to insulin.

Lactation. Metformin is excreted in breast milk. No adverse effects have been observed in newborns/infants. Due to insufficient safety data, breastfeeding is not recommended during treatment with DIAFORMIN®. The decision to discontinue breastfeeding should be made considering the necessity of the drug for the mother and the potential risk to the infant.

Fertility. Metformin had no effect on 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 reaction speed when driving or operating machinery. DIAFORMIN® does not affect reaction speed when driving or operating machinery, as monotherapy with the drug does not cause hypoglycemia.

However, caution is advised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Method of Administration and Dosage

Adults.

Monotherapy or combination therapy with other oral hypoglycemic agents.

The usual initial dose is 500 mg or 850 mg 2–3 times daily, taken during or after meals.

After 10–15 days of treatment, the dose should be adjusted according to serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

The maximum recommended dose is 3000 mg daily in 3 divided doses.

For high-dose therapy, Diaformin®, film-coated tablets 1000 mg, should be used.

When switching to treatment with Diaformin®, the previous antidiabetic medication must be discontinued.

Combination therapy with insulin.

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

Children.

Monotherapy or combination therapy with insulin.

Diaformin® can be used in children aged 10 years and older and adolescents. The usual initial dose is 500 mg or 850 mg of Diaformin® once daily, taken during or after meals. After 10–15 days of treatment, 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 daily in 2–3 divided doses.

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

Patients with renal impairment. Diaformin® may be used in patients with moderate renal impairment, stage IIIa (creatinine clearance 45–59 mL/min or eGFR 45–59 mL/min/1.73 m²), only in the absence of other conditions that may increase the risk of lactic acidosis, and with dose adjustment: the initial dose is 500 mg or 850 mg of metformin hydrochloride once daily. The maximum dose is 1000 mg daily, divided into 2 doses. Renal function should be closely monitored (every 3–6 months).

If creatinine clearance or eGFR decreases to < 45 mL/min or < 45 mL/min/1.73 m², respectively, metformin must be discontinued immediately.

Children. Diaformin® can be administered to children aged 10 years and older.

Overdose.

Hypoglycemia was not observed following administration of 85 g of the drug. However, in this case, lactic acidosis developed. A significant overdose of metformin or concomitant risk factors may lead to the development of lactic acidosis. Lactic acidosis is a medical emergency and requires hospitalization. Hemodialysis is the most effective method for removing lactate and metformin from the body.

Adverse Reactions

The most common adverse reactions, especially at the beginning of treatment, are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously. To prevent gastrointestinal adverse effects, it is recommended to gradually increase the dosage and administer the drug 2–3 times daily with meals or immediately after meals.

Metabolism: lactic acidosis, decreased vitamin B12 levels or vitamin B12 deficiency.

With prolonged use of the drug, vitamin B12 absorption may be reduced, resulting in decreased serum vitamin B12 levels. This has been observed when metformin was administered to patients with megaloblastic anemia.

Nervous system: taste disturbances.

Gastrointestinal tract: 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 divide the daily dose into 2–3 doses taken with meals or immediately after meals.

Hepatobiliary system: abnormal liver function tests or hepatitis, which completely resolve after discontinuation of metformin.

Skin and subcutaneous tissue: skin reactions including erythema, itching, and urticaria.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as 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.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets in a blister. 3 or 6 blisters per carton (bulk packaging from the manufacturer USV Private Limited, India).

Prescription status

Prescription only.

Manufacturer

JSC "Farmak".

Manufacturer's address and place of business

74, Kyrylivska Street, Kyiv, 04080, Ukraine.