Diformin®

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

Composition:

Active substance: metformin;

One tablet contains metformin hydrochloride 500 mg;

Excipients: potato starch, microcrystalline cellulose, povidone, polyethylene glycol (macrogol 4000), magnesium stearate;

One tablet contains metformin hydrochloride 850 mg;

Excipients: potato starch, lactose monohydrate, microcrystalline cellulose, povidone, polyethylene glycol (macrogol 4000), calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: 500 mg tablets are white or almost white, round-shaped, with flat cylindrical surface, beveled edge and a score line;

850 mg tablets are white or almost white, elongated-shaped, with biconvex surface, with or without a score line.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulins. Biguanides. ATC code A10BA02.

Pharmacological Properties.

Pharmacodynamics.

Metformin is a biguanide with a hypoglycemic 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 cause hypoglycemia mediated by this mechanism.

Metformin acts via three mechanisms:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, 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 (GLUT).

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

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

Pharmacokinetics.

Absorption. After oral administration of metformin, the time to reach maximum concentration (T_max) is approximately 2.5 hours. The absolute bioavailability of 500 mg or 850 mg tablets is about 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces amounts to 20–30%.

After oral administration, absorption of metformin is saturable and incomplete.

It is presumed that the pharmacokinetics of metformin absorption are nonlinear. At 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 (C_max) 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 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. 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 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 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, thus prolonging elimination half-life and resulting in increased plasma levels of metformin.

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

For reducing diabetes-related complications in adult patients with type 2 diabetes mellitus and excess body weight, as first-line therapy following ineffective dietary management.

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 risk of renal function impairment, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (particularly 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, especially during fasting, undernutrition, or hepatic impairment.

Iodinated contrast agents. 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 for use").

Combinations that should be used with caution. Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, particularly 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 glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Diaformin® 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 administration 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 elimination of metformin, leading to increased plasma concentrations of metformin;

• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal elimination of metformin.

Therefore, particular caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as metformin plasma 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 diarrhoea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended, and medical attention should be sought.

Metformin therapy should be initiated with caution in patients receiving medicinal products that may acutely impair renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic impairment, 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; coma may subsequently develop. If any symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin immediately and seek urgent medical advice.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated plasma lactate concentration (> 5 mmol/L), increased anion gap, and increased lactate/pyruvate ratio.

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

If signs and symptoms suggestive of MELAS or MIDD occur after initiating metformin, treatment with metformin should be discontinued immediately and a prompt diagnostic evaluation should be performed.

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

Cardiac function. Patients with heart failure have an increased risk of 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. Intravascular administration of iodinated contrast media may cause 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 "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

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

Children. Prior to initiating metformin therapy, a confirmed diagnosis of type 2 diabetes mellitus must be established. One-year controlled clinical studies have not shown any effect of metformin on growth or 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 receiving metformin, particularly during the period of puberty.

Children aged 10 to 12 years. Controlled clinical studies in 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. The medicinal product 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 necessary.

Metformin commonly reduces serum vitamin B12 levels, potentially leading to deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, 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 anaemia or newly developed neuropathy), and current clinical guidelines for testing and treating vitamin B12 deficiency should be followed. Periodic monitoring of vitamin B12 levels is recommended 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 corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycaemia; however, caution is advised when metformin is used concomitantly with insulin or other oral hypoglycaemic agents (e.g., sulfonylureas or meglitinides).

DIAFORMIN® 850 mg tablets contain lactose; therefore, this medicinal product in this dosage should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

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, pre-eclampsia, 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 related to hyperglycaemia 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 malformations or fetal/neonatal toxicity following exposure to metformin during the periconceptional period and/or during pregnancy.

Limited and inconclusive evidence exists regarding the long-term effects of metformin on offspring weight following in utero exposure. Available data suggest that metformin does not 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.

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

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the medicinal product, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should take into account the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility. Metformin did not affect fertility in animal studies 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 drive and use machines.

Monotherapy with metformin does not affect the ability to drive or operate machinery, as the medicinal product does not cause hypoglycaemia. However, caution is advised when metformin is used in combination with other hypoglycaemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycaemia.

Method of Administration and Dosage.

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

Monotherapy or combination therapy in combination with other oral hypoglycemic agents.

The usual starting dose is 500 mg or 850 mg two to three 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 high-dose therapy is required, use Diaformin®, film-coated tablets, 1000 mg.

The maximum recommended dose is 3000 mg daily, divided into three doses.

When switching to Diaformin® therapy, the previous antidiabetic agent should be discontinued.

Combination therapy with insulin.

To achieve better blood glucose control, metformin and insulin may be used together in combination therapy. The usual starting dose is 500 mg or 850 mg of Diaformin® two to three 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 selected based on assessment of renal function, which should be performed regularly (see section "Special Instructions").

Renal impairment. eGFR should be evaluated before initiating treatment with metformin-containing medicinal products and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should undergo more frequent monitoring of renal function, for example every 3–6 months.

Children.

Monotherapy or combination therapy with insulin.

The drug Diaphragmin® can be used in children aged 10 years and adolescents. The usual starting dose is 500 mg or 850 mg of Diaphragmin® once daily, taken during or after a meal. After 10–15 days, the dose should be adjusted based on blood serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

The maximum recommended dose is 2000 mg per day, divided into 2–3 doses.

Children.

The drug Diaphragmin® is indicated for the treatment of children aged 10 years and older.

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 the development of lactic acidosis. Lactic acidosis is a medical emergency requiring hospital treatment. 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 in most cases. To prevent the occurrence of these adverse effects, a gradual dose escalation is recommended, along with administration of 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 (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

Within each system-organ class, adverse reactions are listed in decreasing order of clinical significance.

Metabolic disorders

Common: vitamin B12 deficiency/reduction.

Very rare: lactic acidosis (see section "Special precautions").

Long-term use of the drug may impair vitamin B12 absorption, resulting in decreased serum vitamin B12 levels. This potential cause of vitamin B12 deficiency should be considered if a patient presents with megaloblastic anemia.

From the nervous system

Common: taste disturbances.

From the gastrointestinal system

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 in most cases. To prevent gastrointestinal adverse effects, gradual dose escalation is recommended, along with administration of the daily dose in 2–3 divided doses during or after meals.

From the liver and biliary system

Very rare: liver function test abnormalities or hepatitis, which completely resolve after discontinuation of metformin.

From the skin and subcutaneous tissue

Very rare: skin reactions including erythema, pruritus, urticaria.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio 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 drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

DIAFORMIN® 500 mg: 3 years.

DIAFORMIN® 850 mg: 5 years.

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

Storage conditions: Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging: 10 tablets in a blister. 3 or 6 blisters in a carton.

Prescription status: Prescription only.

Manufacturer: JSC "Farmak".

Manufacturer's address and place of business:
74, Kyrylivska Street, Kyiv, 04080, Ukraine.