Diformin®

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

Composition:

Active substance: metformin hydrochloride;

1 tablet contains 500 mg or 850 mg or 1000 mg of metformin hydrochloride;

Excipients: potato starch, povidone K-30, magnesium stearate;

film coating Opadry II 85F19250 Clear: polyethylene glycol, polysorbate 80, polyvinyl alcohol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

500 mg tablets: white or almost white, round-shaped, biconvex tablets, film-coated;

850 mg tablets: film-coated, elongated-shaped, biconvex tablets with a score line, white or almost white;

1000 mg tablets: film-coated, white or almost white, elongated-shaped, biconvex tablets with a score line.

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

Pharmacological Properties.

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic activity. It reduces glucose levels in blood plasma both in the fasting state and after meals. It does not stimulate insulin secretion and therefore does not cause hypoglycemia mediated through this mechanism.

Metformin acts via three pathways:

• 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 affecting glycogen synthase. It increases the transport capacity of all known types of glucose membrane transporters (GLUT).

In addition to its effects on glycemia, metformin exerts a beneficial effect on lipid metabolism. This effect has been demonstrated in controlled medium- or long-term clinical trials using therapeutic doses: metformin reduces levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

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

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 in healthy volunteers is approximately 50–60%. The fraction of the drug not absorbed and excreted in feces after oral administration is 20–30%.

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

Nonlinear pharmacokinetics of metformin absorption is presumed. With recommended dosages 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 concentrations of metformin (Cmax) 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% decrease in Cmax, a 25% reduction in the area under the plasma concentration-time curve (AUC), and a 35-minute increase in Tmax were observed. The clinical significance of these changes is unknown.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Its maximum concentration in whole blood is lower than in plasma 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.

Excretion. Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, elimination half-life (t½) is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged t½ and consequently increased plasma metformin levels.

Special patient groups

Renal impairment

Limited data are available for patients with moderate renal impairment; therefore, systemic exposure to metformin in this group compared to patients with normal renal function cannot be precisely determined. Dose adjustment is therefore required based on clinical efficacy and tolerability (see section "Dosage and administration").

Pediatric population

A single-dose study with 500 mg of metformin hydrochloride showed that the pharmacokinetic profile in children is similar to that in healthy adult volunteers.

Data on multiple dosing in children are limited to one study.

After repeated administration of 500 mg metformin twice daily for 7 days in children, Cmax and systemic exposure (AUC0-t) were approximately 33% and 40% lower, respectively, compared to adult patients with type 2 diabetes receiving repeated 500 mg doses twice daily for 14 days.

Since dosage is individually titrated based on glycemic control, the above information has limited clinical relevance.

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 together 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 first-line therapy following ineffective dietary treatment.

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 a 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

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

Iodinated contrast media. Metformin should be discontinued in patients before or during radiological procedures involving iodinated contrast agents and should not be restarted earlier than 48 hours after the procedure, only after re-evaluation and confirmation of stable renal function (see sections "Special precautions for use" and "Dosage and administration").

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, particularly loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required at the initiation of treatment with these medicinal products or when used in combination 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. The dose of Diaformin® should be adjusted 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 (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 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 renal impairment, cardiopulmonary disease, or sepsis. In acute renal impairment, metformin accumulates, 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 advice should be sought.

Caution should be exercised when initiating medications in patients receiving metformin 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, any conditions associated with hypoxia, and concomitant use of medications 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; coma may develop later. If any symptom suggestive of lactic acidosis occurs, the patient must discontinue metformin and seek immediate medical attention.

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

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome) and maternally 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 metformin use, metformin therapy should be discontinued immediately and prompt diagnostic evaluation initiated.

Renal function. eGFR should be assessed before initiating 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 developing hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure provided regular monitoring of cardiac and renal function is performed. 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 not 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 performed under general, spinal, or epidural anesthesia and not restarted earlier than 48 hours after surgery or resumption of oral intake, and only after re-evaluation and confirmation of stable renal function.

Children. Before initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. One-year controlled clinical studies have shown no effect of metformin on growth or 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 receiving metformin, especially during puberty.

Children aged 10 to 12 years. Controlled clinical studies involving 15 children aged 10 to 12 years showed that the efficacy and safety of metformin in this patient group were comparable to those in older children and adolescents. The drug 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. Carbohydrate metabolism parameters should be monitored regularly.

Metformin commonly reduces serum vitamin B12 levels, potentially leading to deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and in patients with known risk factors for 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. Periodic monitoring of vitamin B12 levels is recommended in patients with risk factors for deficiency. Metformin therapy should be continued as long as it is tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency 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 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 related to hyperglycemia for both mother and child.

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

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

Limited and inconclusive evidence exists regarding the effect of metformin on long-term weight outcomes in children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed during pregnancy, although data on long-term outcomes 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 adverse effects have not been observed in breastfed newborns/infants. However, due to insufficient safety data, 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 to the infant.

Fertility. Metformin had no effect on fertility in animals when administered at a dose of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to affect reaction speed when driving or operating machinery.

Metformin monotherapy does not affect reaction speed when driving 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.

Dosage and Administration

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

Monotherapy or combination therapy with other oral hypoglycemic agents

The usual starting dose is 500 mg or 850 mg of metformin 2–3 times daily, taken with meals or shortly after meals.

After 10–15 days, the dose should be adjusted based on serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

For high-dose therapy, use Diaformin®, film-coated tablets, 1000 mg.

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

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

Combination therapy with insulin

To achieve better glycemic control, metformin and insulin may be used together. The usual starting 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.

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

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

Children

Monotherapy or combination therapy with insulin

The medicinal product Diaphormin® can be administered to children aged 10 years and older and adolescents. The usual initial dose is 500 mg or 850 mg of Diaphormin® once daily during or after a meal. After 10–15 days, the dose should be adjusted according to blood plasma glucose measurements.

Gradual dose escalation reduces gastrointestinal side effects.

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

Children.

The medicinal product Diaphormin® is indicated for treatment in children aged 10 years and older.

Overdose.

When the medicinal product 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 method 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 in most cases. To prevent the occurrence of these adverse effects, it is recommended to gradually increase the dosage and to divide the daily dose into 2–3 administrations.

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 (≥1/10,000 and <1/1000), very rare (<1/10,000).

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

Disorders of metabolism

Common: vitamin B12 deficiency.

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

With prolonged use of the drug, absorption of vitamin B12 may decrease, leading to reduced serum levels. This possible cause of vitamin B12 deficiency should be considered if a patient presents with megaloblastic anemia.

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 often occur at the beginning of treatment and usually resolve spontaneously. To prevent gastrointestinal adverse effects, it is recommended to gradually increase the dosage and to administer the daily dose in 2–3 divided doses with 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.

Pediatric population

In published post-marketing data and controlled clinical trials in a limited pediatric population aged 10–16 years who received metformin for 1 year, adverse effects in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions. Store at temperatures 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.

74, Kyrylivska Street, Kyiv, 04080, Ukraine