Tsukrolit

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CUKROLIT (CUKROLIT)

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet contains metformin hydrochloride 500 mg, or 850 mg, or 1000 mg;

Excipients: povidone K90, magnesium stearate;

Tablet coating: hypromellose (E 464), polyethylene glycol 6000 (E 1521), polyethylene glycol 400 (E 1521).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

500 mg tablets: white to yellowish, biconvex, round, film-coated tablets, with embossing MA on one side. Tablet diameter: 11.0 ± 0.3 mm. 850 mg tablets: white to yellowish, biconvex, oval, film-coated tablets, with a score line between embossing M and B on one side and a score line on the other side. Tablet size: 17.9 × 10.0 mm ± 0.3 mm. 1000 mg tablets: white to yellowish, biconvex, oval, film-coated tablets, with embossing MC on one side and a score line on the other side. Tablet size: 19.2 × 9.2 mm ± 0.3 mm.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic activity. It reduces glucose levels in blood plasma both in the fasting state and after food intake. It does not stimulate insulin secretion and therefore does not cause hypoglycemia 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 glucose absorption.

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

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

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

Pharmacokinetics.

Absorption.

After oral administration of metformin, the time to reach maximum plasma concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin in 500 mg or 800 mg tablet formulations is approximately 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces is 20–30%.

Following oral administration, metformin absorption is saturable and incomplete. It is presumed that metformin absorption is nonlinear. When metformin is administered 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 (Cmax) did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption. After oral administration of 850 mg, 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, while time to maximum concentration is approximately the same. Erythrocytes likely represent a secondary distribution compartment for metformin. 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 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 increased metformin plasma levels.

Special patient groups.

Renal impairment.

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

Pediatric population.

In a single-dose study of 500 mg metformin hydrochloride, the pharmacokinetic profile in pediatric patients was similar to that in healthy adults.

Data on multiple-dose administration are limited to one study.

Following 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 diabetes receiving repeated 500 mg doses twice daily for 14 days.

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

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when diet 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 older and adolescents.

For reducing complications of diabetes in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line medicinal product after failed dietary therapy.

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 renal function impairment, 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 for use.

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

Iodinated contrast agents. 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 "Special precautions").

Combinations that should be used with caution. Some 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, 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 medicinal products or when using them in combination with metformin. Medicinal products causing hyperglycemic effects (systemic and topical glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of Sukrolit should be adjusted during and after discontinuation of such concomitant 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 the efficacy of metformin;
• 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 concentrations of metformin;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.

Therefore, particular caution is recommended when co-administering these medicinal products 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 the efficacy of metformin.

Special precautions.

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 cases of dehydration (severe diarrhea 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 cautiously with agents that may acutely impair renal function (e.g., antihypertensive drugs, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, 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 dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. 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), elevated plasma lactate concentration in serum (> 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 immediately discontinued 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 altering 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 under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and 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 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 interventions performed under general, spinal, or epidural anesthesia, and not resumed earlier than 48 hours after surgery or until oral nutrition is re-established, and only after reassessment 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 shown no effect of metformin on growth and sexual maturation in children. However, data on the long-term effects of metformin on growth and sexual maturation are lacking; 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 demonstrated that the efficacy and safety of metformin in this patient group were comparable to those 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. Carbohydrate metabolism parameters should be monitored regularly.

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 known to cause vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if deficiency is suspected (e.g., anemia or neuropathy). Periodic monitoring of vitamin B12 is recommended in patients with risk factors for deficiency. Metformin therapy should be continued as long as it is tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be administered 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 hyperglycemia during the periconception period and pregnancy is associated with an increased 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 body of data from pregnant women (over 1000 pregnancy 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 with metformin use during the periconception period and/or pregnancy.

Evidence regarding long-term intrauterine effects of metformin on children's body weight is limited and inconclusive. Metformin appears not to affect motor and social development in children up to 4 years of age whose mothers received it during pregnancy, although long-term outcome data are limited.

If clinically necessary, metformin may be considered during pregnancy and the periconception 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 consider the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin did not affect fertility in animals 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 affect reaction speed when driving or operating machinery.

Metformin monotherapy does not affect reaction speed when driving or operating machinery, as the medicinal product 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.

Method of Administration and Dosage

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 of metformin hydrochloride taken 2–3 times daily, 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 per day), every 2 tablets of the medicinal product Sukrolit 500 mg may be replaced by 1 tablet of the medicinal product Sukrolit 1000 mg.

The maximum recommended dose is 3000 mg per day, administered in 3 divided doses.

When switching from another antidiabetic agent, the previous medication should be discontinued and metformin initiated as described above.

Combination therapy with insulin.

To achieve better glycemic control, metformin and insulin can be used together. The usual initial dose of metformin hydrochloride is 500 mg or 850 mg 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 dosage must be adjusted based on assessment of renal function, which should be performed regularly (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. 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 medicinal product Sukrolit may be used in children aged 10 years and older and adolescents. The usual initial dose is 500 mg or 850 mg of Sukrolit 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 helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg per day, administered in 2–3 divided doses.

Overdose.

Symptoms. Hypoglycemia has not been observed following administration of up to 85 g of the medicinal product. However, in such cases, lactic acidosis may develop. Significant metformin overdose or concomitant risk factors can lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital setting. 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, diarrhoea, 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 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 (> 1/1/1000 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 nutritional disorders.
Common: vitamin B12 deficiency/decreased 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, diarrhoea, 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 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.

Paediatric population.
In published and post-marketing data and controlled clinical trials in a limited paediatric 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.
Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.
3 years.

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

Packaging.
10 tablets in a blister; 3 blisters in a cardboard box, or 10 tablets in a blister; 5 blisters in a cardboard box.

Prescription status.
Prescription only.

Manufacturer.
SAG MANUFACTURING, S.L.U.

Manufacturer's address and location of operations.
Carretera Nacional 1 Km 36, San Agustín del Guadalix, 28750 Madrid, Spain.