Insufor

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

Composition:

Active substance: metformin;

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

Excipients: povidone, pregelatinized starch, crospovidone, magnesium stearate, Opadry® II White 85F18422 (partially hydrolyzed polyvinyl alcohol; titanium dioxide (E 171); macrogol 4000; talc).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

Film-coated tablets, 500 mg, 850 mg: white, round, biconvex film-coated tablets;

Film-coated tablets, 1000 mg: white, oval, biconvex film-coated tablets with a break line on both sides.

Pharmacotherapeutic group.

Agents affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulins. Biguanides. ATC code A10B A02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Metformin is a biguanide with antihyperglycemic activity, reducing both fasting and postprandial hyperglycemia. It does not stimulate insulin secretion and does not cause hypoglycemia.

Metformin reduces fasting hyperinsulinemia, and when used in combination with insulin, it reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• Metformin reduces glucose production in the liver;
• Metformin enhances peripheral glucose uptake and utilization, partly by improving insulin action;
• Metformin alters glucose metabolism in the intestine: portal glucose uptake increases while intestinal absorption from food decreases. Additional intestinal mechanisms include increased release of glucagon-like peptide-1 (GLP-1) and reduced bile acid reabsorption. Metformin alters the gut microbiome;
• Metformin may improve lipid profile in patients with hyperlipidemia.

In clinical trials, body weight remained stable or decreased slightly during metformin treatment.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK) and enhances the transport capacity of all types of glucose membrane transporters (GLUT).

Pharmacokinetics.

Absorption

After oral administration, the time to reach maximum concentration (Cmax) of metformin is approximately 2.5 hours (Tmax). The absolute bioavailability of the 500 mg or 800 mg tablet formulation 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.

Nonlinear pharmacokinetics of metformin are expected. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and are less than 1 µg/mL. In controlled clinical trials, maximum plasma concentrations (Cmax) of metformin did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption.

After an oral dose of 850 mg, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute prolongation of 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 peak is approximately the same. Erythrocytes likely serve as 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 patients with impaired renal function, 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 patient group cannot be precisely assessed compared to patients with normal renal function. 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 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.

As 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 exercise therapy are ineffective, particularly 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 diabetes in adult patients with type 2 diabetes and excess body weight as a first-line agent after ineffective dietary therapy.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients 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 renal function impairment, dehydration, severe infections, shock.
• Conditions that may lead to tissue hypoxia (especially acute conditions or exacerbations of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
• Hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interactions.

Combinations not recommended for use.

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

Iodinated contrast agents. Metformin should be discontinued before or during radiological procedures involving iodinated contrast media 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 "Method of administration and dosage" and "Special precautions").

Combinations requiring 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, 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 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 concomitant 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 metformin concentrations;
• inhibitors of both OCT1 and OCT2 (e.g., crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

Therefore, special caution is recommended when co-administering these agents with metformin, particularly 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.

Risk of lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in acute renal impairment, cardiopulmonary disease, or sepsis. Acute renal impairment leads to accumulation of metformin, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of the medicinal product is recommended, and medical advice should be sought.

Care should be taken when initiating treatment with medicinal products that may acutely worsen renal function (e.g., antihypertensives, diuretics, and NSAIDs) during metformin therapy. 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.

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

If any symptoms suggestive of lactic acidosis occur, the medicinal product should be discontinued immediately and medical attention should be sought without delay.

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 starting metformin, metformin treatment should be discontinued immediately and prompt diagnostic evaluation initiated.

Effect on renal function

Renal function (eGFR) should be assessed before initiating and regularly during treatment (see section "Dosage and administration"). The medicinal product is contraindicated in patients with eGFR <30 mL/min. If conditions affecting renal function occur (see section "Contraindications"), metformin should be temporarily discontinued.

Effect on cardiac function

Patients with heart failure have an increased risk of hypoxia and renal impairment. The medicinal product may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. The medicinal product is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Concomitant use with iodinated contrast agents

Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. The medicinal product 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

The medicinal product 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 nutrition, and only after reassessment and confirmation of stable renal function.

Use in children

Before initiating treatment, a diagnosis of type 2 diabetes mellitus must be confirmed. Controlled clinical studies of one year's duration have shown no effect of metformin on growth and 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 treated with metformin, especially during puberty.

Controlled clinical studies have shown that efficacy and safety of metformin in 15 children aged 10 to 12 years were comparable to those in older children and adolescents.

The medicinal product should be used with particular caution in children aged 10 to 12 years.

Risk of decreased plasma vitamin B12 levels

Metformin may reduce vitamin B12 levels, potentially leading to deficiency. The risk of vitamin B12 deficiency increases with higher metformin doses, longer duration of treatment, and in patients with risk factors for vitamin B12 deficiency. If deficiency is suspected (e.g., in patients with megaloblastic anemia or newly developed neuropathy), plasma vitamin B12 levels should be measured and current clinical guidelines for investigation and treatment of vitamin B12 deficiency followed. Patients with risk factors for vitamin B12 deficiency should undergo periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is well tolerated and not contraindicated, with corrective treatment for vitamin B12 deficiency administered according to current clinical guidelines.

Other precautions

During treatment with the medicinal product, patients should adhere to a diet with evenly distributed carbohydrate intake throughout the day. Patients with excess body weight should continue following a low-calorie diet. Glycemic parameters should be monitored regularly.

Metformin monotherapy does not cause hypoglycemia; however, caution is required when the medicinal product is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides).

Use during pregnancy or breastfeeding

Pregnancy

Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational 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 of hyperglycemia for both mother and child.

Metformin crosses the placenta in amounts that may be as high as maternal concentrations.

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

There are some unconfirmed data on the long-term effect of metformin on weight 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 in utero, although data on long-term outcomes are limited.

If clinically indicated, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an alternative to insulin.

Lactation

Metformin is excreted in breast milk, but no adverse effects have 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 for the infant.

Fertility

Metformin did not affect fertility in animals 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

Metformin monotherapy does not affect reaction speed when driving or operating machinery, as it does not cause hypoglycemia. However, the medicinal product should be used with caution when administered concomitantly with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Dosage and Administration

Monotherapy or combination therapy with other oral hypoglycemic agents

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

The usual initial dose of metformin is 500 mg or 850 mg two to three times daily, taken during or after meals.

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

Gradual dose escalation helps reduce gastrointestinal side effects.

When high doses (2000–3000 mg per day) of metformin are required, every two 500 mg tablets may be replaced with one 1000 mg tablet.

The maximum recommended daily dose of metformin is 3000 mg per day, divided into three doses.

When switching from another antidiabetic medicinal product, treatment with the previous agent should be discontinued and metformin initiated as described above.

Combination therapy with insulin

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

To achieve better blood glucose control, metformin and insulin can be used in combination therapy. The usual initial dose of metformin is 500 mg or 850 mg two to three times daily, while the insulin dose should be adjusted based on plasma glucose measurements.

Elderly patients

Renal function may be reduced in these patients; therefore, the dose of metformin 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

Renal function (eGFR) should be assessed before initiating metformin therapy and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should have renal function monitored more frequently, for example every 3–6 months.

Children aged 10 years and older

The usual starting dose of metformin is 500 mg or 850 mg once daily, taken during or after a meal.

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

Gradual dose escalation helps reduce gastrointestinal side effects.

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

Children.

This medicinal product is indicated for use in children aged 10 years and older.

Overdose.

Hypoglycemia was not observed following administration of metformin at a dose of 85 g. 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 elimination of lactate and metformin from the body.

Side effects

The most common adverse reactions at the beginning of metformin therapy 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 reactions, a gradual dose escalation is recommended, along with administration of the daily dose in 2–3 divided doses.

Adverse reactions are classified by frequency of occurrence as follows: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1,000 and <1/100), rare (>1/10,000 and <1/1,000), very rare (<1/10,000). Within each organ system class, adverse reactions are listed in order of decreasing 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 commonly occur at the start of metformin therapy and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse effects, a gradual dose escalation is recommended, along with administration of the daily dose in 2–3 divided doses taken 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 rash, erythema, pruritus, and urticaria.

Children

According to published data, post-marketing experience, and results of controlled clinical trials in which metformin was administered for 1 year to a limited number of children and adolescents aged 10–16 years, the type and severity of adverse reactions in this population were similar to those observed in adults.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any 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.

Storage conditions

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging

Film-coated tablets, 500 mg and 850 mg: 15 tablets in a blister; 2, 4, or 6 blisters per cardboard box.

Film-coated tablets, 1000 mg: 10 tablets in a blister; 3, 6, or 9 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLД MEDICINE ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine.