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

Composition:

Active substance: repaglinide;

1 tablet contains 1 mg of repaglinide;

Excipients:

potassium polacrilin, meglumine, microcrystalline cellulose, maize starch, povidone, glycerin, poloxamer, anhydrous calcium hydrogen phosphate, magnesium stearate, iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of light yellow to yellow color.

Pharmacotherapeutic group. Other blood glucose-lowering agents, excluding insulin.

ATC code A10BX02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Repaglinide is a rapid-acting oral insulin secretagogue. It rapidly reduces blood glucose levels by stimulating insulin secretion from the pancreas, with the effect depending on the number of functioning β-cells in the pancreatic islets.

Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a specific protein, distinct from other insulin secretagogues. This leads to depolarization of β-cells and results in the opening of calcium channels, increasing intracellular calcium influx, which stimulates insulin secretion.

Effects related to pharmacodynamics

In patients with type 2 diabetes, an increase in insulin concentration in blood occurs within 30 minutes after oral administration of repaglinide. This reduces blood glucose levels throughout the period of food absorption. The elevated insulin level persists only during the postprandial period. Plasma concentrations of repaglinide decline rapidly, with low levels observed in patients with type 2 diabetes within 4 hours after administration.

Clinical efficacy and safety

After oral administration of repaglinide in doses ranging from 0.5 to 4 mg in patients with type 2 diabetes, a dose-dependent reduction in glucose concentration has been demonstrated. Based on clinical trial results, repaglinide should be taken with main meals (prandial dosing). The drug is generally taken 15 minutes before a meal, although the timing may vary from immediately before the meal up to 30 minutes before eating.

Pharmacokinetics.

Absorption

Repaglinide is rapidly absorbed from the gastrointestinal tract, leading to a rapid increase in plasma concentration. Peak plasma concentration of repaglinide is reached within 1 hour after administration. After the peak, plasma levels decline rapidly. The pharmacokinetics of repaglinide are characterized by a mean absolute bioavailability of 63% (coefficient of variation 11%). Administration of repaglinide immediately before a meal, 15 or 30 minutes before a meal, or in the fasting state does not significantly affect pharmacokinetic parameters. In clinical trials, high inter-individual variability (60%) in plasma concentrations of repaglinide was observed; within the same patient, variability ranged from low to moderate (35%). Since repaglinide dosing is based on individual clinical response, high inter-individual variability does not affect the drug's efficacy.

Distribution

The pharmacokinetics of repaglinide are characterized by a low volume of distribution (30 L, corresponding to distribution in intracellular fluid). Repaglinide is highly bound (98%) to plasma proteins.

Elimination

Repaglinide is rapidly eliminated from plasma within 4–6 hours. The elimination half-life (t_1/2) is approximately 1 hour. Repaglinide is completely metabolized. Its metabolites do not cause clinically significant hypoglycemia.

Repaglinide and its metabolites are primarily excreted via bile. A small fraction (approximately 8%) of the administered dose is recovered in urine as metabolites. Less than 2% of the dose is found in feces.

Special patient populations

The effect of repaglinide is increased in patients with hepatic impairment and in elderly patients with type 2 diabetes. The AUC (AUC_0–∞) after a single 2 mg dose (4 mg in patients with hepatic impairment) was 31.4 ng/mL/h (28.3) in healthy volunteers, 304.9 ng/mL/h (228.0) in patients with hepatic impairment, and 117.9 ng/mL/h (83.8) in elderly patients with type 2 diabetes.

After 5 days of treatment with repaglinide (2 mg three times daily) in patients with severe renal impairment (creatinine clearance: 20–39 mL/min), results showed a statistically significant twofold increase in exposure (AUC) and t_1/2 compared to patients with normal renal function.

Pediatric population

Data are lacking.

Non-clinical safety data

Standard preclinical studies revealed no special hazard for humans with repaglinide. Studies in animals showed that repaglinide has no teratogenic effects. However, reproductive toxicity was observed in animal studies. Embryotoxicity and limb malformations were observed in fetuses and newborn animals from animals treated with high doses of repaglinide during late pregnancy and lactation. Repaglinide was detected in the milk of experimental animals.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM), when adequate control of blood glucose levels cannot be achieved by diet, weight reduction, and physical exercise.

The use of repaglinide in combination with metformin or thiazolidinediones is also indicated in patients with type 2 diabetes mellitus in whom adequate glycemic control cannot be achieved with these agents used alone.

Treatment should be initiated as an adjunct to diet or physical exercise to reduce meal-related blood glucose levels.

Contraindications.

Known hypersensitivity to repaglinide or to any of the excipients;
type 1 diabetes mellitus (insulin-dependent diabetes mellitus), C-peptide-negative diabetes;
diabetic ketoacidosis, with or without coma;
severe hepatic impairment;
concomitant use with gemfibrozil;
pregnancy;
breastfeeding.

Interaction with other medicinal products and other forms of interaction.

It is known that certain medicinal products may affect repaglinide clearance. The possibility of such interactions must be considered by the physician when prescribing the drug.

In vitro data indicate that the metabolism of repaglinide is primarily mediated by CYP2C8 and CYP3A4 enzymes. Studies in healthy volunteers have shown that 2C8 is the most important enzyme in repaglinide metabolism, while 3A4 plays a minor role. However, inhibition of 2C8 leads to an increased relative contribution of 3A4. Therefore, the metabolism and clearance of repaglinide may be altered when co-administered with agents that inhibit or induce the activity of cytochrome P450 enzymes. Particular caution should be exercised when repaglinide is used concomitantly with inhibitors of 2C8 and 3A4. In vitro data also show that repaglinide is actively taken up into hepatocytes via the organic anion transporting polypeptide (OATP1B1). Medicinal products that inhibit OATP1B1 (e.g., cyclosporine) may potentially increase repaglinide plasma concentrations.

Medicinal products that may potentiate and/or prolong the hypoglycemic effect of repaglinide:

gemfibrozil, trimethoprim, rifampicin, ketoconazole, itraconazole, clarithromycin, cyclosporine, deferasirox, clopidogrel, other antidiabetic agents, monoamine oxidase inhibitors (MAO), non-selective beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, salicylates, nonsteroidal anti-inflammatory drugs, octreotide, anabolic steroids, alcohol.

Following concomitant administration of 600 mg gemfibrozil twice daily and repaglinide (single dose 0.25 mg), the AUC increased 8.1-fold and Cmax in plasma increased 2.4-fold in healthy volunteers. The elimination half-life in plasma increased from 1.3 hours to 3.7 hours, which may enhance and prolong the glucose-lowering effect of repaglinide. When gemfibrozil was administered, repaglinide plasma concentration increased 28.6-fold over 7 hours. Concomitant use of gemfibrozil and repaglinide is contraindicated (see Contraindications section).

No clinically relevant pharmacokinetic interaction was observed between fenofibrate and repaglinide.

Following concomitant administration of 160 mg trimethoprim twice daily (a weak CYP2C8 inhibitor) and repaglinide (single dose 0.25 mg), AUC increased 1.6-fold, Cmax increased 1.4-fold, and t½ increased 1.2-fold; however, no statistically significant effect on blood glucose levels was observed. Administration of subtherapeutic doses of repaglinide did not produce a pharmacodynamic effect. Since the safety of this combination has not been established for repaglinide doses above 0.25 mg and trimethoprim doses above 320 mg, concomitant use of these agents should be performed with caution. If treatment is necessary, careful monitoring of blood glucose levels and the patient's clinical status is recommended.

Administration of rifampicin (a potent inducer of CYP3A4 and CYP2C8, acting as both an inducer and inhibitor of repaglinide metabolism) at a dose of 600 mg daily for 7 days, followed by a single 4 mg dose of repaglinide on day 7, resulted in a 50% reduction in AUC (a result of combined induction and inhibition). When repaglinide was administered 24 hours after the last dose of rifampicin, AUC decreased by 80% (due to induction alone).

When repaglinide and rifampicin are used concomitantly, the dose of repaglinide should be adjusted based on careful monitoring of blood glucose levels at the following time points: at the start of rifampicin treatment (acute inhibition), after several days of rifampicin use (combined induction and inhibition), after discontinuation of rifampicin (induction only), and one week after stopping rifampicin, when its inductive effect has subsided.

The effect of ketoconazole (a potent competitive inhibitor of CYP3A4) on the pharmacokinetics of repaglinide was studied in healthy volunteers. Administration of ketoconazole 200 mg twice daily concomitantly with repaglinide (single dose 4 mg) increased AUC and Cmax by 1.2-fold; the glucose concentration profile changed by less than 8%.

Concomitant use of 100 mg itraconazole (a CYP3A4 inhibitor) was also studied in healthy volunteers. AUC increased 1.4-fold. No clinically significant changes in blood glucose levels were observed.

When 250 mg clarithromycin (a CYP3A4 inhibitor) and repaglinide were administered concomitantly in healthy volunteers, AUC increased 1.4-fold and Cmax increased 1.7-fold. Insulin AUC increased 1.5-fold (Cmax increased 1.6-fold). The mechanism of this interaction has not yet been fully elucidated.

A study in healthy volunteers receiving repaglinide (single dose 0.25 mg) showed that cyclosporine (100 mg), an inhibitor of CYP3A4 and OATP1B1, increased the maximum concentration of repaglinide 1.8-fold and AUC 2.5-fold. Since the safety of this combination has not been established for repaglinide doses above 0.25 mg, concomitant use of these agents should be avoided. If treatment is necessary, careful monitoring of blood glucose levels and the patient's clinical status is recommended.

Concomitant administration of deferasirox (a moderate inhibitor of CYP2C8 and CYP3A4) at a dose of 30 mg/kg body weight daily for 4 days and repaglinide (single dose 0.5 mg) in healthy volunteers resulted in a 2.3-fold increase in repaglinide exposure (AUC) (90% confidence interval [2.03–2.63]) and a 1.6-fold increase in Cmax (90% confidence interval [1.42–1.84]), leading to a minor (but statistically significant) reduction in blood glucose levels. Since interactions between these agents have not been established at repaglinide doses above 0.5 mg, their concomitant use should be avoided. If treatment is necessary, careful monitoring of blood glucose levels and the patient's clinical status is recommended (see section "Special precautions").

Concomitant use of the CYP2C8 inhibitor clopidogrel (loading dose 300 mg) increased AUC_0–∞ 5.1-fold, and continued use (75 mg daily) increased AUC_0–∞ 3.9-fold. A minor but statistically significant reduction in blood glucose levels was observed. If treatment is necessary, careful monitoring of blood glucose levels and the patient's clinical status is recommended (see section "Special precautions").

Beta-blockers may mask the symptoms of hypoglycemia.

Concomitant administration of cimetidine, nifedipine, estrogen, or simvastatin (substrates of CYP3A4) with repaglinide does not significantly affect its pharmacokinetic parameters.

Drug interaction studies conducted in healthy volunteers have shown that repaglinide does not clinically significantly affect the pharmacokinetics of digoxin, theophylline, or warfarin. Therefore, dose adjustment is not required when these agents are used concomitantly with repaglinide.

Medicinal products that may reduce the hypoglycemic effect of repaglinide:

oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones, and sympathomimetics. When initiating or discontinuing these agents in patients receiving repaglinide, careful monitoring of glycemic levels is required.

Children

No drug interaction studies have been conducted in children and adolescents.

Special precautions for use

Repaglinide should be prescribed when blood glucose levels are inadequately controlled by diet, physical activity, and weight reduction.

If a patient, whose glycemic control has been stabilized with oral antidiabetic agents, is exposed to stress (e.g., fever, trauma, infections, or surgery), glycemic control may deteriorate. In such cases, it may become necessary to discontinue repaglinide and temporarily switch to insulin therapy.

Hypoglycemia

Repaglinide, like other insulin secretagogues, may cause hypoglycemia.

Combination therapy with insulin secretagogues

In many patients, the hypoglycemic effect of oral antidiabetic agents decreases over time with prolonged use. This may be related to the progression of diabetes or reduced responsiveness to the drug. This phenomenon is known as secondary failure and should be distinguished from primary failure, in which a patient does not respond to the drug upon initial administration. Before diagnosing secondary failure, it is essential to consider adjusting the dose and to verify the patient's adherence to dietary and exercise recommendations.

Repaglinide acts via a specific binding site with a short-term effect on β-cells. The use of repaglinide in patients with secondary failure to insulin secretagogues has not been studied in clinical trials.

Clinical trials investigating combination therapy with other insulin secretagogues have not been conducted.

Combination therapy with neutral protamine Hagedorn (NPH) insulin or thiazolidinediones

Studies on combination therapy with NPH insulin or thiazolidinediones have been conducted. However, a risk/benefit assessment is required for other forms of combination therapy.

Combination therapy with metformin

When repaglinide is used in combination with metformine, the risk of hypoglycemia is increased.

Combination therapy with other agents

Patients receiving concomitant medications that affect repaglinide metabolism should be treated with caution or repaglinide should not be used at all (see section "Interaction with other medicinal products and other forms of interaction"). If combination therapy is necessary, careful monitoring of blood glucose levels and the patient's clinical condition is required.

Acute coronary syndrome

Treatment with repaglinide may be associated with an increased risk of acute coronary syndrome (e.g., myocardial infarction).

Special patient groups

Elderly patients

Clinical studies involving patients aged 75 years and older have not been conducted.

Patients with renal impairment

Renal impairment does not significantly affect repaglinide. However, 8% of the repaglinide dose is excreted by the kidneys, and total repaglinide clearance is reduced in renal insufficiency. Since insulin sensitivity is increased in diabetic patients with renal impairment, caution is required when determining the dosage.

Patients with hepatic impairment

Clinical studies in patients with hepatic impairment have not been conducted.

Debilitated or malnourished patients

Initial and maintenance dosing, as well as dose titration, should be performed with particular care in these patients to avoid hypoglycemia.

Use during pregnancy or breastfeeding

Pregnancy

Studies on the use of repaglinide in pregnant women have not been conducted. The use of repaglinide should be avoided during pregnancy.

Breastfeeding

Studies on the use of repaglinide in breastfeeding women have not been conducted. Repaglinide should not be used in women who are breastfeeding.

Fertility

Information on reproductive toxicity studies in animals is provided in the section "Data from preclinical safety".

Ability to affect reaction speed when driving or operating machinery

Repaglinide has no direct effect on reaction speed when driving or operating machinery, but it may lead to hypoglycemia.

Patients should be advised to take preventive measures to avoid hypoglycemia while driving. This is particularly important for patients with impaired awareness of hypoglycemia symptoms or those who frequently experience hypoglycemic episodes. In such cases, the appropriateness of driving should be carefully evaluated.

Administration and Dosage

The drug should be administered orally before each main meal (i.e., preprandially), with the dose individually adjusted to optimize glycemic control. In addition to the patient's self-monitoring of blood and/or urine glucose levels, the physician should periodically monitor blood glucose concentrations to determine the minimum effective dose of the drug. The level of glycated hemoglobin is also an informative indicator for monitoring the patient's response to treatment. Periodic monitoring is necessary to detect inadequate reduction in blood glucose concentration when the maximum recommended dose is used (i.e., primary failure), as well as to identify the absence of an appropriate decrease in blood glucose levels after an initially effective treatment period (i.e., secondary failure).

Initial Dose

The physician should select the dose according to the patient's response. The recommended initial dose is 0.5 mg (administer repaglinide at the corresponding dosage strength). Dose titration should begin after 1–2 weeks (the interval determined by the patient's response to treatment). If the patient has previously been taking another oral antidiabetic agent, the recommended initial dose is 1 mg.

Maintenance Therapy

The maximum recommended single dose before main meals is 4 mg. The maximum daily dose should not exceed 16 mg.

Patients Previously on Other Oral Hypoglycemic Agents

Patients may be directly switched from other oral hypoglycemic agents to repaglinide. An exact dose equivalence between repaglinide and other oral hypoglycemic agents has not been established. The maximum recommended initial dose for patients being switched to repaglinide is 1 mg before each main meal.

If blood glucose levels are not adequately controlled with metformin, thiazolidinediones, or repaglinide alone, these agents may be used concomitantly. The metformin dose should be maintained unchanged while repaglinide is added. The initial dose of repaglinide is 0.5 mg (administer repaglinide at the corresponding dosage strength). Dose titration should be performed according to blood glucose concentrations.

Administration Method

The drug should be taken orally, usually within 15 minutes before starting a meal; however, the time of administration may vary from immediately before the meal to up to 30 minutes before eating (i.e., preprandially for two-, three-, or four-times-daily meals). If a patient skips a meal (or has an additional meal), the corresponding dose of the drug should be skipped (or added).

Children

The drug is not recommended for use in children (under 18 years of age) due to insufficient data on the safety and efficacy of repaglinide in this patient group.

Overdose

Repaglinide was administered over 6 weeks in weekly increasing doses from 4 to 20 mg four times daily. No safety concerns were recorded. Since the potential for hypoglycemia was prevented in this study by increased caloric intake, relative overdose could lead to pronounced reduction in blood glucose concentration and development of hypoglycemic symptoms (dizziness, sweating, tremor, headache). If such symptoms occur, appropriate measures should be taken to normalize blood glucose levels (e.g., ingestion of carbohydrates). In cases of more severe hypoglycemia accompanied by seizures, loss of consciousness, or coma, intravenous glucose should be administered.

Adverse Reactions.

Safety Data

The most commonly observed adverse effects are related to changes in blood glucose levels, such as hypoglycemia. The frequency of such reactions depends on individual patient characteristics: dietary habits, drug dosage, level of physical activity, and stress.

Based on experience with repaglinide and other antidiabetic agents, adverse effects can be categorized by frequency as follows: common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

Immune system:

very rare – allergic reactions*.

Metabolism and nutrition disorders:

common – hypoglycemia; frequency not known – hypoglycemia with loss of consciousness and hypoglycemic coma.

Eye disorders:

very rare – visual disturbances (refraction abnormalities)*.

Cardiac and vascular disorders:

rare – cardiovascular disorders.

Gastrointestinal disorders:

common – abdominal pain, diarrhea; very rare – vomiting, constipation; frequency not known – nausea.

Hepatobiliary disorders:

very rare – liver function abnormalities, increased liver enzymes*.

Skin and subcutaneous tissue disorders:

frequency not known – hypersensitivity reactions*.

*See section "Description of selected adverse reactions".

Description of selected adverse reactions

Allergic reactions

Generalized hypersensitivity reactions (e.g. anaphylactic reactions) or immune-mediated reactions such as vasculitis.

Visual disturbances (refraction abnormalities)

Fluctuations in blood glucose levels may lead to temporary disturbances in visual acuity, particularly at the beginning of treatment.

Liver function abnormalities, increased liver enzymes

Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. In most cases, the increases were mild and transient, and very few patients had to discontinue treatment due to elevated liver enzymes. Severe liver dysfunction has been observed very rarely.

Hypersensitivity reactions

Hypersensitivity reactions to the drug may manifest as redness, itching, rash, and urticaria. Due to different chemical structures, cross-allergic reactions with sulfonylurea drugs are unlikely.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

15 tablets in a blister; 2, 4, or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Rivopharm SA, Switzerland.

Manufacturer's address.

Centro Insema, 6928 Manno, Switzerland.

Marketing Authorization Holder.

INSUPHAR LABORATORIES LIMITED, United Kingdom.

Insvada