Diaglinide (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

A10BX02 (Repaglinide)

Active Substance

Repaglinide (Rec.INN registered by WHO)

Dosage Forms

	Diaglinide	Tablets 1 mg: 30 or 60 pcs.
		Tablets 2 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white with a grayish or yellowish tint, round, flat-cylindrical, with a bevel and a score.

Excipients: poloxamer (type 188), meglumine, lactose monohydrate, microcrystalline cellulose, polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

Tablets white with a grayish or yellowish tint, round, flat-cylindrical, with a bevel.

Excipients: poloxamer (type 188), meglumine, lactose monohydrate, microcrystalline cellulose, polacrilin potassium, colloidal silicon dioxide, magnesium stearate.

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; other hypoglycemic drugs, other than insulins

Pharmacological Action

Oral hypoglycemic drug. Stimulates the release of insulin from functioning pancreatic β-cells. Blocks ATP-dependent channels in β-cell membranes via target proteins, which leads to depolarization of β-cells and opening of calcium channels. The increased influx of calcium ions induces insulin secretion. In patients with type 2 diabetes mellitus, the insulinotropic response to food intake is observed within 30 minutes after administration. This ensures a decrease in blood glucose concentration throughout the meal period. At the same time, the plasma concentration of repaglinide decreases rapidly, and 4 hours after drug administration, low concentrations of repaglinide are detected in the plasma of patients with type 2 diabetes mellitus. When repaglinide is used in the dose range from 0.5 to 4 mg, a dose-dependent decrease in glucose concentration is noted.

Pharmacokinetics

Absorption

When taken orally, the absorption of repaglinide from the gastrointestinal tract is high. Time to reach C_max is 1 hour. The average bioavailability of repaglinide is 63% (coefficient of variability is 11%). Since the dose titration of repaglinide is carried out depending on the response to therapy, interindividual variability does not affect the effectiveness of therapy.

Distribution and Metabolism

V_d is 30 L. Plasma protein binding is 98%. It is completely metabolized in the liver under the influence of CYP3A4 to inactive metabolites.

Excretion

It is excreted mainly with bile, by the kidneys – 8% in the form of metabolites, through the intestines – 1%. T_1/2 is 1 hour.

Pharmacokinetics in special clinical cases

The use of repaglinide in usual doses in patients with impaired liver function may lead to higher concentrations of repaglinide and its metabolites than in patients with normal liver function. In this regard, the use of repaglinide is contraindicated in patients with severe liver dysfunction, and in patients with mild to moderate liver dysfunction, Repaglinide should be used with caution. The intervals between dose adjustments should also be increased to more accurately assess the response to therapy.

AUC and C_max are the same in patients with normal renal function and in patients with mild or moderate renal impairment. In patients with severe renal impairment, an increase in AUC and C_max was noted, but only a weak correlation was found between repaglinide concentration and creatinine clearance. It appears that patients with impaired renal function do not need to adjust the initial dose. However, subsequent dose increases in patients with type 2 diabetes mellitus in combination with severe renal impairment requiring hemodialysis should be performed with caution.

Indications

• Type 2 diabetes mellitus (in case of ineffectiveness of diet, weight loss and physical activity) in monotherapy or in combination with metformin or thiazolidinediones in cases where satisfactory glycemic control cannot be achieved with monotherapy with repaglinide or metformin or thiazolidinediones.

ICD codes

Dosage Regimen

Diaglinide^® is prescribed as an addition to diet and physical activity to reduce blood glucose concentration; its administration should be timed with meals.

The drug is taken orally before main meals, usually 15 minutes before the start of a meal, but can also be taken in the interval from 30 minutes before a meal to the immediate moment of eating.

The dose of the drug is selected individually for each patient depending on the blood glucose concentration.

The initial dose is 0.5 mg/day, if the patient was taking another oral hypoglycemic drug – 1 mg. Dose adjustment is carried out once a week or once every 2 weeks (while focusing on blood glucose concentration as an indicator of response to therapy). The average daily dose is 4 mg 3 times/day; maximum is 16 mg/day.

Transfer of patients from therapy with other oral hypoglycemic drugs to therapy with repaglinide can be carried out immediately. However, no exact relationship has been identified between the dose of repaglinide and the dose of other hypoglycemic drugs. The recommended maximum initial dose of repaglinide when switching from other hypoglycemic drugs is 1 mg before the main meal.

Combination therapy

Repaglinide may be prescribed in combination with metformin or thiazolidinediones in case of inadequate blood glucose control on monotherapy with metformin, thiazolidinediones or repaglinide. In this case, the same initial dose of repaglinide is used as in monotherapy. Then the dose of each drug is adjusted depending on the achieved blood glucose concentration.

Special patient groups

It is not recommended to prescribe Repaglinide to persons under 18 years of age due to the lack of sufficient data on its safety and efficacy in this group of patients.

Adverse Reactions

The most common side effect is hypoglycemia, the frequency of which, as with the use of any type of diabetes therapy, depends on individual factors, such as eating habits, drug dose, physical activity and stress. The following are side effects observed with the use of repaglinide and other oral hypoglycemic agents. All side effects are distributed by frequency of occurrence: common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (<1/10,000) and unknown (cannot be estimated from available data).

From the immune system very rarely – generalized hypersensitivity reactions or immunological reactions such as vasculitis may be detected; unknown – hypersensitivity reactions such as itching, rash, urticaria.

From metabolism: common – hypoglycemia; unknown – hypoglycemic coma, hypoglycemia with loss of consciousness. As with the use of other hypoglycemic agents, hypoglycemia may develop with the use of repaglinide. These reactions are mostly mild and can be eliminated by taking carbohydrates. In severe reactions, medical attention may be required, in particular, intravenous administration of dextrose (glucose). The risk of hypoglycemia may increase with interactions of repaglinide with other drugs.

From the organ of vision very rarely – visual disturbances. Changes in blood glucose concentration can lead to visual disturbances, especially at the initial stage of therapy with hypoglycemic drugs. However, these changes are usually transient.

From the cardiovascular system rarely – cardiovascular diseases. The risk of cardiovascular disease is increased in type 2 diabetes mellitus. An increased risk of acute coronary syndrome was identified in patients receiving Repaglinide compared with patients receiving a sulfonylurea derivative, but not compared with patients receiving metformin or acarbose. However, a causal relationship has not been established.

From the digestive system common – abdominal pain, diarrhea; very rarely – vomiting, constipation; unknown – nausea.

From the liver and biliary tract very rarely – impaired liver function; in very rare cases, severe liver dysfunction has been reported (a causal relationship with repaglinide has not been established), increased activity of liver enzymes.

Contraindications

• Type 1 diabetes mellitus;
• Diabetic ketoacidosis; diabetic precoma and coma;
• Infectious diseases, major surgical interventions and other conditions requiring insulin therapy;
• Severe liver dysfunction;
• Simultaneous administration of gemfibrozil;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years;
• Known hypersensitivity to repaglinide or to any of the components of the drug.

Clinical studies in patients under 18 years of age and over 75 years of age have not been conducted.

With caution (need for more careful monitoring) should be used for mild to moderate liver dysfunction, febrile syndrome, chronic renal failure, alcoholism, general severe condition, malnutrition.

Use in Pregnancy and Lactation

Studies on the use of repaglinide in pregnant women and nursing mothers have not been conducted. Therefore, the safety of repaglinide in pregnant women has not been studied. If it is necessary to use the drug during breastfeeding, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

With caution should be used for mild to moderate liver dysfunction.

Use in Renal Impairment

With caution the drug should be used for chronic renal failure.

Pediatric Use

It is not recommended to prescribe Repaglinide to persons under 18 years of age due to the lack of sufficient data on its safety and efficacy in this group of patients.

Geriatric Use

Clinical studies in patients over 75 years of age have not been conducted.

Special Precautions

Repaglinide is indicated for unsatisfactory glycemic control and persistence of symptoms of diabetes mellitus during diet therapy and exercise.

Since Repaglinide is a drug that stimulates insulin secretion, it can cause hypoglycemia. With combination therapy, the risk of hypoglycemia increases.

Major surgical interventions and trauma, extensive burns, infectious diseases with febrile syndrome may require discontinuation of oral hypoglycemic drugs and prescription of insulin.

It is necessary to regularly monitor fasting and postprandial blood glucose concentrations.

Patients should be warned about the increased risk of hypoglycemia when taking alcohol, NSAIDs, and during fasting. Dose adjustment is necessary during physical and emotional stress, changes in diet.

In patients with exhaustion, as well as patients receiving inadequate nutrition, caution should be exercised when selecting the initial and maintenance dose and its titration to avoid hypoglycemia.

Dose selection in patients with type 2 diabetes mellitus in combination with severe renal impairment should be carried out with caution.

Prescribing usual doses of repaglinide in patients with impaired liver function may lead to higher concentrations of repaglinide and its metabolites than in patients with normal liver function. In this regard, the prescription of repaglinide is contraindicated in patients with severe liver dysfunction, and in patients with mild to moderate liver dysfunction, Repaglinide should be used with caution. The intervals between dose adjustments should also be increased to more accurately assess the response to therapy.

Effect on ability to drive vehicles and machinery

Patients’ ability to concentrate and reaction speed may be impaired during hypoglycemia and hyperglycemia, which may be dangerous in situations where this ability is especially necessary (for example, when driving vehicles or working with machines and mechanisms). Patients should be advised to take measures to prevent the development of hypoglycemia and hyperglycemia when driving vehicles and working with mechanisms. This is especially important for patients with no or reduced severity of warning symptoms of developing hypoglycemia or those suffering from frequent episodes of hypoglycemia. In these cases, the advisability of performing such work should be considered.

Overdose

Overdose may lead to the development of hypoglycemia. Symptoms feeling of hunger, increased sweating, palpitations, tremor, anxiety, headache, insomnia, irritability, depression, speech and vision disorders.

When using repaglinide in patients with type 2 diabetes mellitus in a weekly increasing dose from 4 to 20 mg 4 times a day (with each meal) for 6 weeks, relative overdose was observed, manifested by an excessive decrease in glucose concentration with the development of symptoms of hypoglycemia.

Treatment if symptoms of hypoglycemia appear, appropriate measures should be taken to increase blood glucose concentration (take dextrose orally or foods rich in carbohydrates). In case of severe hypoglycemia (loss of consciousness, coma), dextrose is administered intravenously. After regaining consciousness – intake of easily digestible carbohydrates (to avoid recurrent hypoglycemia).

Drug Interactions

Possible interaction of repaglinide with drugs affecting glucose metabolism should be taken into account.

The metabolism, and thus the clearance of repaglinide, may be altered by drugs that exert an effect by suppressing or activating enzymes from the cytochrome P450 group. Particular caution should be exercised when prescribing repaglinide concomitantly with inhibitors of CYP2C8 and CYP3A4.

Inhibitors of the anion-transporting protein OATP1B1 (e.g., cyclosporine) may also increase the plasma concentration of repaglinide.

The following drugs may enhance and/or prolong the hypoglycemic effect of repaglinide: gemfibrozil, trimethoprim, rifampicin, clarithromycin, ketoconazole, itraconazole, cyclosporine, other hypoglycemic drugs, MAO inhibitors, non-selective beta-blockers, ACE inhibitors, salicylates, NSAIDs, octreotide, ethanol and anabolic steroids.

Beta-blockers may mask the symptoms of hypoglycemia.

Concomitant administration of cimetidine, nifedipine or simvastatin (which are substrates of CYP3A4) with repaglinide does not have a significant effect on the pharmacokinetic parameters of repaglinide.

Repaglinide does not clinically significantly affect the pharmacokinetic properties of digoxin, theophylline or warfarin when used in healthy volunteers. Thus, there is no need to adjust the dose of these drugs when used concomitantly with repaglinide.

The following drugs may weaken the hypoglycemic effect of repaglinide: oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.

Concomitant use of oral contraceptives (ethinyl estradiol/levonorgestrel) does not lead to a clinically significant change in the overall bioavailability of repaglinide, although the maximum concentration of repaglinide is achieved earlier. Repaglinide does not clinically significantly affect the bioavailability of levonorgestrel, but its effect on the bioavailability of ethinyl estradiol cannot be excluded.

In this regard, during the prescription or withdrawal of the above drugs, patients already receiving Repaglinide should be under close observation for timely detection of impaired glycemic control.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.