Diaglinide, tablets 2 mg 30 pcs

Diaglinide is an oral hypoglycemic agent, it stimulates insulin release from functioning beta cells of the pancreas.

Blocks ATP-dependent channels in the membranes of beta cells through target proteins, which leads to depolarization of beta cells and the opening of calcium channels. The increased influx of calcium ions induces insulin secretion.

In patients with type 2 diabetes an insulinotropic response to a meal is observed within 30 min after the meal. This provides a decrease in blood glucose concentration during the whole period of the meal. At the same time, the plasma concentration of repaglinide decreases rapidly, and 4 hours after taking the drug, low concentrations of repaglinide are detected in the plasma of patients with type 2 diabetes. There is a dose-dependent decrease in glucose concentrations when repaglinide is used in the dose range from 0.5 to 4 mg.

Pharmacokinetics:

In oral administration, absorption of repaglinide from the gastrointestinal tract is high. Time of reaching maximum concentration is 1 hour. Average bioavailability of repaglinide is 63 % (coefficient of variability is 11 %). Since repaglinide dose titration depends on the response to therapy, interindividual variability does not affect the effectiveness of therapy.

The volume of distribution is 30 liters. Binding to plasma proteins – 98%. It is fully metabolized in the liver under the influence of CYP3A4 to inactive metabolites. It is excreted mainly with bile, 8 % by kidneys as metabolites and 1 % by intestine. Elimination half-life is 1 hour.

Hepatic failure

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 hepatic impairment, and repaglinide should be used with caution in patients with mild to moderate hepatic impairment. Intervals between dose adjustments should also be increased to more accurately assess response to therapy.

Renal failure

The area under the curve “concentration-time” (AUC) and maximum plasma concentration (C) of repaglinide are similar in patients with normal renal function and in patients with mild to moderate renal impairment. In patients with severe renal impairment an increase in AUC and C was observed, but only a weak correlation between repaglinide concentration and creatinine clearance was found. It seems that patients with impaired renal function do not need an initial dose adjustment. However, subsequent dose escalation in patients with type 2 diabetes mellitus in combination with severe renal impairment, in which hemodialysis is required, should be performed with caution.

Indications

Type 2 diabetes mellitus (when diet, weight loss, and exercise are ineffective) in monotherapy or in combination with metformin or thiazolidinedione in cases where satisfactory glycemic control cannot be achieved with repaglinide or metformin or thiazolidinedione monotherapy.

Active ingredient

Composition

Active ingredient:

repaglinide 500 mcg

Associates:

Poloxamer – 3 mg,

Meglumine – 10 mg,

Lactose monohydrate – 47.8 mg,

microcrystalline cellulose – 33.7 mg,

Polacryline potassium – 4 mg,

Silicon dioxide colloid – 500 µg,

Magnesium stearate – 500 µg.

How to take, the dosage

Diaglinide is prescribed as an adjunct to diet and exercise to lower blood glucose concentrations and should be taken in conjunction with meals.

The drug is taken orally before main meals, usually 15 minutes before a meal, but can also be taken between 30 minutes before a meal and the time of the immediate meal.

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

The starting dose is 0.5 mg/day of Diaglinide (if the patient has taken another oral hypoglycemic drug, 1 mg). Dose adjustment is carried out once a week or once every 2 weeks (with reference to blood glucose concentration as an indicator of response to therapy). The average daily dose is 4 mg three times daily; maximum dose is 16 mg/day.
Transfer patients from therapy with other oral hypoglycemic drugs to therapy with repaglinide may be performed immediately. However, no exact ratio between the dose of repaglinide and the dose of other hypoglycemic drugs has been found. The recommended maximum starting dose of repaglinide, when transferring from other hypoglycemic drugs, is 1 mg before the main meal.

Combination therapy

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

Particular groups of patients

The administration of repaglinide to persons younger than 18 years of age is not recommended due to insufficient data on its safety and effectiveness in this group of patients.

Interaction

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

The metabolism, and thus clearance of repaglinide, may be altered by drugs that affect by inhibiting or activating cytochrome P-450 enzymes. Special caution should be exercised when concomitant administration of CYP2C8 and CYP3A4 inhibitors with repaglinide. Inhibitors of the anion-transporting protein OATP1B1 (e.g., cyclosporine) may also increase the plasma concentration of repaglinide.

The following drugs may increase and/or prolong the hypoglycemic effect of repaglinide:
Gemfibrozil, trimethoprim, rifampicin, clarithromycin, ketoconazole, itraconazole, cyclosporine, other hypoglycemic drugs, monoamine oxidase inhibitors, non-selective beta-adrenoblockers, angiotensin-converting enzyme inhibitors, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), octreotide, ethanol and anabolic steroids.
Beta-adrenoblockers may mask symptoms of hypoglycemia.

The concomitant administration of cimetidine, nifedipine or simvastatin (which are CYP3A4 substrates) with repaglinide has no significant effect on the pharmacokinetic parameters of repaglinide.

Repaglinide has no clinically significant effect on 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 coadministered with repaglinide.

The following drugs may weaken the hypoglycemic effect of repaglinide:

The oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, glucocorticosteroids, danazol, thyroid hormones, and sympathomimetics.

The co-administration of oral contraceptives (ethinylestradiol/levonorgestrel) does not result in clinically significant changes in the total bioavailability of repaglinide, although the maximum concentration of repaglinide is reached earlier. Repaglinide has no clinically significant effect on the bioavailability of levonorgestrel, but its effect on the bioavailability of ethinylestradiol cannot be excluded.

In this regard, patients already receiving repaglinide should be closely monitored for timely detection of impaired glycemic control while prescribing or withdrawing the above drugs.

Special Instructions

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

The blood glucose concentration on an empty stomach and after meals should be monitored regularly. The patient should be warned about the increased risk of hypoglycemia in cases of taking alcohol, NSAIDs, and fasting.
Dose adjustment is necessary in case of physical and emotional stress, changes in diet.

In patients with emaciation, as well as in patients receiving malnutrition, caution is necessary in choosing the initial and maintenance dose, and its titration, in order to avoid hypoglycemia.

Repaglinide is indicated when glycemia control is poor and diabetes symptoms persist with diet therapy and exercise.

Because repaglinide is a drug that stimulates insulin secretion, it may cause hypoglycemia. The risk of hypoglycemia increases with combination therapy.

Particular patient groups

Renal insufficiency

Dose selection in patients with type 2 diabetes combined with severe renal impairment should be done with caution.

Hepatic impairment

Prescribing conventional doses of repaglinide in patients with impaired liver function may result in higher concentrations of repaglinide and its metabolites than in patients with normal liver function. In this regard, repaglinide is contraindicated in patients with severe hepatic impairment (see section “Contraindications”), and in patients with mild to moderate hepatic impairment, repaglinide should be used with caution. Intervals between dose adjustments should also be increased to more accurately assess the response to therapy.

Impact on the ability to drive vehicles and operate machinery.

Patients’ ability to concentrate and reaction speed may be impaired during hypoglycemia and hyperglycemia, which may pose a risk in situations where this ability is particularly needed (such as driving or operating machinery and machines).

Patients should be advised to take steps to prevent hypoglycemia and hyperglycemia when driving vehicles and operating machinery. This is especially important for patients with absence or reduced severity of symptom precursors of developing hypoglycemia or suffering from frequent episodes of hypoglycemia. In these cases, consideration should be given to the appropriateness of performing such work.

Contraindications

Side effects

The most common side effects are hypoglycemia, the frequency of which depends, as with any therapy with

diabetes, on individual factors such as dietary habits, drug dose, exercise, and stress.
The side effects observed with repaglinide and other oral hypoglycemic agents are listed below.

All side effects are categorized into groups according to the frequency of development, defined as: frequently (≥1/100 to

Immune system disorders

Very rare: Generalized hypersensitivity reactions or immunological reactions such as vasculitis may be detected.

Unknown: hypersensitivity reactions such as itching, rash, urticaria.

Metabolic disorders

Often: hypoglycemia.

Unknown: hypoglycemic coma, hypoglycemia with loss of consciousness.

As with other hypoglycemic agents, hypoglycemia may develop when using repaglinide. These reactions are in most cases not severe and can be corrected by taking carbohydrates. In severe reactions, medical assistance may be required, in particular, intravenous administration of dextrose (glucose). The risk of hypoglycemia may increase in case of interactions of repaglinide with other drugs (see section “Interactions with other medicinal products”).

Visual disorders

Very rare: visual disturbances.

Changes in blood glucose concentrations may lead to visual disturbances, especially at the initial stage of therapy with hypoglycemic drugs. However, these changes are usually transient.

Cardiovascular system disorders

Rarely: cardiovascular disorders.

The risk of cardiovascular disease is increased in type 2 diabetes mellitus. An increased risk of acute coronary syndrome has been found in patients treated with repaglinide compared to patients treated with a sulfonylurea derivative, but not compared to patients treated with metformin or acarbose. However, a causal relationship has not been established.

Gastrointestinal disorders

Often: abdominal pain, diarrhea.

Very rarely: vomiting, constipation.

Unknown: nausea.

Liver and biliary tract disorders

Very rare: disorders of liver function.

In very rare cases, severe liver function abnormalities have been reported; however, a causal relationship with repaglinide has not been established.

Very rare: increased activity of “hepatic” enzymes.

Overdose

In case of overdose, hypoglycemia may develop. Symptoms: hunger, increased sweating, palpitations, tremor, anxiety, headache, insomnia, irritability, depression, speech and vision disorders.

When repaglinide was used in patients with type 2 diabetes at weekly increasing doses of 4 to 20 mg 4 times daily (with each meal) for 6 weeks, relative overdose was observed, manifested by excessive reduction in glucose concentration with the development of symptoms of hypoglycemia.

In case of symptoms of hypoglycemia, appropriate measures should be taken to increase blood glucose concentration (ingest dextrose or products rich in carbohydrates). In severe hypoglycemia (loss of consciousness, coma) dextrose is administered intravenously. After recovery of consciousness, intake of easily digestible carbohydrates (to avoid the recurrence of hypoglycemia).