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Pharmacological properties

Novonorm is a fast-acting oral stimulator of insulin secretion. repaglinide rapidly reduces blood glucose, stimulating the secretion of insulin by the pancreas, and the effect of the drug depends on the number of functioning β-cells that are preserved in the islets of the pancreas.

Repaglinide blocks ATP-dependent potassium channels in the β-cell membrane with a special protein. This causes depolarization of the outer membranes of β-cells and leads to the opening of calcium channels, increases the influx of calcium ions into the cell, stimulating insulin secretion.

In patients with type II diabetes, an increase in plasma insulin concentration occurs within 30 minutes after ingestion of repaglinide. This provides a decrease in plasma glucose throughout the entire period of assimilation of food intake. The concentration of repaglinide in blood plasma decreases rapidly, its low level is noted in patients with type II diabetes within 4 hours after taking it. After taking 0.5-4 mg of repaglinide in patients with type II diabetes, a dose-dependent decrease in glucose concentration was found. Based on the results of clinical studies, it is recommended to take repaglinide before meals (preprandial administration). The drug is usually taken 15 minutes before meals, however, the time of administration can vary from intake directly to food - 30 minutes before meals.

Pharmacokinetics Repaglinide is easily absorbed in the digestive tract, which leads to a rapid increase in the concentration of the drug in blood plasma.

Cmax achieved 1 hour after administration. After reaching a maximum, the concentration level of the drug in blood plasma rapidly decreases and repaglinide is eliminated over 4-6 hours. T½ from blood plasma is about 1 hour. The pharmacokinetics of repaglinide is characterized by average absolute bioavailability (63%, coefficient of variation 11%), low volume of distribution (30 l, which corresponds to the distribution in intracellular fluid) and rapid elimination from plasma. In clinical studies, a high (60%) variability in the concentration of repaglinide in the blood plasma of different patients was noted; in the same patient, its level ranges from low to moderate (35%). Since the selection of the dose of repaglinide is based on the clinical response of the patient, high variability in different patients does not affect the effectiveness of the drug.

Renal failure. In patients with type II diabetes with renal failure of varying severity, the pharmacokinetics of repaglinide after taking a single dose, as well as in a stable state, were determined. In patients with normal renal function and its mild to moderate impairment, AUC and C valuesmax were the same (56.7 and 57.2 ng / (ml / h), respectively; 37.5 and 37.7 ng / ml). In patients with a pronounced decrease in renal function, the values ​​of these indicators were slightly increased (98.0 ng / (ml / h) and 50.7 ng / ml). However, in this study, a weak correlation was found between the level of repaglinide and creatinine clearance. For patients with renal dysfunction, it is not necessary to select an initial dose of repaglinide. The next dose increase for patients with type II diabetes with severe impaired renal function or renal failure, which requires hemodialysis, should be carried out with caution.

Liver failure. In a single dose-open study conducted with 12 healthy volunteers and 12 patients with chronic liver disease (the severity of which was determined using the Child-Pugh scale and caffeine clearance), it was found that in patients with moderate to severe hepatic impairment serum total and free repaglinide is higher and lasts longer than in healthy individuals (healthy AUC - 91.6 ng / (ml / h), in patients - 368.9 ng / (ml / h); Cmax in healthy patients - 46.7 ng / ml, in patients - 105.4 ng / ml). AUC values ​​correlated with caffeine clearance levels.The plasma glucose concentration profile in the patients of both examined groups was the same. When taken in usual doses, patients with impaired liver function are exposed to higher concentrations of repaglinide and its metabolites than healthy ones. Thats why for patients with impaired liver function, repaglinide should be used with caution. When using the drug, it is necessary to increase the intake intervals in order to fully evaluate the patients response.

Repaglinide easily binds (98%) to plasma proteins.

Taking repaglinide immediately before meals (15 or 30 minutes) or on an empty stomach does not significantly affect the value of pharmacokinetics. Repaglinide is completely metabolized mainly with the participation of CYP 2C8 and CYP 3A4 enzymes. Its metabolites do not cause clinically significant hypoglycemia.

Repaglinide and its metabolites are excreted mainly with bile; a small fraction of the accepted dose of the drug (about 8%) is detected in the urine as metabolites, 2% of the active substance in feces.

Indications

Type II diabetes mellitus (non-insulin-dependent), when, using diet, weight loss and physical activity, satisfactory control of blood glucose levels cannot be achieved.

The use of repaglinide in combination with metformin or thiazolidinediones is also indicated for patients with type II diabetes mellitus who cannot achieve satisfactory glycemic control by taking these drugs separately. Treatment should be started as an addition to diet and exercise to reduce blood glucose levels, the introduction of the drug should be timed to meals.

Application

Repaglinide is taken before each main meal (that is, preprandial), while the dose is individually selected in order to optimize glycemic control. In addition to the patients self-monitoring of blood and urine glucose levels, the doctor should periodically monitor the concentration of glucose in the blood of patients to determine the minimum effective dose of the drug. the level of glycosylated hemoglobin is also an informative indicator when monitoring the patients response to treatment. periodic monitoring is necessary to detect an inadequate decrease in blood glucose concentration below the lower acceptable level (i.e. primary insufficiency), as well as to detect the absence of a corresponding decrease in blood glucose level after an effective initial treatment period (i.e. secondary insufficiency).

The drug is usually taken within 15 minutes from the start of a meal, however, the intake time can vary from just before a meal to 30 minutes before a meal (that is, preprandial with 2-, 3- and 4-time meals). If the patient missed a meal (or had an additional meal), he should accordingly skip (or add) a dose of the drug.

Initial dose. The selection of the dose of the drug is carried out by the doctor in accordance with the patients response, which is determined by the level of glucose in the blood. Patients who have not previously received hypoglycemic drugs are recommended to start with a dose of 0.5 mg per meal. Dose selection begins after 1-2 weeks (the period is determined by the patients response to treatment). If the patient took another oral hypoglycemic agent, then 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.

Transfer of patients from taking other oral hypoglycemic drugs. Patients can be immediately transferred from other oral hypoglycemic drugs to receive repaglinide. The exact relationship between doses of repaglinide and other oral hypoglycemic agents has not been established.The recommended maximum starting dose for patients who are being transferred to repaglinide is 1 mg before meals.

Combination therapy If the blood glucose level is not effectively controlled by taking metformin, thiazolidinediones or repaglinide, these drugs can be taken simultaneously. The initial dose of repaglinide is the same as with monotherapy. The dose of each drug should be selected based on changes in blood glucose levels.

Contraindications

Hypersensitivity to repaglinide or any other component of the drug novonorm; type I diabetes mellitus (insulin-dependent diabetes mellitus, c-peptide negative diabetes); diabetic ketoacidosis with developed or undeveloped coma; severe liver dysfunction; During pregnancy and breastfeeding; simultaneous use with gemfibrozil.

Side effects

The most commonly detected side effects are associated with changes in blood glucose levels, i.e. hyperglycemia and hypoglycemia. the frequency of occurrence of such reactions depends on both the characteristics of the treatment and the individual characteristics of the patient — eating habits, dose of the drug, physical activity and stress.

Based on the experience of using repaglinide and other hypoglycemic drugs, the following side effects were noted: often (≥1 / 100 to 1/10); infrequently (≥1 / 1,000 to ≤1 / 100); rarely (≥1 / 10,000 to ≤1 / 1000) or very rarely (≤1 / 10,000); the frequency of occurrence has not been established (based on the available data, it is not possible to assess).

Disorders from the immune system: very rarely - allergies; generalized hypersensitivity reactions (i.e. anaphylactic reactions) or immune reactions such as vasculitis.

Metabolic disorders: often - hypoglycemia; frequency not established: hypoglycemic coma and hypoglycemia with loss of consciousness.

When using repaglinide, like other sugar-lowering drugs, hypoglycemia can occur. Its symptoms include anxiety, dizziness, sweating, tremors, hunger, and difficulty concentrating. Typically, these reactions are mild and can be stopped with meals containing carbohydrates. In severe cases requiring medical attention, it may be necessary to / in the introduction of glucose. Interactions with other drugs may increase the risk of hypoglycemia (see INTERACTIONS).

Visual impairment: very rarely - visual impairment.

Fluctuations in glucose levels can cause temporary visual impairment, especially at the beginning of treatment with hypoglycemic agents. Typically, these changes are transient in nature.

Cardiovascular disorders: rarely, cardiovascular disease.

Type II diabetes is associated with an increased risk of cardiovascular disease. One epidemiological study revealed an increased risk of developing acute coronary syndrome in patients treated with repaglinide compared with metformin or acarbose. However, a causal relationship has not been established.

Gastrointestinal disorders: rarely - abdominal pain, diarrhea; very rarely - vomiting, constipation; frequency not established - nausea.

In clinical studies, gastrointestinal disorders such as abdominal pain, diarrhea, nausea, vomiting, and constipation are noted. The frequency and severity of these symptoms did not differ from those of other oral insulin secretion stimulants.

Hepatobiliary disorders: very rarely - impaired liver function.

Severe dysfunction of the liver is noted very rarely, while their relationship with taking repaglinide has not been established; very rarely - increased activity of liver enzymes. In most cases, it was moderate and short-lived.Only a very small number of patients were forced to interrupt treatment with the drug due to increased activity of liver enzymes.

Diseases of the skin and subcutaneous tissue: frequency not established - hypersensitivity reactions.

Hypersensitivity reactions to the drug may manifest as redness, itching, and urticaria.

special instructions

Repaglinide is prescribed in cases of unsatisfactory control of blood glucose levels against a background of diet and exercise.

Repaglinide, like other stimulants of insulin secretion, can cause the development of hypoglycemia. With combined treatment, the risk of hypoglycemia increases. If a patient who has stabilized glycemic control with oral hypoglycemic drugs has been stressed (fever, trauma, infectious disease, or surgical intervention), he may have impaired glycemic control. In such cases, it may be necessary to stop taking repaglinide and temporarily switch to insulin.

In many patients, with an increase in the period of taking oral hypoglycemic drugs, their hypoglycemic effect decreases. This may be due to the progression of the severity of diabetes or to a weakening of the bodys response to the drug. This phenomenon is called secondary failure, it should be distinguished from primary failure, in which the patient does not respond to the drug, taken for the first time.

Before establishing a diagnosis of secondary insufficiency, it is necessary to try to change the dose, as well as to verify the accuracy of the patients recommendations on diet and exercise.

To date, no clinical studies have been conducted in patients aged 18 and 75 years.

Dose selection for weakened and emaciated patients should be carried out especially carefully to avoid the development of hypoglycemia (see APPLICATION).

Special groups of patients

Liver failure. When taking normal doses in patients with impaired liver function, the concentration of repaglinide and its metabolites may be higher than with normal liver function. This is why patients with impaired liver function need to be careful when taking repaglinide (see CONTRAINDICATIONS). It is necessary to increase the intervals when taking a dose in order to fully evaluate the patients response (see Pharmacokinetics).

Renal failure. Although there is a weak correlation between the level of repaglinide and creatinine clearance, the clearance of these compounds in the blood plasma of patients with severe renal failure is reduced. Since in patients with diabetes complicated by renal failure, insulin sensitivity increases, care must be taken when selecting a dose of the drug (see Pharmacokinetics).

During pregnancy and breastfeeding. Studies on the use of repaglinide in pregnant and lactating women have not been conducted. That is why it is not possible to assess the safety of its use in pregnant women. In animal experiments, it has been shown that repaglinide does not have a teratogenic effect. Non-teratogenic malformations of the extremities were detected in fetuses and newborn rats born to rats who were given high doses of the drug in the last stage of pregnancy and during lactation. Repaglinide is found in the milk of experimental animals.

Children. Repaglinide is not recommended for use in children under the age of 18 due to insufficient data on safety and / or effectiveness in this group of patients.

Ability to drive vehicles and work with mechanisms. With hypoglycemia in patients, a decrease in the ability to concentrate attention and speed of reaction is possible. This can pose a certain risk in situations where these abilities become especially important (for example, when driving vehicles or machinery).

Patients should be advised to take precautionary measures to avoid hypoglycemia while driving. This is especially important for those who have mild symptoms - precursors of hypoglycemia, or those who often have hypoglycemia attacks. In these conditions, the appropriateness of driving a vehicle should be assessed.

Interactions

As you know, some drugs can affect glucose metabolism. this should be considered when selecting doses of repaglinide.

According to in vitro data, the enzymes CYP 2C8 and CYP 3A4 are mainly involved in the metabolism of repaglinide. Repaglinide actively enters the liver cells with the participation of a protein transporting organic anions (OATP1B - organic anion transporting protein). A study in healthy volunteers showed that the most important enzyme in repaglinide metabolism is CYP 2C8. At the same time, blocking CYP 2C8 leads to a slight decrease in the metabolism of repaglinide, since this increases the relative contribution of CYP 3A4. Accordingly, the metabolism and clearance of repaglinide can change when taking drugs that inhibit activity or induce the synthesis of enzymes of the P450 cytochrome family. Particular care should be taken when taking repaglinide simultaneously with CYP 2C8 and CYP 3A4 inhibitors. Drugs that inhibit OATP1B (e.g. cyclosporine) can also potentially increase the concentration of repaglinide in blood plasma.

The following drugs can enhance and / or prolong the hypoglycemic effect of repaglinide: gemfibrozil, trimethoprim, rifampicin, ketoconazole, itraconazole, clarithromycin, cyclosporine, other antidiabetic drugs, MAO inhibitors, non-selective β-adrenoreceptor blockers, steroids, inhibitors, inhibitors, inhibitors, inhibitors, inhibitors, inhibitors, inhibitors alcohol.

In a study of drug interactions conducted in healthy volunteers, it was found that after taking 2 times a day 600 mg of gemfibrozil (a CYP 2C8 inhibitor and OATP1B1) and repaglinide (0.25 mg 1 time per day), the AUC value increased by 8.1 times, and its Cmax in blood - 2.4 times. Duration his T½ from blood increased from 1.3 to 3.7 hours, which can enhance and prolong the hypoglycemic effect of repaglinide. The combined use of gemfibrozil and repaglinide is contraindicated (see CONTRAINDICATIONS),

After simultaneous administration 2 times a day, 160 mg of trimethoprim (a weak CYP 2C8 inhibitor) and repaglinide (0.25 mg 1 time per day), the AUC value increased 1.6 times, its Cmax - 1.4 times, a T½ - 1.2 times; however, no statistically significant effect on blood glucose was detected. Reception of subtherapeutic doses of repaglinide did not cause a pharmacodynamic effect. Since the safety of this combination was established for repaglinide at a dose of no higher than 0.25 mg, and trimethoprim at a dose of 320 mg, the simultaneous administration of these drugs should be carried out with caution. If a decision is made on the need for treatment with a combination of these drugs, then careful monitoring of the blood glucose level, as well as the clinical condition of the patient, should be carried out.

Rifampicin, a potent inducer of SURA ZA4 and SUR2 C8, acts as an inducer and inhibitor of repaglinide metabolism. Reception of rifampicin at a dose of 600 mg for 7 days with the addition of repaglinide on the 7th day (4 mg once a day) led to a 50% decrease in AUC (the result of combined induction and inhibition). If repaglinide was taken 24 hours after the last dose of rifampicin, the AUC value decreased by 80% (result of induction).

With simultaneous treatment with rifampicin and repaglinide, it is necessary to select the dose of the latter, which should be based on the data of careful monitoring of blood glucose concentration in the following periods: at the beginning of taking rifampicin (acute inhibition), after several days of taking rifampicin (combined induction and inhibition), after canceling rifampicin (induction only) and 1 week after stopping the use of rifampicin when its inductive effect passes.

Admission 2 times a day for 200 mg of ketoconazole (a potent inhibitor of SUR ZA4) simultaneously with repaglinide (4 mg 1 time per day) increases the values ​​of AUC and Cmax 1.2 times; the glucose concentration profile changes by less than 8%.

Concomitant use with repaglinide 100 mg of itraconazole (an inhibitor of SUR ZA4) was also investigated in healthy volunteers. It was found that the AUC value increases by 1.4 times. No significant changes in blood glucose levels were observed in the subjects.

After taking 2 times a day, 250 mg of clarithromycin (an inhibitor of SURA ZA4) and repaglinide (0.25 mg 1 time per day) AUC increased by 1.4 times, Cmax - 1.7 times. Moreover, the area under the curve "insulin concentration in blood serum - time" increased by 1.5 times (Cmax - 1.6 times). The mechanism of this interaction has not yet been clarified.

A study on healthy volunteers who took repaglinide (0.25 mg) showed that cyclosporine (100 mg), which is an inhibitor of cytochrome ZA4 (SUR ZA4) and a potent inhibitor of OATP1B, increases 1.8 times Cmax repaglinide and 2.5 times increases AUC.

Β-adrenergic blockers can mask the symptoms of hypoglycemia.

The simultaneous administration of cimetidine, nifedipine, estrogen or simvastatin (substrates SUR ZA4) with repaglinide does not significantly affect the values ​​of its pharmacokinetics.

Studies of drug interactions conducted in healthy volunteers indicate that repaglinide does not have a clinically significant effect on the pharmacokinetics of digoxin, theophylline, and warfarin. Therefore, when taking these drugs simultaneously with repaglinide, dose selection should not be carried out.

The following drugs can weaken the hypoglycemic effect of repaglinide: oral contraceptives, rifampicin, barbiturates, thiazides, corticosteroids, danazole, thyroid hormones, and sympathomimetics. The simultaneous administration of oral contraceptives (ethinyl estradiol / levonorgestrel) does not significantly affect the overall bioavailability of repaglinide, although at the same time its peak concentration is reached earlier. Repaglinide does not have a clinically significant effect on the bioavailability of levonorgestrel, although its effect on the bioavailability of ethinyl estradiol cannot be ruled out. When prescribing or canceling the above drugs in patients receiving repaglinide, it is necessary to carefully monitor changes in the level of glycemia.

Overdose

In clinical trials, patients with type II diabetes mellitus received repaglinide in weekly increasing doses of 4 to 20 mg before each of four meals for 6 weeks. however, a small number of adverse reactions not associated with a decrease in blood glucose were recorded. since in this study the possibility of hypoglycemia was prevented by an increased calorie content of food, relative overdose could lead to a marked decrease in blood glucose concentration and the development of symptoms of hypoglycemia (dizziness, increased sweating, tremor, headache, etc.). if such symptoms occur, adequate measures should be taken to normalize the level of glucose in the blood (intake of carbohydrates inside). with more severe hypoglycemia, accompanied by convulsions, loss of consciousness or coma, it is necessary to introduce intravenous glucose.

Storage conditions

In a dry place at a temperature of 15-25 ° C. Store in the original packaging.

Tags: NovoNorm® [Repaglinide]