Pharmacological properties
Pharmacodynamics. Novonorm is a fast-acting oral insulin secretagogue. Repaglinide rapidly lowers blood glucose levels by stimulating insulin secretion by the pancreas, and the effect of the drug depends on the number of functioning β-cells remaining in the pancreatic islets.
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, increasing the influx of calcium ions into the cell, which stimulates insulin secretion.
In patients with type II diabetes, an increase in the concentration of insulin in the blood plasma occurs within 30 minutes after oral administration of repaglinide. This provides a decrease in the level of glucose in the blood plasma throughout the entire period of assimilation of the food taken. The concentration of repaglinide in the blood plasma decreases rapidly, its low level is noted in patients with type II diabetes within 4 hours after its administration. After taking 0.5-4 mg of repaglinide, patients with type II diabetes have been found to have a dose-dependent decrease in glucose concentration. 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, but the time of administration may vary from taking it immediately before meals to 30 minutes before meals.
Pharmacokinetics. Repaglinide is readily absorbed from the gastrointestinal tract, leading to a rapid increase in plasma drug concentrations.
C max is reached 1 h after administration. After reaching the maximum, the concentration of the drug in the blood plasma decreases rapidly and repaglinide is eliminated within 4-6 h. T ½ from the blood plasma is about 1 h. The pharmacokinetics of repaglinide are characterized by average absolute bioavailability (63%, coefficient of variation 11%), low volume of distribution (30 l, which corresponds to distribution in intracellular fluid) and rapid elimination from the blood plasma. In clinical studies, 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 impairment. In patients with type 2 diabetes mellitus with varying degrees of renal impairment, the pharmacokinetics of repaglinide were determined after a single dose and at steady state. In patients with normal renal function and mild to moderate renal impairment, AUC and Cmax values were similar (56.7 and 57.2 ng/(ml/h, respectively); 37.5 and 37.7 ng/ml). In patients with severe renal impairment, these values were slightly higher (98.0 ng/(ml/h, respectively) and 50.7 ng/ml). However, this study revealed a weak correlation between repaglinide levels and creatinine clearance. It is not necessary to adjust the initial dose of repaglinide for patients with renal dysfunction. Subsequent dose increases for patients with type 2 diabetes mellitus with severe renal impairment or renal failure requiring hemodialysis should be carried out with caution.
Hepatic impairment. In an open-label, single-dose study conducted in 12 healthy volunteers and 12 patients with chronic liver disease (severity assessed by Child-Pugh score and caffeine clearance), it was found that in patients with moderate to severe hepatic impairment, serum concentrations of total and free repaglinide were higher and sustained longer than in healthy subjects (AUC in healthy subjects 91.6 ng/(ml/h), in patients 368.9 ng/(ml/h); Cmax in healthy subjects 46.7 ng/ml, in patients 105.4 ng/ml). The AUC values correlated with the level of caffeine clearance. The plasma glucose concentration profile in patients in both groups was similar. When taken in normal doses, patients with impaired liver function are exposed to higher concentrations of repaglinide and its metabolites than healthy subjects. Therefore, repaglinide should be used with caution in patients with impaired liver function. When using the drug, it is necessary to increase the dosing intervals in order to fully assess the patient's response.
Repaglinide binds readily (98%) to plasma proteins.
Taking repaglinide immediately before meals (15 or 30 minutes) or on an empty stomach does not significantly affect the pharmacokinetics. Repaglinide is completely metabolized mainly by CYP 2C8 and CYP 3A4. Its metabolites do not cause clinically significant hypoglycemia.
Repaglinide and its metabolites are excreted mainly in the bile; a small fraction of the administered dose (about 8%) is found in the urine as metabolites, 2% of the active substance in the feces.
Indication
Type 2 diabetes (insulin-dependent), when diet, weight loss, and exercise fail to achieve satisfactory control of blood glucose levels.
Repaglinide is also indicated in combination with metformin or thiazolidinediones in patients with type 2 diabetes mellitus who are not adequately controlled with these drugs alone. Treatment should be initiated as an adjunct to diet and exercise to lower blood glucose levels, and should be given with meals.
Repaglinide is taken before each main meal (i.e. preprandial), with the dose individually adjusted to optimize glycemic control. In addition to self-monitoring of blood and urine glucose levels by the patient, the physician should periodically monitor the patient's blood glucose levels to determine the minimum effective dose of the drug. The level of glycosylated hemoglobin is also an informative indicator in monitoring the patient's response to treatment. Periodic monitoring is necessary to detect an inadequate decrease in blood glucose concentration below the lower permissible level (i.e. primary failure), as well as to detect the absence of an adequate decrease in blood glucose levels after an effective initial period of treatment (i.e. secondary failure).
The drug is usually taken within 15 minutes of the start of a meal, but the time of administration can vary from immediately before a meal to 30 minutes before a meal (i.e. preprandial for 2-, 3- and 4-course meals). If the patient misses a meal (or has an extra meal), he should, accordingly, skip (or add) the dose of the drug.
Initial dose. The dose of the drug is selected by the doctor in accordance with the patient's 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 with each meal. Dose selection begins after 1-2 weeks (the period is determined by the patient's response to treatment). If the patient was taking another oral hypoglycemic 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.
Transferring patients from other hypoglycemic agents. Patients can be transferred directly from other hypoglycemic agents to repaglinide. The exact dose ratio of repaglinide to other oral hypoglycemic agents has not been established. The recommended maximum initial dose for patients transferred to repaglinide is 1 mg before meals.
Combination therapy. If blood glucose levels are not adequately controlled by metformin, thiazolidinediones or repaglinide, these drugs can be used in combination. The starting dose of repaglinide is the same as for monotherapy. The dose of each drug should be adjusted based on blood glucose responses.
Contraindication
Hypersensitivity to repaglinide or any other component of NovoNorm; type 1 diabetes mellitus (insulin-dependent diabetes mellitus, C-peptide negative diabetes); diabetic ketoacidosis with or without coma; severe liver dysfunction; pregnancy and breastfeeding; simultaneous use with gemfibrozil.
Side effects
The most frequently observed side effects are related to changes in blood glucose levels, i.e. hyperglycemia and hypoglycemia. The frequency 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 experience with repaglinide and other hypoglycemic drugs, the following side effects have been reported: common (≥1/100 to 1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000) or very rare (≤1/10,000); frequency not established (cannot be estimated from the available data).
Immune system disorders: very rare - allergy; generalised 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, as with other blood sugar-lowering drugs, hypoglycemia may occur. Its symptoms include anxiety, dizziness, increased sweating, tremor, hunger and difficulty concentrating. These reactions are usually mild and can be treated with food containing carbohydrates. In severe cases requiring medical attention, intravenous glucose may be necessary. Interactions with other drugs may increase the risk of hypoglycemia (see Interactions with other drugs).
Visual acuity impairment: very rare - visual impairment.
Fluctuations in glucose levels may cause temporary visual impairment, especially at the beginning of treatment with hypoglycemic agents. These changes are usually temporary.
Cardiovascular disorders: rarely - cardiovascular disease.
Type 2 diabetes is associated with an increased risk of cardiovascular disease. One epidemiological study found an increased risk of 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.
Hepatobiliary disorders: very rarely - liver dysfunction.
Severe liver dysfunction is very rare, and their relationship with repaglinide has not been established; very rare - increased 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 liver enzymes.
Skin and subcutaneous tissue disorders: frequency not established - hypersensitivity reactions.
Hypersensitivity reactions to the drug may manifest as redness, itching, and hives.
Special instructions
Repaglinide is prescribed in cases of unsatisfactory blood glucose control on the background of diet and exercise.
Repaglinide, like other insulin secretagogues, can cause hypoglycemia. The risk of hypoglycemia increases with combination therapy. If a patient whose glycemic control is stabilized with antidiabetic drugs is exposed to stress (fever, trauma, infectious diseases or surgery), glycemic control may deteriorate. In such cases, it may be necessary to discontinue repaglinide and temporarily switch to insulin.
In many patients, the hypoglycemic effect of antidiabetic drugs decreases with increasing duration of treatment. This may be due to the progression of diabetes or to a weakening of the body's response to the drug. This phenomenon is called secondary insufficiency, and should be distinguished from primary insufficiency, in which the patient does not respond to the drug taken for the first time.
Before diagnosing secondary insufficiency, it is necessary to try to change the dose, as well as check the accuracy of the patient's compliance with dietary and exercise recommendations.
To date, no clinical studies have been conducted in patients between the ages of 18 and 75 years.
Dose selection for weakened and exhausted patients should be carried out especially carefully to avoid the development of hypoglycemia (see Method of administration).
Special patient groups
Hepatic impairment. When taking the usual doses in patients with impaired liver function, the concentration of repaglinide and its metabolites may be higher than with normal liver function. Therefore, caution should be exercised when taking repaglinide in patients with impaired liver function (see Adverse Reactions). Dose intervals should be increased in order to fully assess the patient's response (see Pharmacokinetics).
Renal impairment: Although there is a weak correlation between repaglinide levels and creatinine clearance, plasma clearance of these compounds is reduced in patients with severe renal impairment. Since insulin sensitivity is increased in diabetic patients complicated by renal impairment, caution should be exercised in dose selection (see Pharmacokinetics).
Pregnancy and breast-feeding. Studies on the use of repaglinide in pregnant and lactating women have not been conducted. Therefore, it is not possible to assess the safety of its use in pregnant women. Animal studies have shown that repaglinide is not teratogenic. Non-teratogenic limb malformations have been found in fetuses and newborns of rats born to rats given high doses of the drug in the last stage of pregnancy and during lactation. Repaglinide has been found in the milk of experimental animals.
Children: Repaglinide is not recommended for use in children below 18 years of age due to insufficient data on safety and/or efficacy in this patient group.
Ability to drive and use machines. Hypoglycemia may impair the ability to concentrate and react. This may pose a risk in situations where these abilities are particularly important (e.g. driving or operating machinery).
Patients should be advised to take precautions to avoid hypoglycemia while driving. This is especially important for those who have mild symptoms of hypoglycemia or who have frequent episodes of hypoglycemia. In these conditions, the appropriateness of driving should be assessed.
Interactions
It is known that some drugs can affect glucose metabolism. This should be taken into account when selecting repaglinide doses.
The following drugs may enhance and/or prolong the hypoglycemic effect of repaglinide: gemfibrozil, trimethoprim, rifampicin, ketoconazole, itraconazole, clarithromycin, cyclosporine, other antidiabetic drugs, MAO inhibitors, non-selective β-blockers, ACE inhibitors, salicylates, non-steroidal anti-inflammatory drugs, octreotide, anabolic steroids, alcohol.
In a drug interaction study conducted in healthy volunteers, it was found that after simultaneous administration of 600 mg gemfibrozil (an inhibitor of CYP 2C8 and OATP1B1) twice daily and repaglinide (0.25 mg once daily), the AUC value increased 8.1-fold and its Cmax in the blood increased 2.4-fold. Its T½ from the blood increased from 1.3 to 3.7 h, which may enhance and prolong the hypoglycemic effect of repaglinide. The simultaneous use of gemfibrozil and repaglinide is contraindicated (see Side effects).
After simultaneous administration of 160 mg of trimethoprim (a weak CYP 2C8 inhibitor) twice daily and repaglinide (0.25 mg once daily), the AUC value increased 1.6-fold, its Cmax - 1.4-fold, and T½ - 1.2-fold; however, no statistically significant effect on blood glucose levels was detected. Subtherapeutic doses of repaglinide did not cause any pharmacodynamic effect. Since the safety of this combination has been established for repaglinide at a dose not 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 to treat with a combination of these drugs, careful monitoring of blood glucose levels and the patient's clinical condition should be carried out.
Rifampicin, a potent inducer of CYP3A4 and CYP2C8, acts as both an inducer and an inhibitor of repaglinide metabolism. Administration of 600 mg of rifampicin for 7 days, followed by repaglinide (4 mg once daily) on day 7, resulted in a 50% decrease in AUC (a result of combined induction and inhibition). When repaglinide was administered 24 hours after the last dose of rifampicin, the AUC was reduced by 80% (a result of induction).
When treating rifampicin and repaglinide simultaneously, the dose of repaglinide should be selected based on careful monitoring of blood glucose levels at the following times: at the start of rifampicin administration (acute suppression), several days after rifampicin administration (combined induction and inhibition), after discontinuation of rifampicin administration (induction only), and 1 week after discontinuation of rifampicin administration, when its inductive effect has passed.
Administration of 200 mg of ketoconazole (a potent CYP3A4 inhibitor) twice daily with repaglinide (4 mg once daily) increased AUC and Cmax by 1.2-fold, while the glucose concentration profile changed by less than 8%.
Concomitant administration of 100 mg of itraconazole (a CYP3A4 inhibitor) with repaglinide was also studied in healthy volunteers. It was found that the AUC value increased by 1.4 times. No significant changes in blood glucose levels were observed in the subjects.
After taking 250 mg of clarithromycin (CYP 3A4 inhibitor) twice daily and repaglinide (0.25 mg once daily), AUC increased 1.4-fold and Cmax increased 1.7-fold. The area under the serum insulin concentration-time curve increased 1.5-fold (Cmax increased 1.6-fold). The mechanism of this interaction has not yet been elucidated.
In a study in healthy volunteers taking repaglinide (0.25 mg), cyclosporine (100 mg), which is a cytochrome 3A4 (CYT 3A4) inhibitor and a potent OATP1B inhibitor, increased repaglinide Cmax by 1.8-fold and AUC by 2.5-fold.
Beta-blockers may mask the symptoms of hypoglycemia.
Concomitant administration of cimetidine, nifedipine, estrogen, or simvastatin (CYP 3A4 substrates) with repaglinide does not significantly affect the values of its pharmacokinetic parameters.
Drug interaction studies in healthy volunteers have shown that repaglinide has no clinically significant effect on the pharmacokinetics of digoxin, theophylline and warfarin. Therefore, no dose adjustment is required when these agents are co-administered with repaglinide.
The following drugs may reduce the hypoglycemic effect of repaglinide: oral contraceptives, rifampicin, barbiturates, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics. Concomitant administration of oral contraceptives (ethinyl estradiol/levonorgestrel) does not significantly affect the overall bioavailability of repaglinide, although the 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 excluded. When prescribing or withdrawing the above drugs in patients receiving repaglinide, it is necessary to carefully monitor changes in glycemia.
In clinical studies, patients with type 2 diabetes mellitus received repaglinide in weekly increasing doses from 4 to 20 mg before each of four meals for 6 weeks. At the same time, a small number of adverse reactions not related to a decrease in blood glucose levels were observed. Since in this study the possibility of hypoglycemia was prevented by the increased calorie content of the meal, a relative overdose could lead to a pronounced 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 blood glucose levels (intake of carbohydrates). In more severe hypoglycemia, accompanied by convulsions, loss of consciousness or coma, glucose should be administered intravenously.
Storage conditions
In a dry place at a temperature of 15-25 ° C. Store in the original packaging.
