Active substanceRepaglinideRepaglinide Similar drugsTo uncover Diaglinide® pills inwards AKRIKHIN HFK, JSC Russia Iglynide pills inwards Pharmasintez-Tyumen, Open Company Russia Novonorm® pills inwards Novo Nordisk A / S Denmark Dosage form: & nbspPills. Composition:1 tablet contains:Active substance: repaglinide - 0.5 mg / 1.0 mg / 2.0 mg.Excipients: Poloxamer 188 0.143 mg / 0.286 mg / 0.572 mg Povidone 1.543 mg / 1,686 mg / 1,972 mg, meglumine 0.250 mg / 0.500 mg / 1.000 mg corn starch 10.00 mg / 10.00 mg / 10.00 mg calcium hydrogenphosphate anhydrous 38.20 mg / 38.20 mg / 38.20 mg microcrystalline cellulose (E460) 38.264 mg / mg 36.928 / 35.006 mg, 85% glycerin (glycerol), 1.400 mg / 1.400 mg / 1.400 mg, polacrilin potassium (potassium polyacrylate ) 4.000 mg / 4.000 mg / 4.000 mg magnesium stearate 0.700 mg / 0.700 mg / 0.700 mg of iron oxide (E172) yellow (tablet dosage 1.0 mg), 0.300 mg of iron oxide (E172), red (for a dosage of 2 tablets , 0 mg) 0.150 mg. Description:Tablets with a dosage of 0.5 mg:Round, white, biconvex tablets; one side is marked with the symbol of the Company (bull Apis).Tablets with a dosage of 1 mg:Round, yellow, biconvex tablets; one side is marked with the symbol of the Company (bull Apis).Tablets with a dosage of 2 mg:Round, brownish-pink, biconvex tablets; one side is marked with the symbol of the Company (bull Apis). Pharmacotherapeutic group:Hypoglycemic agent for oral administration. ATX: & nbspA.10.B.X Other hypoglycemic drugsA.10.B.X.02 Repaglinide Pharmacodynamics:Mechanism of actionNovonorm® is a short-acting oral hypoglycemic preparation. Rapidly reduces the glucose level in the blood, stimulating the release of insulin pancreas. It binds to the β-cell membrane with a protein-receptor specific for the drug. This leads to the blocking of ATP-dependent potassium channels and the depolarization of the cell membrane, which in turn facilitates the opening of calcium channels. The intake of calcium inside the β-cell stimulates the secretion of insulin.PharmacodynamicsIn patients with type 2 diabetes, an insulinotropic reaction is observed within 30 minutes after ingestion. This ensures a decrease in blood glucose levels throughout the meal period. At the same time, the level of repaglinide in plasma rapidly decreases, and 4 hours after taking the drug in plasma of patients with type 2 diabetes, low concentrations of the drug are detected.Clinical efficacy and safetyA dose-dependent decrease in blood glucose levels is observed in patients with type 2 diabetes with a prescription of repaglinide in the dose range of 0.5 to 4 mg. The results of clinical studies have shown that repaglinide should be taken before meals (prepandial dosing). Pharmacokinetics:AbsorptionRepaglinide is rapidly absorbed from the gastrointestinal tract, which is accompanied by a rapid increase in its concentration in the plasma. The maximum concentration of repaglinide in plasma is reached within one hour after administration. After reaching the maximum concentration (Cmax), the plasma content decreases rapidly.Clinically significant differences between the pharmacokinetics of repaglinide when taken directly before meals, 15 minutes or 30 minutes before meals or fasting were not detected.The pharmacokinetics of repaglinide are characterized by an average absolute bioavailability of 63% (the variability factor (CV) is 11%).In clinical studies, a high interindividual variability (60%) of repaglinide concentration in plasma was detected.The intra-individual variability ranges from low to moderate (35%). Since the titration of repaglinide dose is carried out depending on the patient's clinical response to therapy, interindividual variability does not affect the effectiveness of therapy. DistributionThe pharmacokinetics of repaglinide are characterized by a low volume distribution of 30 liters (in accordance with the distribution in the intracellular fluid), as well as a high degree of binding to human plasma proteins (more than 98%).ExcretionAfter reaching the maximum concentration (Cmax), the plasma content decreases rapidly. The half-life of the drug (t1 / 2) is approximately one hour. Repaglinide completely eliminated from the body within 4-6 hours. Repaglinide is completely metabolized, mainly by the CYP2C8 isoenzyme, but also, albeit to a lesser extent, by the CYP3A4 isoenzyme, and there has been no identifiableabolite having a clinically significant hypoglycemic effect.Metabolites of repaglinide are excreted mainly by the intestine, while less than 2% of the drug is found in the stool in unchanged form. A small part (approximately 8%) of the administered dose is found in urine, mainly in the form of metabolites.Renal insufficiency:Pharmacokinetic parameters of repaglinide in a single admission and in a state of equilibrium were evaluated in patients with type 2 diabetes mellitus and renal dysfunction of varying severity.The area values under the concentration-time curve (AUC) and Cmax were the same in patients with normal renal function and in patients with mild to moderate renal insufficiency (mean values were 56.7 ng / ml · hour compared to 57.2 ng / ml · hour, and 37.5 ng / ml compared to 37.7 ng / ml, respectively). In patients with severe renal dysfunction, increased values of AUC and Cmax (98.0 ng / ml · hour and 50.7 ng / ml, respectively), but this study revealed a weak correlation between the concentration of repaglinide and creatinine clearance. It seems that patients with impaired renal function do not need to adjust the initial dose. However, a subsequent increase in dose in patients with type 2 diabetes combined with severe renal dysfunction requiring hemodialysis should be carried out with caution.Liver failure:An open study was conducted, involving a single reception of repaglinide by 12 healthy volunteers, as well as 12 patients with chronic liver disease (CKD), which was classified according to the Child-Pugh scale, as well as the significance of caffeine clearance.In patients with moderate or severe hepatic impairment detected higher and persists longer time concentrations of total and unbound repaglinide serum than in healthy volunteers (AUC in healthy volunteers = 91.6 ng / ml · hour; AUC in patients with CKD = 368.9 ng / ml · hour; Cmax in healthy volunteers = 46.7 ng / ml, Cmax in patients with CKD = 105.4 ng / ml). The value of AUC was statistically correlated with caffeine clearance. Differences in the concentration of glucose between these groups were not detected. Thus, when taking conventional doses of repaglinide in patients with impaired liver function, higher concentrations of repaglinide and its metabolites will be achieved than in patients with normal liver function. Consequently, in patients with impaired liver function repaglinide should be used with caution. Also, the intervals between dose adjustments should be increased in order to more accurately assess the response to therapy. Preclinical safety data Preclinical data based on pharmacological safety studies, repeated dose toxicity, genotoxicity and carcinogenic potential have not revealed any hazard to humans. Studies in animals have shown that repaglinide does not have a teratogenic effect.Anomalies in the development of limbs not teratogenic in nature were observed in embryos and newborn rats born from female rats receiving high doses of repaglinide in the last third of pregnancy and during lactation. Repaglinide was found in the milk of animals. Indications:Diabetes mellitus type 2 with ineffectiveness of diet therapy, exercise and weight loss.In patients with type 2 diabetes mellitus repaglinide can also be used in combination with metformin or thiazolidinediones in cases where satisfactory control of glycemia can not be achieved with monotherapy with repaglinide, metformin or thiazolidinediones. Contraindications:- Known hypersensitivity to repaglinide or to any of the components of the drug;- Type 1 diabetes mellitus;- Diabetic ketoacidosis; diabetic precoma and coma;- Infectious diseases, large surgical interventions and other conditions requiring insulin therapy;- Pregnancy and the period of breastfeeding;- Severe liver dysfunction;- Simultaneous administration of gemfibrozil (see section "Interaction with other drugs").Clinical studies in patients under the age of 18 years and older than 75 years were not conducted. Carefully:(the need for more careful observation) should be used for violations of liver function of mild and moderate degree, febrile syndrome, chronic renal failure, alcoholism, general severe condition, malnutrition. Pregnancy and lactation:Studies in pregnant women and women during breastfeeding were not conducted. Therefore, the safety of repaglinide use in pregnant women and women during breastfeeding has not been studied.Information on studies of reproductive toxicity of repaglinide carried out on animals is presented in section Pharmacokinetics. Dosing and Administration:Novonorm® is prescribed as an adjunct to diet and exercise to reduce blood glucose, its administration should be timed to meals.The drug is taken orally in front of the main meals (i.e., preprandial 2, 3 or 4 times a day). It is recommended to take the drug 15 minutes before the main meal. Allowed to take the drug in the range of 0 to 30 minutes.Patients who may miss meals (or additional meals) should receive an instruction, respectively, about the omission (or additional admission) of the dose of the drug.The dose is selected individually for each patient, depending on the concentration of glucose in the blood. In addition to controlling the blood and / or urine glucose levels that the patient is carrying out, it is also necessary that the blood glucose concentration is determined periodically by the physician, which will establish the minimum effective dose for the patient. The concentration of glycosylated hemoglobin is also an indication of the patient's response to therapy. Periodic monitoring of glucose concentration is necessary to detect an inadequate decrease in blood glucose in the first appointment of a patient with repaglinide at the recommended maximum dose (ie, the patient has "primary resistance"), and to detect a hypoglycemic response to this drug after previous effective therapy that is, the patient's "secondary resistance").In patients with type 2 diabetes mellitus,in which diabetes is usually well controlled by diet, during periods of temporary loss of glycemic control, it may be sufficient to conduct a short course of repaglinide therapy.In case of simultaneous application with other medicinal products - see the sections "Interaction with other medicines" and "Special instructions".Initial doseThe dose of the drug is determined by the doctor depending on the level of glucose in the blood.For patients who have never before received other oral hypoglycemic drugs, the recommended initial single dose before the main meal is 0.5 mg. Correction of the dose is carried out once a week or once in 2 weeks (while focusing on the concentration of glucose in the blood as an indicator of response to therapy). If the patient changes from taking another oral hypoglycemic to Novonorm®, the recommended initial dose before each main meal should be 1 mg.Maximum dosesThe recommended maximum single dose before main meals is 4 mg. The total maximum daily dose should not exceed 16 mg.Patients who have previously received other oral hypoglycemic drugs:Transfer of patients from therapy with other oral hypoglycemic drugs to repaglinide therapy can be performed immediately. At the same time, there was no exact correlation between the dose of repaglinide and the dose of other hypoglycemic drugs.The recommended maximum initial dose for patients who are transferred to repaglinide, is 1 mg before each main meal.Combination TherapyRepaglinide may be administered in combination with metformin or thiazolidinediones in case of inadequate control of blood glucose concentration 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 reached concentration of glucose in the blood.Children and teensThe efficacy and safety of repaglinide treatment in persons younger than 18 years of age have not been investigated. No data available. Side effects:The most frequent side effects are changes in the concentration of glucose in the blood, ie, hypoglycemia.The frequency of such reactions depends, as with any type of diabetes therapy, on individual factors, such as eating habits, the dose of the drug, physical stress and stress.Below are the side effects observed with repaglinide and other oral hypoglycemic agents. All side effects are divided into groups according to the frequency of development, defined as: often (>1/100 to <1/10); infrequently (>1 / 1,000 to <1/100); rarely (>1 / 10,000 to <1 / 1,000); very rarely (<1 / 10,000) and is unknown (it is impossible to estimate based on available data).Immune system disordersVery rarely: allergic reactions.Generalized hypersensitivity reactions (eg, anaphylactic reaction) or immunological reactions, such as vasculitis, may be detected.Disorders from the metabolism and nutritionOften: hypoglycemia.Unknown: hypoglycemic coma, hypoglycemia with loss of consciousness.As with other hypoglycemic agents, hypoglycemia may develop with repaglinide. Hypoglycemia can be manifested by the following symptoms: anxiety, dizziness, increased sweating, tremors, hunger, difficulty concentrating. In most cases, these reactions are mild and can be eliminated by taking carbohydrates. In severe reactions, medical attention may be required, in particular, intravenous dextrose (glucose). The risk of developing hypoglycemia may increase with the interaction of repaglinide with other drugs (see section "Interaction with other drugs").Disturbances on the part of the organ of sightVery rarely: visual disturbances.Changes in the concentration of glucose in the blood can lead to visual disturbances, especially at the initial stage of therapy with hypoglycemic drugs. However, usually these changes are transient.Disorders from the digestive systemOften: abdominal pain, diarrheaVery rarely: vomiting, constipationUnknown: nauseaComplaints of abnormalities from the digestive system - abdominal pain, diarrhea, nausea, vomiting and constipation were noted during clinical trials. However, the frequency and severity of these symptoms did not differ from those of other oral preparations that stimulated insulin secretion.Disturbances from the liver and bile ductsVery rarely: hepatic dysfunctionIn very rare cases, serious violations of liver function have been reported, but a causal relationship with repaglinide has not been established.Very rarely: increased activity of "liver enzymes."In most cases, these increases were minor and transient, and only a very small number of patients discontinued therapy because of increased activity "hepatic enzymes."Disturbances from the skin and subcutaneous tissuesUnknown: hypersensitivityHypersensitivity reactions such as redness, pruritus, rash and urticaria may be detected. Overdose:In a clinical study, patients with type 2 diabetes received repaglinide in a weekly increasing dose of 4 to 20 mg 4 times a day (with each meal) for 6 weeks. In addition to the desired reduction in blood glucose, single adverse reactions were observed that did not affect the drug safety profile.Due to the increase in calorie intake in this study, hypoglycemia was not observed,however, a relative overdose can manifest itself as an excessive decrease in the concentration of glucose in the blood with the development of symptoms of hypoglycemia (dizziness, increased sweating, tremor, headache, etc.). If these symptoms appear, appropriate measures should be taken to increase the blood glucose concentration (ingest dextrose or foods rich in carbohydrates). In severe hypoglycemia (loss of consciousness, coma) intravenously injected with dextrose. Interaction:There are a number of drugs that affect the clearance of repaglinide. The physician should consider possible interactions.In vitro: Repaglinide is metabolized mainly under the influence of CYP2C8 and CYP3A4 isoenzymes. Clinical studies involving healthy volunteers have shown that the most important isoenzyme involved in the metabolism of repaglinide is CYP2C8, while CYP3A4 plays a lesser role, but its relative contribution may increase when the CYP2C8 isoenzyme is inhibited. Consequently, the metabolism, and thus the clearance of repaglinide, can vary under the influence of drugs that have an effect, inhibiting or inducing cytochrome P-450 isoenzymes.Particular care should be taken when using inhibitors of isoenzymes CYP2C8 and CYP3A4 with repaglinide.Based on in vitro and in vivo data repaglinide is actively absorbed by the liver (anion-transporting protein OATPl B1). OATPl Bl inhibitors (eg, ciclosporin) can also increase the concentration of repaglinide in plasma.The following drugs can enhance and / or prolong the hypoglycemic effect of repaglinide: gemfibrozil, trimethoprim, rifampicin, clarithromycin, ketoconazole, itraconazole, ciclosporin, other hypoglycemic drugs, monoamine oxidase inhibitors, nonselective beta-adrenoblockers, angiotensin-converting enzyme inhibitors, salicylates, non-steroidal anti-inflammatory drugs, octreotide, alcohol and anabolic steroids.Studies on drug interactions in healthy volunteers have shown that the simultaneous use of gemfibrozsh (600 mg twice a day) inhibitor of the isoenzyme CYP2C8 and OATPlB1, and repaglinide (once in a dose of 0.25 mg) led to an increase in the AUC value of repaglinide in 8.1 times, the value of Cmax - by 2.4 times, as well as to an increase t1/2 from 1.3 to 3.7 hours, which could lead to an increase and prolongation of the hypoglycemic effect of repaglinide. In this regard, the simultaneous use of gemfibrozil and repaglinide is contraindicated due to a significant increase in the concentration of repaglinide in the blood plasma.Studies on drug interactions between repaglinide and fenofibrate have not been conducted.With the simultaneous use of trimethoprim (160 mg twice daily), a weak inhibitor of the isoenzyme CYP2C8, and repaglinide (once, at a dose of 0.25 mg), there was a slight increase in AUC, Cmax, and t1/2 (1.6 times, 1.4 times and 1.2 times, respectively), but there was no statistically significant effect on the concentration of glucose in the blood. However, a similar lack of pharmacodynamic effect was detected in subtherapeutic doses of repaglinide. Since the safety profile of such a combination was not evaluated at doses exceeding 0.25 mg for repaglinide and 320 mg for trimethoprim, caution should be exercised while using these drugs. If nevertheless, the need for simultaneous use of these drugs has arisen, careful monitoring of blood glucose concentration as well as clinical observation should be carried out.Rifampicin, which is a powerful inducer of the isoenzyme CYP3A4, as well as the isoenzyme CYP2C8, is both an inducer and an inhibitor of metabolism of repaglinide. When the patients first received rifampicin (600 mg) for 7 days, and then, on the 7th day, the therapy was added repaglinide (4 mg once), a 50% decrease in the AUC (the effects of the combination of induction and inhibition) was recorded. In the event that repaglinide was administered 24 hours after the last dose of rifampicin, a decrease in AUC of repaglinide was registered by 80% (ie, only inducing effect was manifested).With the simultaneous use of rifampicin and repaglinide, a dosage adjustment of repaglinide may be required, which should be based on careful monitoring of blood glucose levels; control should be performed at the beginning of rifampicin therapy (acute inhibition); after dose administration (mixed effect - inhibition and induction); then with the abolition of rifampicin (induction only), and finally about one week after the rifampicin cancellation, when the inducing effect of rifampicin is no longer manifested.Impact ketoconazole, which is a prototype of potent inhibitors of the isoenzyme CYP3A4, on the pharmacokinetics of repaglinide was studied in healthy volunteers. With the administration of ketoconazole (200 mg per day), simultaneously with repaglinide (4 mg once), an increase in the mean systemic effect of repaglinide (AUC and Cmax) by 1.2 times was recorded, while the blood glucose concentrations changed by less than 8 %.Interaction itraconazole (inhibitor of the isoenzyme CYP3A4) at a dose of 100 mg was also studied in healthy volunteers, and an increase in AUC was shown by a factor of 1.4. At the same time, there was no significant effect on the concentration of glucose in healthy volunteers.In studies on healthy volunteers, the combined use of 250 mg clarithromycin, which, due to the mechanism of action, is a potent inhibitor of the CYP3A4 isoenzyme, there was a slight increase in the systemic effect of repaglinide (AUC increased by 1.4 times and Cmax increased 1.7-fold), while the mean serum AUC increased 1.5 times , and Cmax - 1.6 times. The exact mechanism of this interaction is unclear.Cyclosporin (100 mg), inhibitor of the isoenzyme CYP3A4 and a potent inhibitor of OATPlB1, increased Cmax repaglinide (0.25 mg once) 1.8 times and AUC 2.5 times in studies on healthy volunteers.Since drug interactions were not evaluated at doses exceeding 0.25 mg for repaglinide, simultaneous administration of cyclosporin and repaglinide is recommended. If nevertheless the need for simultaneous administration of these drugs has arisen, careful monitoring of blood glucose concentration should be carried out, as well as clinical observation of patients (see section "Special instructions").The study of interactions in healthy volunteers showed that the simultaneous administration of deferasirox (30 mg / kg / day, 4 days), a weak inhibitor of CYP2C8 and CYP3A4, and repaglinide (once, 0.5 mg) resulted in an increase in the systemic effect of repaglinide (AUC increased in 2.3 times, and Cmax - by 62%); while there was a small but significant decrease in the concentration of glucose in the blood. With simultaneous appointment deferazirox and repaglinide, it is necessary to consider reducing the dose of repaglinide and to carry out a careful control of the concentration of glucose in the blood. β-Adrenoblockers can mask the symptoms of hypoglycemia.Simultaneous application cimetidine, nifedipine, estrogens or simvastatin (all these preparations are substrates of the isoenzyme CYP3A4) with repaglinide did not have a significant effect on the pharmacokinetic parameters of repaglinide.Repaglinide has no clinically significant effect on the pharmacokinetic properties digoxin, theophylline or warfarin in a stable state when used in healthy volunteers. Thus, there is no need to correct the doses of these drugs when they are used together with repaglinide. The following substances can reduce the hypoglycemic effect of repaglinide:oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazide derivatives, glucocorticosteroids, danazol, thyroid hormones and sympathomimetics.Joint application oral contraceptives (ethinyl estradiol / levonorgestrel) does not lead to a clinically significant change in the overall bioavailability of repaglinide, although the maximum concentrations of repaglinide are reached earlier. Repaglinide clinically significant does not affect the bioavailability of levonorgestrel, but its effect on the bioavailability of ethinylestradiol can not be ruled out.In this regard, during the period of application or withdrawal of these drugs, patients who are already receiving repaglinide, should be carefully monitored for the timely detection of violations of glycemic control. Special instructions:Repaglinide is shown at unsatisfactory control of a glycemia and preservation of signs of a diabetes mellitis against a background of dietotherapy, physical exercises and weight reduction. Because the repaglinide is a preparation that stimulates the secretion of insulin, it can cause hypoglycemia. With combined therapy, the risk of hypoglycemia increases. In a patient with achieved stabilization of diabetes mellitus with the help of any hypoglycemic drug, the impact of any stressor factor, for example, fever, trauma, infection, or surgical intervention, can lead to impaired glycemic control. In such cases, it may be necessary to cancel repaglinide and temporary appointment of insulin therapy. The hypoglycemic effect of oral hypoglycemic drugs in many patients is weakened over time. This can be due to both the progression of the severity of the course of diabetes mellitus, and the weakening of the response to the drug.This phenomenon is known as "secondary resistance", and it should be distinguished from "primary resistance", in which the drug is ineffective in a particular patient already at the first appointment. Before evaluating the situation in the patient as a "secondary resistance", you should make a dose adjustment, as well as check the accuracy of the patient's recommendations on diet and exercise.In patients with malnutrition, as well as in patients receiving malnutrition, care should be taken when choosing an initial and maintenance dose, and titration, in order to avoid hypoglycemic reactions (See section "Method of administration and dose").Individual clinical studies involving patients younger than 18 and older than 75 years were not conducted.Special patient groupsLiver failure. The administration of conventional doses of repaglinide in patients with impaired liver function can lead to higher concentrations of repaglinide and its metabolites in plasma than in patients with normal liver function.Concerning, repaglinide Do not administer to patients with severe impairment of liver function.section "Contraindications"), and patients with other disorders of liver function repaglinide should be administered with caution. To fully assess the response to therapy, you should extend the intervals between dose adjustments (see the section "Pharmacokinetics").Renal failure. Although only a weak association between repaglinide concentration and creatinine clearance is revealed, the overall clearance of plasma drugs in patients with severe renal disease is reduced. Since the sensitivity to insulin is increased in patients with diabetes mellitus and kidney damage, the dose selection for such patients should be performed with caution (see section "Pharmacokinetics"). Effect on the ability to drive transp. cf. and fur:The ability of patients to concentrate and respond to the reaction may be impaired during hypoglycemia, which can be dangerous in situations where this ability is particularly necessary (for example, in the management of vehicles or working with mechanisms). Patients should be advised to take measures to prevent the development of hypoglycemia in the management of vehicles and work with mechanisms.This is especially important for patients with absence or reduction in the severity of symptoms-harbingers of developing hypoglycemia or frequent episodes of hypoglycaemia. In these cases, you should consider the feasibility of doing such work. Form release / dosage:Tablets 0.5; 1; 2 mg. Packaging:For 15 tablets in a blister pack of aluminum foil on both sides. For 2 or 6 blisters together with instructions for use in a cardboard box. Storage conditions:List B. Inaccessible to children. In a dry place at a temperature of 15 - 25 ° C. Shelf life:5 years.Do not use after the expiration date. Terms of leave from pharmacies:On prescription Registration number:P N 015435/01 Date of registration:25.12.2008 The owner of the registration certificate:Novo Nordisk A / SNovo Nordisk A / S Denmark Manufacturer: & nbspNOVO NORDISK, A / S Denmark Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark Information update date: & nbsp09.08.2015 Illustrated instructions × Illustrated instructions Instructions