INSVADA
TRADE NAME
Insvada
INTERNATIONAL NONPROPRIETARY NAME
Repaglinide
CHEMICAL NAME
(+)-2-Ethoxy-alfa-[[(S)-alfa-isobutyl-о- piperidinobenzyl] carbamoyl]-n-toluylic acid
PHARMACEUTICAL FORM
Tablets.
Description:
Insvada 0.5 mg: round flat white tablets with edge.
Insvada 1 mg: round biconvex tablets from light yellow to yellow colour.
Insvada 2 mg: round biconvex tablets from light pink to red colour.
COMPOSITION
Insvada 0.5 mg
Tablet contains
Active substance: repaglinide 0.5 mg.
Excipients: polacrilin potassium, meglumine, cellulose microcrystalline, maize starch, povidone, glycerol, poloxamer, calcium hydrogen phosphate anhydrous, magnesium stearate.
Insvada 1 mg
Tablet contains
Active substance: repaglinide 1 mg.
Excipients: polacrilin potassium, meglumine, cellulose microcrystalline, maize starch, povidone, glycerol, poloxamer, calcium hydrogen phosphate anhydrous, magnesium stearate, yellow iron oxide.
Insvada 2 mg
Tablet contains
Active substance: repaglinide 2 mg.
Excipients: polacrilin potassium, meglumine, cellulose microcrystalline, maize starch, povidone, glycerol, poloxamer, calcium hydrogen phosphate anhydrous, magnesium stearate, red iron oxide.
ATC CODE A10BX02
PHARMACOTHERAPEUTIC GROUP
Oral hypoglycemic agents.
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMICS
Insvada is an oral new generation short-acting hypoglycemic medication that rapidly lowers blood glucose levels, stimulating the release of insulin by the pancreas; the medication effect depends in the number of functioning β-cells, preserved in the pancreatic islets.
Repaglinide blocks ATP-sensitive potassium channels in the membranes of functionally active pancreatic islet apparatus β-cells, induces their depolarization and сalcium channel opening, evoking the release of insulin. An insulinotropic response is observed within 30 minutes after the administration and is accompanied by blood glucose level lowering in the period of food intake (insulin concentration doesn’t increase between meals).
PHARMACOKINETICS
Absorption
Repaglinide is rapidly and completely absorbed from the gastrointestinal tract that results in a rapid increase of the blood plasma medication concentration. The peak blood plasma concentration (Cmax) is achieved within 1 hour after the administration and reaches 9.8, 18.3 and 26 ng/ml after the administration of doses of 0.5, 1 and 2 mg respectively; when taken with food, Cmax may decrease by 20%. After Cmax is reached, the plasma repaglinide levels rapidly decrease, and the medication is completely excreted from the body within 4-6 hours. The elimination half-life amounts to about 1 hour.
Distribution
Pharmacokinetics of repaglinide is characterized by an average absolute bioavailability (63%, coefficient of variation 11%), low volume of distribution (30 L, corresponding to distribution in intracellular fluid) and rapid elimination from blood plasma. Repaglinide is highly bound to plasma proteins in human body (more than 98%).
Metabolism
Repaglinide is completely metabolized in liver by CYP2C8 and CYP3A4, forming inactive metabolites.
Excretion
Repaglinide and its metabolites are excreted mainly in bile. Less than 2% of the medication is excreted unchanged in feces. Small amount (about 8%) from the dose administered is excreted in urine, primarily in the form of metabolites.
THERAPEUTIC INDICATIONS
Diabetes mellitus type II when a satisfactory glycaemic control is not achieved by means of a diet, weight loss and physical exercises.
POSOLOGY AND ADMINISTRATION
Insvada is taken orally before the main meals. It’s recommended to take the medication 15 minutes prior to the main meal. The medication may be administered in the interval from 0 to 30 minutes. The dose is chosen individually for each patient against the glucose blood concentration. Apart from the glucose blood concentration control, carried out by the patient himself/herself, the glucose blood concentration is subject to control by a physician to establish a minimum effective dose for this patient.
The recommended initial single dose is 0.5 mg. If the patient has taken another oral hypoglycemic agent and the glycated hemoglobin level is 8% or higher, the recommended initial dose of Insvada must be 1-2 mg. The dose is adjusted once a week or once biweekly. The standard single dose amounts to 0.5-4 mg prior to the meal, 2, 3 or 4 times a day. The maximum recommended single dose before main meals amounts to 4 mg. The maximum daily dose should not exceed 16 mg.
In unsatisfactory hyperglycemia control by a monotherapy with metformin, thiazolidinediones or repaglinide, these medications may be administered in combination. The initial dose of repaglinide must be the same as the initial dose in the monotherapy with Insvada. The dose of each medication should be selected on the basis of the blood glucose levels changes.
CONTRAINDICATIONS
- hypersensitivity to repaglinide or to any other drug component;
- diabetes mellitus type I;
- diabetic ketoacidosis with developed or undeveloped comatose state;
- co-administration of gemfibrozil.
SIDE EFFECTS
Hypoglycemia is the most common side effect. The response rate, as well as in the case of any kind diabetes mellitus therapy, depends on individual factors such as food habits, drug dose, physical activity and stress.
The side effects observed while administration of repaglinide and other oral hypoglycemic agents are presented below. The adverse event incidence rate was classified in the following way: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rarely (≥1/10 000, <1/1000), very rarely (<1/10 000) unknown (impossible to evaluate on the basis of the availuable data).
Immune system disorders: very rarely – allergic reations; generelized hypersensitivity reactions or immunological responses such as vasculitis may also occur; unknown - hypersensitivity (such as itch, rash, urticaria).
Endocrine system disorders: rarely - hypoglycemia; unknown - hypoglycemic coma, hypoglycemia with loss of consciousness. As well as while administration of other hypoglycemic agents, in case of repaglinide administration hypoglycemia may appear. Hypoglycemia can be developped with the following symptoms: anxiety, dizziness, hyperhidrosis, tremor, hunger, disturbed attention focusing. These reactions are not serious in most cases and they can be resolved by the administration of carbohydrates. A medical assistance can be required in case of severe reactions (hypoglycemia with loss of consciousness, hypoglycemic coma) particularly the intravenous introduction of dextrose (glucose). Nonetheless, such reactions occur very rarely; it is impossible to determine their incidence rate based on the available data. The increased risk of glucopenia can be observed in interactions of repaglinide with other drugs.
Vision organ disorders: very rarely - visual disturbance. The changes in the blood glucose concentrations may lead to the visual disturbances, especially at the begining of the therapy with hypoglycemic agents. However, these changes are transient.
Cardiovascular system disorders: rare – cardio-vascular disease. An increased cardiovascular disease risk is observed in individuals with type 2 diabetes mellitus. The data obtained from the epidemiological study assume an increased risk of acute coronary syndrome in the patients, who have administred repaglinide (1.85%), in comparison with patients, who have administred sulphonylurea (1%), but not in comparison with patients, who have administred metformin and acarbose.
Digestive system disorders: often - abdominal pains, diarrhea; very rarely - vomiting, constipation; with not determined incidence rate - nausea. Complaints related with the digestive system disorders (abdominal pain, diarrhea, vomitting, nausea and constipation) were reported during the clinical studies. However the incidence rate and severity of these symptoms didn’t differ from those in case of administration of oral agents stimulating insulin secretion.
Hepatobiliary disorders: very rarely – hepatic disfunction (the cases of severe acute liver failure were reported, nonetheless, a cause-and-effect relation with repaglinide wasn’t determined), increased liver enzyme activity (rare cases of increased liver enzyme activity were observed on the background of the treatment with repaglinide). In most cases such increases were insignificant and transient and only small number of patients stopped the therapy due to the increased liver enzyme activity.
SPECIAL INDICATIONS
Being an insulin-stimulating drug, Insvada may induce hypoglycemia. Concomitant administration of Insvada with insulin is not recommended due to the increased risk of hypoglycemia development.
Glycemia control in patients with diabetes mellitus stabilized with any hypoglycemic drug may worsen under the influence of stress factors (fever, injury, infection, or surgery). Such cases may require withdrawal of repaglinide and switch to insulin therapy.
Hypoglycemic effect of oral hypoglycemic drugs in many patients reduces with time, which may be determined both by progression of diabetes mellitus and decrease of response to the drug. This phenomenon is known as "secondary resistance", and it must be distinguished from "primary resistance": in the latter case the drug is ineffective in a certain patient right upon the first administration. Before considering the situation as "secondary resistance" of the patient, perform dose adjustment and check the patient`s compliance with the recommendations concerning the diet and physical activity.
Exercise caution in choosing the initial and maintaining doses in exhausted and undernourished patients in order to avoid hypoglycemic reactions.
Administration of standard doses of repaglinide in patients with hepatic failure may lead to higher plasma concentrations of repaglinide and its metabolites than those in patients with normal hepatic function. Thus, repaglinide should not be prescribed to patients with severe hepatic failure and should be prescribed with caution to those with other hepatic dysfunctions. To assess the response to therapy comprehensively, prolong intervals between dose adjustments.
Though relation between repaglinide concentration and creatinine clearance is weak, the total plasma clearance of the drugs in patients with severe renal failure decreases. Due to the increased sensitivity to insulin in patients with diabetes mellitus and renal failure exercise caution performing dose titration in such patients.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
The ability of the patients to the attention concentration and reaction rapidity can be disturbed during hypoglycemia and hyperglycemia. Patients are advised to recommend taking measures to prevent the development of hypoglycemia and hyperglycemia while driving and using machines.
USE DURING PREGNANCY AND LACTATION
The safety of the medicine administration during pregnancy is not establishe, therefore its administration is contraindicated.
Small amount of repaglinide is excreted into breast milk; therefore in case of necessity to prescribe the drug during lactation it is necessary to stop the breastfeeding.
USE IN PEDIATRICS
The efficacy and safety of the medicine administration in children and adolescents under 18 years old are not established.
INTERACTIONS WITH OTHER DRUGS
It is necessary to take into account the possible interaction of repaglinide with drugs affecting glucose metabolism.
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 β-adrenergic blocking agents, ACE inhibitors, salicylates, NSAIDs, octreotide, ethanol, and anabolic steroids.
Concurrent administration of gemfibrozil (600 mg twice a day) - CYP2C8 and ОАТР1В1 isoenzyme inhibitor - and repaglinide (0.25 mg once a day) increased the repaglinide AUC by 8.1-fold and Сmах by 2.4-fold, as well as prolonged the half-life from 1.3 to 3.7 hours, which may result in enhanced and prolonged hypoglycemic effect of repaglinide. Therefore, the concomitant use of gemfibrozil and repaglinide is contraindicated.
The co-administration of ketoconazole (200 mg a day) with repaglinide (a single dose of 4 mg) resulted in an increase in repaglinide systemic exposure (AUC and Сmах) by 1.2-fold, with blood glucose concentrations altered by less than 8%.
Interaction with 100 mg itraconazole (an inhibitor of CYP3A4) has also been studied in healthy subjects, and a 1.4-fold AUC increase has been recorded. No significant effect on the glucose level in healthy volunteers was observed.
In studies conducted in healthy volunteers, the concomitant administration of 250 mg clarithromycin, a potent mechanism-based inhibitor of CYP3A4, slightly increased repaglinide systemic exposure, with mean serum insulin AUC increased by 1.5-fold, and Сmах - by 1.6-fold. The exact mechanism of this interaction is not clear.
Cyclosporine (100 mg), an inhibitor of CYP3A4 isoenzyme and a potent inhibitor of ОАТР1В1, increased repaglinide (0.25 mg) Сmах repaglinide by 1.8-fold and AUC by 2.5-fold in studies in healthy volunteers.
β-adrenoreceptor blocking agents may mask the symptoms of hypoglycemia.
Co-administration of cimetidine, nifedipine, oestrogen, or simvastatin with repaglinide did not significantly influence the pharmacokinetic parameters of repaglinide.
Repaglinide has no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustment of these compounds when co-administered with repaglinide is therefore not necessary.
The following substances may reduce the hypoglycemic effect of repaglinide: Oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazide derivatives, GC, danazol, thyroid hormones and sympathomimetics.
Co-administration of oral contraceptives (ethinylestradiol/levonorgestrel) does not result in a clinically significant change in repaglinide systemic bioavailability, although maximum concentrations of repaglinide occur earlier. Repaglinide has no clinically significant effect on the bioavailability of levonorgestrel, but its effects on ethinylestradiol bioavailability cannot be excluded. Therefore, when these drugs are administered to or withdrawn from patients receiving repaglinide, the patients should be observed closely for glycaemic control.
Rifampicin is a potent inducer of СУРЗА4 and СУР2С8 that acts both as an inducer and inhibitor of repaglinide metabolism. 7-days administration of rifampicin at a dose of 600 mg followed by co-administration of repaglinide (4 mg once a day) at Day 7 resulted in decreased AUC by 50%. When repaglinide was taken 24 hours after the last rifampicin dose, an 80% reduction of AUC was observed. Concomitant administration of rifampicin and repaglinide may require repaglinide dose adjustment, which should be based on carefully monitored blood glucose concentrations. The monitoring should be carried out at the beginning of rifampicin treatment (acute inhibition), following dosing (mixed inhibition and induction), then on rifampicin withdrawal (induction alone), and, finally, approximately one week after rifampicin withdrawal, when an inductive effect of rifampicin is no longer present.
OVERDOSE
Symptoms: dizziness, hyperhidrosis, tremor, headache.
Treatment: it is necessary to take the necessary measures to increase the blood glucose concentration (to take dextrose for oral administration or food with high carbohydrate content). In case of severe hypoglycemia (loss of consciousness, coma) it is required an intravenous injection of dextrose.
PACKAGING
Tablets.
15 tablets in a blister.
2, 4 or 6 blisters together with a leaflet in a carton box.
STORAGE CONDITIONS
Store at a temperature not exceeding 25°С.
Keep out of reach of children!
SHELF LIFE
3 years from the date of manufacture.
Do not apply after the expiry date.
SALES TERMS
Sold under prescription.
MANUFACTURER
The holder of Trade Mark and Marketing Authorization is
"INSUPHAR LABORATORIES LTD", GREAT BRITAIN.
Manufactured by
"Rivopharm S.A.", Centro Insema, 6928 Manno, Switzerland.
Web Page: http://www.drsertus.com/
