Nateglinide

When ATH:
A10BX03

Characteristic.

Nateglinid-oral gipoglikemicescoe means, used in the treatment of diabetes mellitus type 2. White powder; freely soluble in methanol, ethyl alcohol and chloroform; soluble in ether, it is soluble in acetonitrile and octanol, practically insoluble in water. Molecular weight 317,45.

Pharmacological action.
Hypoglycemic.

Application.

According to Physicians Desk Reference (2005), nateglinid is indicated as monotherapy to lower blood glucose in patients with diabetes mellitus type 2 (insulin-dependent diabetes mellitus), in which control of blood glucose levels is insufficient diet and exercise and who were not treated for a long time other hypoglycemic agents.

Nateglinide is also shown for therapy in combination with metformin in patients with inadequate glycemic control on background metformin (replace nateglinide metformin is not recommended).

Contraindications.

Hypersensitivity, diabetes mellitus type 1, diabetic ketoacidosis (in this case shows insulin treatment).

Restrictions apply.

Childhood (safety and effectiveness of using nateglinide in pediatric not installed), Use in Geriatrics (There were no differences in the safety and efficacy of nateglinide in patients 65 years or older and younger patients 65 years; It does not exclude the increased sensitivity of some older patients to therapy nateglinide), Patients with moderate or severe liver disease (the use in this group of patients studied).

It should not be translated into treatment nateglinide (or added to the treatment regimen nateglinide) patients with inadequate glycemic control on background levels of glyburide, or other drugs, enhancing insulin secretion.

Pregnancy and breast-feeding.

Nateglinid had no teratogenicity in rats at doses up to 1000 mg / kg (about 60 times the therapeutic dose for humans at the recommended dose 120 mg nateglinida 3 times a day before meals). The rabbits were observed adverse effect on embryo development: increased incidence of gallbladder agenesis or "small" gallbladder (in doses of 500 mg / kg / day, which is approximately 40 times the therapeutic dose for humans at the recommended dose 120 mg 3 times a day before meals).

Nateglinide should not be used during pregnancy (adequate and well-controlled studies in pregnant women has not been).

Effect of nateglinide on generic activities and childbirth is not installed.

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Studies in rats have shown, that nateglinide is excreted in the milk. The ratio of AUC_0-48 between the milk and plasma was approximately 1:4. During the peri- and postnatal period in the offspring of rats, received nateglinid dose 1000 mg / kg / day (about 60 times greater than the therapeutic dose for humans at the recommended dose of nateglinida in 120 mg 3 times a day before meals), had low body weight.

No data on the excretion of nateglinide with human milk. Nateglinide is not recommended for nursing mothers destination.

Side effects.

In clinical studies, received nateglinide 2400 patients with diabetes mellitus type 2; of which approximately 1200 Patients were treated 6 months and longer, 190 - 1 a year or longer.

The incidence of side effects, marked than in 2% cases, patients, poluchavshih nateglinide (n=1441), compared to placebo (n=458). The brackets % placebo patients:

From the nervous system and sensory organs: dizziness - 3,6% (2,2%).

From the respiratory system: upper respiratory tract infection- 10,5% (8,1%), bronchitis- 2,7% (2,6%), cough- 2,4% (2,2%).

From the digestive tract: diarrhea is 3,2% (3,1%).

Metabolism: Hypoglycemia is 2,4% (0,4%).

On the part of the musculoskeletal system: arthropathy — 3,3% (2,2%), accidental injury - 2,9% (1,7%).

Other: pain in the spine is 4,0% (3,7%), flu-like symptoms — 3,6% (2,6%).

Laboratory violation. It notes the increase in the average concentration of uric acid in patients, nateglinide monotherapy or a combination of nateglinide metformin, or monotherapy with metformin, or glyburide monotherapy. Relative difference to placebo was 0,017, 0,026, 0,017 and 0,011 mmol / L, respectively. The clinical significance of this phenomenon is unknown.

Hypoglycemia is relatively uncommon in all treatment regimens in clinical trials. Only 0,3% patients nateglinide was canceled due to hypoglycemia. Symptoms of the gastrointestinal tract, especially diarrhea and nausea, They were equally frequent in patients, treated with the combination of nateglinide and metformin, than patients, receiving only metformin.

Cooperation.

Metabolic studies in vitro shown, that nateglinide is mainly metabolized with participation of cytochrome P450: изоферментов CYP2C9 (70%) and, less, CYP3A4 (30%). Nateglinid is a powerful inhibitor of CYP2C9 izofermenta live, that shows its ability to inhibit in vitro metabolism of tolbutamide. Metabolic effects of inhibition of CYP3A4 have not been revealed in experiments in vitro.

Gliʙurid. Randomized cross studies multi-dose patients with diabetes type 2 nateglinid assigned 120 mg 3 times a day before meals for 1 a day in combination with 10 mg gliburida. There were no clinically obvious changes in the pharmacokinetics of the two substances.

Metformin. In appointing patients with diabetes type 2 nateglinida (120 mg) 3 times a day before meals in combination with metformin 500 mg 3 once a day, not observed clinically obvious changes in the pharmacokinetics of the two substances.

Digoxin. When you assign a healthy volunteers nateglinida 120 mg 3 times a day before meals in combination with a single admission 1 mg digoxin have been noted clinically apparent changes in the pharmacokinetics of both substances.

Warfarin. In the appointment of healthy volunteers 120 mg nateglinida 3 times a day before meals for 4 in combination with single day admission 30 mg of warfarin on the second day there were no changes in the pharmacokinetics of both substances, LA also has not changed.

Diclofenac. The reception in the morning and at lunch 120 mg nateglinida in combination with a single admission 75 mg diclofenac has not led to significant changes in the pharmacokinetics of both substances in healthy volunteers.

Most of nateglinide (98%) strongly bound to plasma proteins, mostly to albumin. In vitro displacement studies with substances, have a high degree of binding, such as furosemide, propranolol, captopril, nikardipin, pravastatin, gliʙurid, warfarin, phenytoin, acetylsalicylic acid, tolbutamide and metformin, showed no effect on the amount of nateglinide binding to plasma proteins. Also, nateglinide had no effect on plasma protein binding of propranolol, gliʙurida, nikardipina, phenytoin, acetylsalicylic acid and tolbutamide in vitro. However, in a clinical setting individual slight deviation.

Some medications, incl. NSAIDs, salicilaty, MAO inhibitors and non-selective beta-blockers may enhance the hypoglycemic effect of nateglinide and other hypoglycemic agents.

Some drugs, including thiazide diuretics, corticosteroids, thyroid hormone analogues, sympathomimetic, may reduce the hypoglycemic effect of nateglinide and other oral hypoglycemic agents. When these drugs are appointed or canceled patient, poluchayushtego nateglinide, We need to monitor the level of glucose.

Interaction with food. The pharmacokinetics of nateglinide does not depend on the composition of food (protein content, fats or carbon). However, C_max greatly reduced when taking nateglinide for 10 minutes before the liquid food. Nateglinide has not any effect on an empty stomach in healthy humans, as shown by the test atsetaminofenovy.

Overdose.

In clinical studies in patients with diabetes mellitus type 2 nateglinid is assigned in increasing doses up to 720 mg / day for 7 days. There were no reports of clinically significant side effects. There were no cases of overdose of nateglinide in clinical trials. However, receiving doses, than recommended, can lead to excessive glyukozosnizhayuschemu effect to the development of symptoms of hypoglycemia. Symptoms of hypoglycemia, is not accompanied by loss of consciousness and neurological disorders, stoped taking glucose orally, dose reduction and / or meal. Severe hypoglycemic reactions with coma, seizures or other neurological symptoms should be docked on / in a glucose. As nateglinide binds strongly with proteins, to remove it from the blood dialysis is ineffective.

Dosing and Administration.

Inside, for 1-30 minutes before meals, before meals. The recommended initial dose and nateglinida as monotherapy or in combination with metformin is 120 mg 3 once a day. Dose nateglinida 60 mg/day as monotherapy, in combination with metformin can be used in patients subject to almost normal levels HbA_1c at the beginning of treatment.

In geriatrics usually do not require a special dose of refinement, but it does not exclude the increased sensitivity in some patients to therapy nateglinide.

In patients with mild renal or hepatic impairment do not require changing the dose of nateglinide. In moderate or severe hepatic impairment have not been studied particular dosage, therefore nateglinide should be used with caution in patients with moderate or severe liver disease.

Precautions.

Gipoglikemiâ. All oral hypoglycemic agents may cause hypoglycemia. The frequency of hypoglycaemia depends on the severity of diabetes, Control of blood glucose levels and other characteristics of the patient. Patients in elderly, patients with poor nutrition, patients with adrenal or pituitary insufficiency are most susceptible to the hypoglycemic effect of this therapy. The risk of hypoglycemia may increase with severe physical exertion, taking alcohol, with insufficient intake of calories (Prolonged or random) or a combination with other oral hypoglycemic agents. There may be difficulties with the identification of hypoglycemia in patients with autonomic (Visceral) neuropathy and / or receiving beta-blockers. To reduce the risk of hypoglycemia nateglinide is assigned to food; patient, skip meals, It should also skip the next reception of nateglinide.

Effect on liver. Nateglinide should be used with caution in patients with moderate or severe liver disease, because its use in these patients has not been studied.

Loss of glycemic control. Transient loss of control of blood glucose levels may occur with fever, infections, injury, surgery. In these cases, instead of the required insulin nateglinide. There may be a secondary failure or reduced efficiency of nateglinide after some period of time.

Laboratory Tests. Response to treatment should be periodically evaluated the value of blood glucose level and HbA_1c.

Cautions.

Patient Information. Patients should be informed of the potential risks of use and useful effects of nateglinide and alternative regimens. It is necessary to explain the risk of hypoglycaemia and its treatment. The patient should be instructed, that taking nateglinide is necessary for 1-30 minutes before a meal. It is necessary to receive the next dose skip nateglinide, If a patient misses a meal, thereby reducing the risk of hypoglycemia. You must discuss with the patient drug interactions. The patient should be informed about the possible interaction with other drugs nateglinide.