İHALE DÜNYASI
İHALE DÜNYASI
Nateglinide Tablets, USP are an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Nateglinide,(-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Nateglinide biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration. Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The 60 mg also contains iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. In addition, the 120 mg contains FD&C Yellow #6/Sunset Yellow Aluminum Lake, iron oxide yellow. this is the structure
Nateglinide Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus.
Nateglinide Tablets USP should be taken 1 to 30 minutes prior to meals. Monotherapy and Combination with Metformin or a Thiazolidinedione The recommended starting and maintenance dose of nateglinide, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals. The 60 mg dose of nateglinide, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA 1c when treatment is initiated. Dosage in Geriatric Patients No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to nateglinide therapy cannot be ruled out. Dosage in Renal and Hepatic Impairment No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, nateglinide should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS , Hepatic Impairment ).
Nateglinide Tablets are contraindicated in patients with: Known hypersensitivity to the drug or its inactive ingredients. Type 1 diabetes. Diabetic ketoacidosis. This condition should be treated with insulin.
In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with nateglinide. Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer. Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of nateglinide patients discontinued due to hypoglycemia. Symptoms suggestive of hypoglycemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue and weakness. Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of nateglinide and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of nateglinide and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in nateglinide patients than placebo patients in controlled clinical trials. Common Adverse Events (?2% in nateglinide patients) in Nateglinide Monotherapy Trials (% of patients) Preferred Term Placebo N=458 Nateglinide N=1441 Upper Respiratory Infection 8.1 10.5 Back Pain 3.7 4.0 Flu Symptoms 2.6 3.6 Dizziness 2.2 3.6 Arthropathy 2.2 3.3 Diarrhea 3.1 3.2 Accidental Trauma 1.7 2.9 Bronchitis 2.6 2.7 Coughing 2.2 2.4 Hypoglycemia 0.4 2.4 During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported. Laboratory Abnormalities Uric Acid: There were increases in mean uric acid levels for patients treated with nateglinide alone, nateglinide in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.
In vitro drug metabolism studies indicate that nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments. Glyburide : In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg nateglinide three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent. Metformin: When nateglinide 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent. Digoxin: When nateglinide 120 mg before meals was administered in combination with a single 1 mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent. Warfarin: When healthy subjects were administered nateglinide 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected. Diclofenac: Administration of morning and lunch doses of nateglinide 120 mg in combination with a single 75 mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent. | Drug Interactions Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid and tolbutamide in vitro . However, prudent evaluation of individual cases is warranted in the clinical setting. Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents, guanethidine, and CYP2C9 inhibitors (e.g., fluconazole, amiodarone, miconazole, oxandrolone) may potentiate the hypoglycemic action of nateglinide and other oral antidiabetic drugs. Certain drugs including thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, rifampin, phenytoin and dietary supplements (St. John's wort) may reduce the hypoglycemic action of nateglinide and other oral antidiabetic drugs. Somatostatin analogues may potentiate or attenuate the hypoglycemic action of nateglinide. When these drugs are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycemic control.