CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Nateglinide tablets are contraindicated in patients with: 1. Known hypersensitivity to the drug or its inactive ingredients. 2. Type diabetes. 3. Diabetic ketoacidosis. This condition should be treated with insulin.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. In clinical trials, approximately 2,600 patients with Type diabetes were treated with nateglinide. Of these, approximately 1,335 patients were treated for 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 NateglinideMonotherapy Trials (% of patients) Placebo N=458NateglinideN=1441Preferred Term Upper Respiratory Infection8.110.5Back Pain3.74.0Flu Symptoms2.63.6Dizziness2.23.6Arthropathy2.23.3Diarrhea3.13.2Accidental Trauma1.72.9Bronchitis2.62.7Coughing2.22.4Hypoglycemia0.42.4 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity:A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with recommended nateglinide dose of 120 mg, three times daily before meals. two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals. No evidence of tumorigenic response was found in either rats or mice.Mutagenesis: Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately16 times the human therapeutic exposure with recommended nateglinide dose of 120 mg three times daily before meals).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.. Pharmacokinetics. AbsorptionFollowing oral administration immediately prior to meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within hour (Tmax) after dosing. When administered to patients with Type diabetes over the dosage range 60 mg to 240 mg three times day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is delay in the rate of absorption characterized by decrease in Cmax and delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to meal.DistributionBased on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to lesser extent acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1 to 10 mcg/mL.MetabolismNateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.In vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).ExcretionNateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for days.. Drug Interactions. In vitro drug metabolism studies indicate that nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to lesser extent CYP3A4 (30%). Nateglinide is 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 randomized, multiple-dose crossover study, patients with Type diabetes were administered 120 mg nateglinide three times day before meals for 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 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 single 1mg 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 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 single 75 mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.. Special Populations. Geriatric: Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.Race: Results of population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.Renal Impairment: Compared to healthy matched subjects, patients with Type diabetes and moderate-to-severe renal insufficiency (CrCl 15 to 50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.Hepatic Impairment: The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Nateglinide should be used with caution in patients with chronic liver disease. (See PRECAUTIONS, Hepatic Impairment.). Pharmacodynamics. Nateglinide is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide is dosed three times daily before meals there is rapid rise in plasma insulin, with peak levels approximately hour after dosing and fall to baseline by hours after dosing.In double-blind, controlled clinical trial in which nateglinide was administered before each of three meals, plasma glucose levels were determined over 12-hour, daytime period after weeks of treatment. Nateglinide was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subjects height. Nateglinide produced statistically significant decreases in fasting and postprandial glycemia compared to placebo.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. total of 3,566 patients were randomized in nine double-blind, placebo- or active-controlled studies to 24 weeks in duration to evaluate the safety and efficacy of nateglinide. 3,513 patients had efficacy values beyond baseline. In these studies nateglinide was administered up to 30 minutes before each of three main meals daily.. Nateglinide Monotherapy Compared to Placebo. In randomized, double-blind, placebo-controlled, 24-week study, patients with Type diabetes with HbA1C >= 6.8 on diet alone were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least months before randomization. The addition of nateglinide before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C and FPG were similar for patients naive to, and those previously exposed to, antidiabetic medications.In this study, one episode of severe hypoglycemia (plasma glucose <36 mg/dL) was reported in patient treated with nateglinide 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with nateglinide had statistically significant mean increases in weight compared to placebo (see Table 1).In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type diabetes were randomized to receive nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Nateglinide monotherapy resulted in significant reductions in mean HbA1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).Table 1: Endpoint results for 24-week, fixed dosestudy of nateglinide monotherapy PlaceboNateglinide 60 mg three times daily before mealsNateglinide 120 mg three times daily before mealsHbA1C (%)N=168N=167N=168Baseline (mean)8 7.98.1Change from baseline (mean)+0.2-0.3 -0.5Difference from placebo (mean) -0.5 -0.7 FPG(mg/dL)N=172N=171N=169Baseline (mean)167.9 161 166.5Change from baseline (mean)+9.1+0.4-4.5Difference from placebo (mean) -8.7 -13.6 Weight (kg)N=170N=169N=166Baseline (mean)85.883.786.3Change from baseline (mean)-0.7+0.3+0.9Difference from placebo (mean) +1 +1.6 a p-value <= 0.004 Nateglinide Monotherapy Compared to Other Oral Antidiabetic Agents. GlyburideIn 24-week, double-blind, active-controlled trial, patients with Type diabetes who had been on sulfonylurea for >= months and who had baseline HbA1C >= 6.5 were randomized to receive nateglinide (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to nateglinide had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.MetforminIn another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type diabetes were randomized to receive nateglinide (120 mg three times daily before meals), metformin 500 mg (three times daily), combination of nateglinide 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least months before randomization.The reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with nateglinide monotherapy (see Table 2). Relative to placebo, nateglinide monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naive to antidiabetic therapy, the reductions in mean HbA1C and mean FPG for nateglinide monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).. Nateglinide Combination Therapy. MetforminIn the active and placebo-controlled study of metformin and nateglinide described above, the combination of nateglinide and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either nateglinide or metformin monotherapy (see Table 2). Nateglinide, alone or in combination with metformin, significantly reduced the prandial glucose elevation from pre--meal to 2-hours post-meal compared to placebo and metformin alone.In this study, one episode of severe hypoglycemia (plasma glucose <= 36 mg/dL) was reported in patient receiving the combination of nateglinide and metformin and four episodes of severe hypoglycemia were reported in single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, nateglinide monotherapy was associated with statistically significant increase in weight, while no significant change in weight was observed with combined nateglinide and metformin therapy (see Table 2).In another 24-week, double-blind, placebo-controlled trial, patients with Type diabetes with HbA1C >= 6.8% after treatment with metformin (>= 1500 mg daily for >= month) were first entered into four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive nateglinide (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with nateglinide and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for nateglinide 60 mg and nateglinide 120 mg plus metformin, respectively).Table 2: End point results for 24-week study of nateglinide monotherapy and combination with metformin PlaceboNateglinide 120 mg three times daily before mealsMetformin 500 mg three times dailyNateglinide 120 mg before meals plus MetforminHbA1C (%)All N=160 N=171 N=172 N=162 Baseline (mean)8.38.38.48.4Change from baseline (mean)+0.4-0.4bc -0.8c -1.5Difference from placebo -0.8a -1.2a -1.9a NaiveN=98N=99N=98N=81Baseline (mean)8.28.18.38.2Change from baseline (mean)+0.3-0.7 -0.8 -1.6Difference from placebo -1 -1.1 -1.9 Non-NaiveN=62N=72N=74N=81Baseline (mean) 8.38.58.78.7Change from baseline (mean) +0.6 +0.004 bc -0.8 -1.4Difference from placebo -0.6 -1.4 -2 FPG (mg/dL) AllN=166N=173N=174N=167Baseline (mean) 194196.5196197.7Change from baseline (mean) +8-13.1 bc -30 -44.9Difference from placebo -21.1 -38 -52.9 Weight (kg)All N=160 N=169 N=169 N=160Baseline (mean) 858586 87.4Change from baseline (mean)-0.4+0.9 bc -0.1+0.2Difference from placebo +1.3 +0.3+0.6a p-value <= 0.05 vs. placebob p-value <= 0.03 vs. metforminc p-value <= 0.05 vs. combinationMetformin was administered three times dailyRosiglitazoneA 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type diabetes not adequately controlled after therapeutic response to rosiglitazone monotherapy mg daily. The addition of nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with nateglinide plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.GlyburideIn 12-week study of patients with Type diabetes inadequately controlled on glyburide 10 mg once daily, the addition of nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

DESCRIPTION SECTION.

DESCRIPTION. Nateglinide tablets USP are oral antidiabetic agent used in the management of Type 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 shownNateglinide is white powder with 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: carnauba wax, copovidone, croscarmellose sodium, mannitol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, corn starch and talc.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Nateglinide tablets should be taken to 30 minutes prior to meals.. Monotherapy and Combination with Metformin or Thiazolidinedione. The recommended starting and maintenance dose of nateglinide tablets, alone or in combination with metformin or thiazolidinedione, is 120 mg three times daily before meals.The 60 mg dose of nateglinide tablets, either alone or in combination with metformin or thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.. Dosage in Geriatric Patients. No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to nateglinide tablets 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 tablets should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).

DRUG INTERACTIONS SECTION.

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, 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 Johns 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.

GERIATRIC USE SECTION.

Geriatric Use. No differences were observed in safety or efficacy of nateglinide between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to nateglinide therapy cannot be ruled out.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Nateglinide tablets USP are available as 60 mg white to off-white, round, biconvex tablets embossed with RDY on one side and 328 on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 10).Bottles of 30 NDC 55111-328-30Bottles of 90 NDC 55111-328-90Bottles of 100 NDC 55111-328-01Bottles of 500 NDC 55111-328-05Unit dose package of 100 (10 10) NDC 55111-328-78Nateglinide tablets USP are available as 120 mg white to off-white, round, biconvex tablets embossed with RDY on one side and 329 on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 10).Bottles of 30 NDC 55111-329-30Bottles of 90 NDC 55111-329-90Bottles of 100 NDC 55111-329-01Bottles of 500 NDC 55111-329-05Unit dose package of 100 (10 10) NDC 55111-329-78StorageStore at 20-25C (68-77F); excursions permitted to 15-30C (59-86F) [See USP Controlled Room Temperature].Dispense in tight container, USP.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Nateglinide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.

LABORATORY TESTS SECTION.

Laboratory Tests. Response to therapies should be periodically assessed with glucose values and HbA1C levels.

NURSING MOTHERS SECTION.

Nursing Mothers. Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). It is not known whether nateglinide is excreted in human milk. Because many drugs are excreted in human milk, nateglinide should not be administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE. In clinical study in patients with Type diabetes, nateglinide was administered in increasing doses up to 720 mg day for days and there were no clinically significant adverse events reported. There have been no instances of overdose with nateglinide in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package Label. Principal Display Panel. Nateglinide Tablets, 60 mg Container Label.

PEDIATRIC USE SECTION.

Pediatric Use. Clinical trials to demonstrate the safety and effectiveness in pediatric patients have not been conducted.

PRECAUTIONS SECTION.

PRECAUTIONS. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide or any other antidiabetic drug.. Hypoglycemia:. All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Nateglinide should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of nateglinide to reduce the risk of hypoglycemia.. Hepatic Impairment:. Nateglinide should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.. Loss of Glycemic Control. Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of nateglinide therapy at such times. Secondary failure, or reduced effectiveness of nateglinide over period of time, may occur.. Information for Patients. Patients should be informed of the potential risks and benefits of nateglinide and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take nateglinide to 30 minutes before ingesting meal, but to skip their scheduled dose if they skip the meal so that the risk of hypoglycemia will be reduced. Drug interactions should be discussed with patients. Patients should be informed of potential drug--drug interactions with nateglinide.. Laboratory Tests. Response to therapies should be periodically assessed with glucose values and HbA1C levels. 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, 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 Johns 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.. Drug/Food Interactions. The pharmacokinetics of nateglinide were not affected by the composition of meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when nateglinide was administered 10 minutes prior to liquid meal. Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity:A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with recommended nateglinide dose of 120 mg, three times daily before meals. two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals. No evidence of tumorigenic response was found in either rats or mice.Mutagenesis: Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately16 times the human therapeutic exposure with recommended nateglinide dose of 120 mg three times daily before meals).. Pregnancy. Pregnancy Category CNateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Nateglinide should not be used during pregnancy.. Labor and Delivery. The effect of nateglinide on labor and delivery in humans is not known.. Nursing Mothers. Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). It is not known whether nateglinide is excreted in human milk. Because many drugs are excreted in human milk, nateglinide should not be administered to nursing woman.. Pediatric Use. Clinical trials to demonstrate the safety and effectiveness in pediatric patients have not been conducted.. Geriatric Use. No differences were observed in safety or efficacy of nateglinide between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to nateglinide therapy cannot be ruled out.

PREGNANCY SECTION.

Pregnancy. Pregnancy Category CNateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with recommended nateglinide dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Nateglinide should not be used during pregnancy.

SPL UNCLASSIFIED SECTION.

structure. carton1. carton2. container1. container2.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 60 mg tablets: white to off-white, round, biconvex tablets embossed with RDY on one side and 328 on other side.120 mg tablets: white to off-white, round, biconvex tablets embossed with RDY on one side and 329 on other side. 60 mg tablets: white to off-white, round, biconvex tablets embossed with RDY on one side and 328 on other side.. 120 mg tablets: white to off-white, round, biconvex tablets embossed with RDY on one side and 329 on other side. Tablets: 60 mg and 120 mg (3).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Administration Instruct patients to take nateglinide to 30 minutes before meals. Instruct patients that skip meals to skip their dose of nateglinide [see Dosage and Administration (2) ]. Hypoglycemia Inform patients that nateglinide can cause hypoglycemia and instruct patients and their caregivers on self-management procedures including glucose monitoring and management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended [see Warnings and Precautions (5.1)]. Lactation Advise patients that use of nateglinide is not recommended while breastfeeding [see Use in Specific Populations (8.2)]. Drug Interactions Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with nateglinide. Rx only Manufactured by: Dr. Reddys Laboratories Limited Bachupally 500 090 INDIA Revised: 1121.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Nateglinide lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity: Nateglinide did not increase tumors in two year carcinogenicity studies conducted in mice and rats. Oral doses of nateglinide up to 900 mg/kg in rats and 400 mg/kg in mice were tested, which produced exposures in rats approximately 30 to 40 times and in mice 10 to 30 times the human therapeutic exposure of nateglinide at dose of 120 mg three times daily, based on AUC. Mutagenesis: Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay or in the in vivo mouse micronucleus test. Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (corresponding to 16 times the MRHD of 120 mg three times per day, based on BSA).).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Nateglinide stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide is dosed before meals, the peak rise in plasma insulin occurs approximately hour after dosing and falls to baseline by hours after dosing.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In patients with Type diabetes, multiple dose administration of nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both area under the curve (AUC) and Cmax. In patients with Type diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for days. Absorption Absolute bioavailability of nateglinide is approximately 73%. Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to meal. Following oral administration immediately prior to meal, the mean peak plasma nateglinide concentrations (Cmax generally occur within hour (Tmax after dosing. Tmax is independent of dose. The pharmacokinetics of nateglinide are not affected by the composition of meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when nateglinide is administered 10 minutes prior to liquid meal as compared to solid meal. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is delay in the rate of absorption characterized by decrease in Cmax and delay in time to peak plasma concentration (Tmax ). Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing. Distribution Following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to lesser extent acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1 to 10 mcg/mL. Elimination In healthy volunteers and patients with type diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours. Metabolism In vitro drug metabolism studies indicate that nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to lesser extent CYP3A4 (30%). The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide. Excretion Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14C -nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C -nateglinide was excreted in the urine as parent compound.Specific Populations Renal Impairment No pharmacokinetic data are available in subjects with mild renal impairment (CrCl 60 to 89 mL/min). Compared to healthy matched subjects, patients with type diabetes mellitus and moderate and severe renal impairment (CrCl 15 to 50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with type diabetes and renal failure on dialysis exhibited reduced overall drug exposure (Cmax decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.In cohort of patients with type diabetes and end-stage renal disease (ESRD) (eGFR 15 mL/min/1.73m2) M1 metabolite accumulation up to 1.2 ng/mL occurred with dosage of 90 mg once daily for to months. In another cohort of patients with type diabetes on hemodialysis, M1 concentration decreased after single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose. Hepatic Impairment In patients with mild hepatic impairment, the mean increase in Cmax and AUC of nateglinide were 37% and 30 respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of nateglinide in patients with moderate-to-severe hepatic impairment. Gender No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Race Results of population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide. Age Age does not influence the pharmacokinetic properties of nateglinide. Drug Interactions:In vitro assessment of drug interactions Nateglinide is 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. 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. In vivoassessment of drug interactions The effect of coadministered drugs on the pharmacokinetics of nateglinide and the effect of nateglinide on pharmacokinetics of coadministered drugs are shown in Tables and 4. No clinically relevant change in pharmacokinetic parameters of either agent was reported when nateglinide was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac.Table 3: Effect of Coadministered Drugs on Pharmacokinetics of NateglinideCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in CmaxChange in AUC Glyburide 10 mg once daily for weeks 120 mg three times day, single dose 8.78% 3.53 Metformin 500 mg three times day for weeks 120 mg three times day, single dose AM: 7.14% PM: 11.4% AM: 1.51% PM: 5.97% Digoxin mg, single dose 120 mg three times day, single dose AM: 2.17% PM: 3.19% AM: 7.62% PM: 2.22% Warfarin 30 mg, single dose 120 mg three times day for days 2.65% 3.72% Diclofenac 75 mg, single dose 120 mg twice daily, single dose dose AM: 13.23% PM: 3.76% AM: 2.2% PM: 7.5% AM: after morning dose; PM: after evening dose; after second dose; increase in the parameter; decrease in the parameter Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs Coadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange inCmax Change inAUC Glyburide 10 mg once daily for weeks 120 mg three times day, single dose 3.18% 7.34% Metformin 500 mg three times day for weeks 120 mg three times day, single dose AM: 10.7% PM: 0.40% AM:13.3% PM: 2.27% Digoxin mg, single dose 120 mg three times day, single dose 5.41% 6.58 Warfarin 30 mg, single dose 120 mg three times day for days R-warfarin: 1.03% S-warfarin: 0.85% R-warfarin: 0.74% S-warfarin: 7.23% Diclofenac 75 mg, single dose 120 mg twice daily, single dose 2.19% 7.97% AM: after morning dose; PM: after evening dose; SD: single dose; increase in the parameter; decrease in the parameter.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Nateglinide is not recommended when breastfeeding (8.2). Lactation: Nateglinide is not recommended when breastfeeding (8.2). 8.1 Pregnancy. Risk SummaryThe available data from published literature and the applicants pharmacovigilance with use of nateglinide in pregnant women are insufficient to identify drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Nateglinide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal reproduction studies, there was no teratogenicity in rats and rabbits administered oral nateglinide during organogenesis at approximately 27 and times the maximum recommended human dose (MRHD), respectively, based on body surface area (BSA). The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c 7 and has been reported to be as high as 20% to 25% in women with HbA1c 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. DataAnimal dataIn embryofetal development studies, nateglinide administered orally during the period of organogenesis was not teratogenic in rats at doses up to 1,000 mg/kg (corresponding to 27 times the MRHD of 120 mg three times per day, based on BSA). In rabbits, embryonic development was adversely affected at 500 mg/kg/day and the incidence of gallbladder agenesis or small gallbladder was increased at dose of 300 and 500 mg/kg (corresponding to 16 and 27 times the MRHD). No such effects were observed at 150 mg/kg/day (corresponding to times the MRHD). In pre-and postnatal development study in rats, nateglinide administered by oral gavage at doses of 100, 300, and 1000 mg/kg/day from gestation day 17 to lactation day 21 resulted in lower body weight in offspring of rats administered nateglinide at 1,000 mg/kg/day (corresponding to 27 times the MHRD). 8.2 Lactation Risk summaryThere are no data on the presence of nateglinide in human milk, the effects on the breastfeeding infant, or the effects on milk production. The drug is present in animal milk. When drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Because the potential for hypoglycemia in breast-fed infants, advise women that use of nateglinide is not recommended while breastfeeding. Data In rat reproduction studies, nateglinide and its metabolite are excreted in the milk following oral dose (300 mg/kg). The overall milk: plasma (M/P) concentration ratio of the total radioactivity was approximately 1.4 based on AUC0-48 values. The M/P ratio of unchanged nateglinide was approximately 2.2. 8.4 Pediatric Use. The safety and effectiveness of nateglinide have not been established in pediatric patients.. 8.5 Geriatric Use. 436 patients 65 years and older, and 80 patients 75 years and older were exposed to nateglinide in clinical studies. No differences were observed in safety or efficacy of nateglinide between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to nateglinide therapy cannot be ruled out.. 8.6 Renal Impairment No dosage adjustment is recommended in patients with mild to severe renal impairment [see Clinical Pharmacology 12.3 )]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment. Use of nateglinide in patients with moderate-to-severe hepatic impairment has not been studied and therefore, should be used with caution in these patients [see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypoglycemia: Nateglinide may cause hypoglycemia. Administer before meals to reduce the risk of hypoglycemia. Skip the scheduled dose of nateglinide if meal is skipped to reduce the risk of hypoglycemia. (5.1)Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide. (5.2) Hypoglycemia: Nateglinide may cause hypoglycemia. Administer before meals to reduce the risk of hypoglycemia. Skip the scheduled dose of nateglinide if meal is skipped to reduce the risk of hypoglycemia. (5.1). Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide. (5.2) 5.1 Hypoglycemia All glinides, including nateglinide, can cause hypoglycemia [see Adverse Reactions (6.1 )]. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy (nerve disease), in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia. Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content), changes in level of physical activity, changes to coadministered medication [see Drug Interactions (7) ], and concomitant use with other antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)]. Patients should take nateglinide before meals and be instructed to skip the dose of nateglinide if meal is skipped [see Dosage and Administration (2)]. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.. 5.2 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide.