ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reaction is also described elsewhere in the labeling:Hypoglycemia [see Warnings and Precautions (5.1)] Hypoglycemia [see Warnings and Precautions (5.1)] Common adverse reactions associated with nateglinide (3% or greater incidence) were upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Common adverse reactions associated with nateglinide (3% or greater incidence) were upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea. (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In clinical trials, approximately 2,600 patients with type diabetes mellitus 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. Table shows the most common adverse reactions associated with nateglinide.Table 1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in Nateglinide-Treated Patients from Pool of 12 to 64 week Placebo Controlled TrialsPlaceboN 458NateglinideN 1441Preferred TermUpper Respiratory Infection8.110.5Back Pain3.74.0Flu Symptoms2.63.6Dizziness2.23.6Arthropathy2.23.3Diarrhea3.13.2Accidental Trauma1.72.9Bronchitis2.62.7Coughing2.22.4HypoglycemiaEpisodes of severe hypoglycemia (plasma glucose less than 36 mg/dL) were reported in two patients treated with nateglinide. Non-severe hypoglycemia occurred in 2.4 of nateglinide treated patients and 0.4 of placebo-treated patients [see Warnings and Precautions (5.1)]. Weight GainPatients treated with nateglinide had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with nateglinide 60 mg (3 times daily) and nateglinide 120 mg (3 times daily) compared to placebo were 1.0 kg and 1.6 kg, respectively. Laboratory TestIncreases in 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. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of nateglinide. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity Reactions: Rash, itching, and urticaria Hepatobiliary Disorders: Jaundice, cholestatic hepatitis, and elevated liver enzymes Hypersensitivity Reactions: Rash, itching, and urticaria Hepatobiliary Disorders: Jaundice, cholestatic hepatitis, and elevated liver enzymes.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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. 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.. 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 max. 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. AbsorptionAbsolute 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 (C max) generally occur within hour (T max) after dosing. max 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 max and delay in time to peak plasma concentration (T max). Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.DistributionFollowing 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. EliminationIn healthy volunteers and patients with type diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours. MetabolismIn 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.ExcretionNateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14 C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14 C-nateglinide was excreted in the urine as parent compound. Specific PopulationsRenal ImpairmentNo 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 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and max. Patients with type diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C max 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/1.73m 2) 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 ImpairmentIn patients with mild hepatic impairment, the mean increase in max 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. GenderNo clinically significant differences in nateglinide pharmacokinetics were observed between men and women. RaceResults of population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide. AgeAge 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 vivo assessment 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 NateglinideAM: after morning dose; PM: after evening dose; after second dose; increase in the parameter; decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in max Change in AUCGlyburide10 mg once daily for weeks120 mg three times day, single dose8.78% 3.53 Metformin500 mg three times day for weeks120 mg three times day, single doseAM: 7.14% PM: 11.4% AM: 1.51% PM: 5.97% Digoxin1 mg, single dose120 mg three times day, single doseAM: 2.17% PM: 3.19% AM: 7.62% PM: 2.22% Warfarin30 mg, single dose120 mg three times day for days2.65% 3.72% Diclofenac75 mg, single dose120 mg twice daily, single doseAM: 13.23% PM: 3.76% AM: 2.2% PM: 7.5% Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered DrugsAM: after morning dose; PM: after evening dose; SD: single dose; increase in the parameter; decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in max Change in AUCGlyburide10 mg once daily for weeks120 mg three times day, single dose3.18% 7.34% Metformin500 mg three times day for weeks120 mg three times day, single doseAM: 10.7% PM: 0.40% AM: 13.3% PM: 2.27% Digoxin1 mg, single dose120 mg three times day, single dose5.41% 6.58 Warfarin30 mg, single dose120 mg three times day for daysR-warfarin: 1.03% S-warfarin: 0.85% R-warfarin: 0.74% S-warfarin: 7.23% Diclofenac75 mg, single dose120 mg twice daily, single dose2.19% 7.97%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Monotherapy. In 24-week, double-blind, placebo-controlled study, patients with type diabetes were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least months before randomization.At Week 24, treatment with nateglinide before meals resulted in statistically significant reductions in mean HbA 1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 5). The reductions in HbA 1C and FPG were similar for patients naive to, and those previously exposed to, antidiabetic medications. Table 5: Endpoint Results for 24-week, Fixed Dose Study of Nateglinide MonotherapyPlaceboNateglinide 60 mg three times daily before mealsNateglinide 120 mg three times daily before mealsHbA 1C (%) = 168N 167N 168 Baseline (mean)8.07.98.1 Change from baseline (mean)+0.2-0.3-0.5 Difference from placebo (mean)-0.5 p-value <= 0.004 -0.7 FPG (mg/dL)N 172N 171N 169 Baseline (mean)167.9161.0166.5 Change from baseline (mean)+9.1+0.4-4.5 Difference from placebo (mean)-8.7 -13.6 14.2 Monotherapy Compared to Glyburide. In 24-week, double-blind, active-controlled trial, patients with type diabetes who had been on sulfonylurea for or more months and who had baseline HbA 1C greater than or equal to 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 statistically significant increases in mean HbA 1C and mean FPG at endpoint compared to patients randomized to glyburide. Table 6: Endpoint Results for 24-Week Study of Nateglinide Monotherapy Compared to GlyburideGlyburide 10 mgOnce dailyNateglinide 60 mgthree times daily before mealsNateglinide 120 mgthree times daily before mealsHbA 1c (%) = 183N 178N 179 Baseline (mean)7.88.07.9 Change from baseline (mean)0.31.31.1 Difference from glyburide1.0 p-value 0.001 0.9 FPG (mmol/L)N 184N 182N 180 Baseline (mean)9.449.679.61 Change from baseline (mean)0.193.062.84 Difference from glyburide2.87 2.66 14.3 Monotherapy and In Combination with Metformin. In 24-week, double-blind, active- and placebo-controlled study, patients with type diabetes were randomized to receive either nateglinide alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), combination of nateglinide 120 mg (three times daily before meals) and metformin (500 mg three times daily), or placebo. 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.At Week 24, statistically significant reductions in mean HbA 1c and FPG were observed with metformin monotherapy compared to nateglinide monotherapy, and the combination of nateglinide and metformin compared to either nateglinide or metformin monotherapy (see Table 7). Compared to placebo, nateglinide monotherapy was associated with statistically significant increase in mean body weight, while no significant change in body weight was observed with metformin monotherapy or combination of nateglinide and metformin therapy (see Table 7). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA 1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA 1C was reduced in the metformin monotherapy group (see Table 7). Table 7: Endpoint Results for 24-Week Study of Nateglinide Monotherapy and Combination with MetforminPlaceboNateglinide 120 mgthree times daily before mealsMetformin 500 mgthree times dailyNateglinide 120 mgbefore meals plus MetforminMetformin was administered three times dailyHbA 1C (%) AllN 160N 171N 172N 162 Baseline (mean)8.38.38.48.4 Change from baseline (mean)+0.4-0.4 p-value <= 0.03 vs. metformin p-value <= 0.05 vs. combination -0.8 -1.5 Difference from placebo-0.8 p-value <= 0.05 vs. placebo -1.2 -1.9 NaiveN 98N 99N 98N 81 Baseline (mean)8.28.18.38.2 Change from baseline (mean)+0.3-0.7 -0.8 -1.6 Difference from placebo-1.0 -1.1 -1.9 Non-NaiveN 62N 72N 74N 81 Baseline (mean)8.38.58.78.7 Change from baseline (mean)+0.6+0.004 -0.8 -1.4 Difference from placebo-0.6 -1.4 -2.0 FPG (mg/dL)AllN 166N 173N 174N 167 Baseline (mean)194.0196.5196.0197.7 Change from baseline (mean)+8.0-13.1 -30.0 -44.9 Difference from placebo-21.1 -38.0 -52.9 In another 24-week, double-blind, placebo-controlled trial, patients with type diabetes with HbA 1C greater than or equal to 6.8% after treatment with metformin (greater than or equal to 1500 mg daily for at least month) were first entered into four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, nateglinide 60 mg and 120 mg three times daily resulted in statistically significantly greater reductions in HbA 1C compared to placebo when added to metformin (-0.4% and -0.6% for nateglinide 60 mg and nateglinide 120 mg plus metformin, respectively). Table 8: Endpoint Results for 24-Week Study of Nateglinide Monotherapy as Add-on to MetforminAll nateglinide/placebo taken three times daily before meals; all metformin 1000 mg twice dailyPlacebo metforminNateglinide 60 mg metforminNateglinide 120 mg metforminHbA 1c (%) = 150N 152N 154 Baseline (mean)8.28.08.2 Change from baseline (mean)0.01-0.4-0.6 Difference from metformin-0.4 p-value 0.003 vs. metformin -0.6 p-value 0.001 vs. metformin 14.4 Add-On Combination Therapy with Rosiglitazone. 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type diabetes not adequately controlled on rosiglitazone mg daily. The addition of nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA 1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with nateglinide compared to +1 kg for patients treated with placebo when added to rosiglitazone. Table 9: Endpoint Results for 24-Week Study of the Effect of Adding Nateglinide or Placebo to RosiglitazonePlacebo +rosiglitazone mg once dailyNateglinide 120 mg before meals +rosiglitazone mg once dailyHbA 1c (%) = 191N 194 Baseline (mean)8.48.3 Change from baseline (mean)0.03-0.7 Difference from rosiglitazone (mean)-0.7 p-value <= 0.0001 14.5 Add-On Combination Therapy with Glyburide. In 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.Table 10: Endpoint Results for 12-week Study of the Effect of Adding Nateglinide or Placebo to GlyburidePlacebo or nateglinide given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of nateglinide or placebo.Placebo +glyburide 10 mg once dailyNateglinide 60 mg before meals +glyburide 10 mg once dailyNateglinide 120 mg before meals +glyburide 10 mg once dailyHbA 1c (%) = 58N 55N 54 Baseline (mean)8.78.78.7 Change from baseline (mean)0.30.2-0.02 Difference from glyburide (mean)-0.1 p-value 0.6959 -0.3 p-value 0.1246.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes list of drugs with clinically important drug interactions when concomitantly administered or withdrawn with nateglinide and instructions for managing or preventing them.Table 2: Clinically Significant Drug Interactions with NateglinideDrugs That May Increase the Blood-Glucose-Lowering Effect of Nateglinide and Susceptibility to HypoglycemiaDrugs:Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g., methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g., amiodarone, fluconazole, voriconazole, sulfinpyrazone) or in patients known to be poor metabolizers of CYP2C9 substrates, alcohol.Intervention:Dose reductions and increased frequency of glucose monitoring may be required when nateglinide is coadministered with these drugs.Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of Nateglinide and Increase Susceptibility to HyperglycemiaDrugs:Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g., lanreotide, octreotide), and CYP inducers (e.g., rifampin, phenytoin and St Johns Wort).Intervention:Dose increases and increased frequency of glucose monitoring may be required when nateglinide is coadministered with these drugs.Drugs That May Blunt Signs and Symptoms of HypoglycemiaDrugs:beta-blockers, clonidine, guanethidine, and reserpineIntervention:Increased frequency of glucose monitoring may be required when nateglinide is coadministered with these drugs.. Drugs That May Increase the Potential for Hypoglycemia: Nateglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered (7) Drugs That May Increase the Potential for Hyperglycemia: Nateglinide dose increases and increased frequency of glucose monitoring may be required when co-administered (7) Drugs That May Blunt Signs and Symptoms of Hypoglycemia: Increased frequency of glucose monitoring may be required when co-administered (7) Drugs That May Increase the Potential for Hypoglycemia: Nateglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered (7) Drugs That May Increase the Potential for Hyperglycemia: Nateglinide dose increases and increased frequency of glucose monitoring may be required when co-administered (7) Drugs That May Blunt Signs and Symptoms of Hypoglycemia: Increased frequency of glucose monitoring may be required when co-administered (7).

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 max. 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. AbsorptionAbsolute 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 (C max) generally occur within hour (T max) after dosing. max 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 max and delay in time to peak plasma concentration (T max). Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.DistributionFollowing 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. EliminationIn healthy volunteers and patients with type diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours. MetabolismIn 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.ExcretionNateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14 C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14 C-nateglinide was excreted in the urine as parent compound. Specific PopulationsRenal ImpairmentNo 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 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and max. Patients with type diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C max 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/1.73m 2) 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 ImpairmentIn patients with mild hepatic impairment, the mean increase in max 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. GenderNo clinically significant differences in nateglinide pharmacokinetics were observed between men and women. RaceResults of population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide. AgeAge 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 vivo assessment 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 NateglinideAM: after morning dose; PM: after evening dose; after second dose; increase in the parameter; decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in max Change in AUCGlyburide10 mg once daily for weeks120 mg three times day, single dose8.78% 3.53 Metformin500 mg three times day for weeks120 mg three times day, single doseAM: 7.14% PM: 11.4% AM: 1.51% PM: 5.97% Digoxin1 mg, single dose120 mg three times day, single doseAM: 2.17% PM: 3.19% AM: 7.62% PM: 2.22% Warfarin30 mg, single dose120 mg three times day for days2.65% 3.72% Diclofenac75 mg, single dose120 mg twice daily, single doseAM: 13.23% PM: 3.76% AM: 2.2% PM: 7.5% Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered DrugsAM: after morning dose; PM: after evening dose; SD: single dose; increase in the parameter; decrease in the parameterCoadministered drugDosing regimen of coadministered drugDosing regimen of nateglinideChange in max Change in AUCGlyburide10 mg once daily for weeks120 mg three times day, single dose3.18% 7.34% Metformin500 mg three times day for weeks120 mg three times day, single doseAM: 10.7% PM: 0.40% AM: 13.3% PM: 2.27% Digoxin1 mg, single dose120 mg three times day, single dose5.41% 6.58 Warfarin30 mg, single dose120 mg three times day for daysR-warfarin: 1.03% S-warfarin: 0.85% R-warfarin: 0.74% S-warfarin: 7.23% Diclofenac75 mg, single dose120 mg twice daily, single dose2.19% 7.97%.

PREGNANCY SECTION.

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 HbA 1c 7 and has been reported to be as high as 20% to 25% in women with HbA 1c 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).

SPL UNCLASSIFIED SECTION.

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.

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 HbA 1c 7 and has been reported to be as high as 20% to 25% in women with HbA 1c 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. DataIn 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 AUC 0-48 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.