effect of nateglinide and increase susceptibility to hyperglycemia drugs: thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and cyp inducers (e.g. rifampin, phenytoin and st john’s 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 hypoglycemia drugs: beta-blockers, clonidine, guanethidine, and reserpine intervention: 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 coadministered ( 7 ) drugs that may increase the potential for hyperglycemia : nateglinide dose increases and increased frequency of glucose monitoring may be required when coadministered ( 7 ) drugs that may blunt signs and symptoms of hypoglycemia : increased frequency of glucose monitoring may be required when coadministered ( 7 )

ding 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 a meal is skipped [see dosage and administration ( 2 )]. patients and caregivers must be educated to recognize and manage hypoglycemia. self-monitoringof blood glucose plays an essential role in the prevention and management of hypoglycemia. in patients athigher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increasedfrequency 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.

r longer. table 1 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 trials placebo n=458 nateglinide n=1441 preferred term upper respiratory infection 8.1 10.5 back pain 3.7 4.0 flu symptoms 2.6 3.6 dizziness 2.2 3.6 arthropathy 2.2 3.3 diarrhea 3.1 3.2 accidental trauma 1.7 2.9 bronchitis 2.6 2.7 coughing 2.2 2.4 hypoglycemia episodes 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 gain patients 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 test increases 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. hypersensitivity reactions: rash, itching, and urticaria hepatobiliary disorders: jaundice, cholestatic hepatitis, and elevated liver enzymes

effect of nateglinide and increase susceptibility to hyperglycemia drugs: thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and cyp inducers (e.g. rifampin, phenytoin and st john’s 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 hypoglycemia drugs: beta-blockers, clonidine, guanethidine, and reserpine intervention: 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 coadministered ( 7 ) drugs that may increase the potential for hyperglycemia : nateglinide dose increases and increased frequency of glucose monitoring may be required when coadministered ( 7 ) drugs that may blunt signs and symptoms of hypoglycemia : increased frequency of glucose monitoring may be required when coadministered ( 7 )

s excreted in rat milk. offspring of rats exposed to 1,000 mg/kg nateglinide (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area) had lower body weight. because the potential for hypoglycemia in nursing infants may exist, a decision should be made as to whether nateglinide should be discontinued in nursing mothers, or if mothers should discontinue nursing. 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 )] .

e dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both auc and c max . in patients with type 2 diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 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 a meal. following oral administration immediately prior to a meal, the mean peak plasma nateglinide concentrations (c max ) generally occur within 1 hour (t max ) after dosing. t max is independent of dose. the pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat, or carbohydrate). however, peak plasma levels are significantly reduced when nateglinide is administered 10 minutes prior to a liquid meal as compared to solid meal. when given with or after meals, the extent of nateglinide absorption (auc) remains unaffected. however, there is a delay in the rate of absorption characterized by a decrease in c max and a 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. distribution following intravenous (iv) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 l in healthy subjects. nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α 1 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 2 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 a 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 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 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 2 diabetes mellitus and moderate and severe renal impairment (crcl 15-50 ml/min) not on dialysis displayed similar apparent clearance, auc, and c max . patients with type 2 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 a cohort of 8 patients with type 2 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 a dosage of 90 mg once daily for 1 to 3 months. in another cohort of 8 patients with type 2 diabetes on hemodialysis, m1 concentration decreased after a single session of hemodialysis. although the hypoglycemic activity of the m1 metabolite is approximately 5 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 c 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. gender no clinically significant differences in nateglinide pharmacokinetics were observed between men and women. race results of a 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 a potential inhibitor of the cyp2c9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. inhibition of cyp3a4 metabolic reactions was not detected in in vitro experiments. 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 3 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 nateglinide coadministered drug dosing regimen of coadministered drug dosing regimen of nateglinide change in c max change in auc glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 8.78% ↓ 3.53% ↓ metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose am: 7.14% ↑ pm: 11.4% ↓ am: 1.51% ↑ pm: 5.97% ↑ digoxin 1 mg, single dose 120 mg three times a day, single dose am: 2.17% ↓ pm: 3.19% ↑ am: 7.62% ↑ pm: 2.22% ↑ warfarin 30 mg, single dose 120 mg three times a day for 4 days 2.65% ↑ 3.72% ↓ diclofenac 75 mg, single dose 120 mg twice daily, single 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 drug dosing regimen of coadministered drug dosing regimen of nateglinide change in c max change in auc glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 3.18% ↓ 7.34% ↓ metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose am: 10.7% ↑ pm: 0.40% ↑ am: 13.3% ↑ pm: 2.27% ↓ digoxin 1 mg, single dose 120 mg three times a day, single dose 5.41% ↓ 6.58% ↑ warfarin 30 mg, single dose 120 mg three times a day for 4 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

teglinide is administered 10 minutes prior to a liquid meal as compared to solid meal. when given with or after meals, the extent of nateglinide absorption (auc) remains unaffected. however, there is a delay in the rate of absorption characterized by a decrease in c max and a 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. distribution following intravenous (iv) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 l in healthy subjects. nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α 1 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 2 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 a 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 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 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 2 diabetes mellitus and moderate and severe renal impairment (crcl 15-50 ml/min) not on dialysis displayed similar apparent clearance, auc, and c max . patients with type 2 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 a cohort of 8 patients with type 2 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 a dosage of 90 mg once daily for 1 to 3 months. in another cohort of 8 patients with type 2 diabetes on hemodialysis, m1 concentration decreased after a single session of hemodialysis. although the hypoglycemic activity of the m1 metabolite is approximately 5 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 c 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. gender no clinically significant differences in nateglinide pharmacokinetics were observed between men and women. race results of a 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 a potential inhibitor of the cyp2c9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. inhibition of cyp3a4 metabolic reactions was not detected in in vitro experiments. 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 3 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 nateglinide coadministered drug dosing regimen of coadministered drug dosing regimen of nateglinide change in c max change in auc glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 8.78% ↓ 3.53% ↓ metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose am: 7.14% ↑ pm: 11.4% ↓ am: 1.51% ↑ pm: 5.97% ↑ digoxin 1 mg, single dose 120 mg three times a day, single dose am: 2.17% ↓ pm: 3.19% ↑ am: 7.62% ↑ pm: 2.22% ↑ warfarin 30 mg, single dose 120 mg three times a day for 4 days 2.65% ↑ 3.72% ↓ diclofenac 75 mg, single dose 120 mg twice daily, single 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 drug dosing regimen of coadministered drug dosing regimen of nateglinide change in c max change in auc glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 3.18% ↓ 7.34% ↓ metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose am: 10.7% ↑ pm: 0.40% ↑ am: 13.3% ↑ pm: 2.27% ↓ digoxin 1 mg, single dose 120 mg three times a day, single dose 5.41% ↓ 6.58% ↑ warfarin 30 mg, single dose 120 mg three times a day for 4 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

dl) 8.0 +0.2 n=172 7.9 -0.3 -0.5 a n=171 8.1 -0.5 -0.7 a n=169 baseline (mean) change from baseline (mean) difference from placebo (mean) 167.9 +9.1 161.0 +0.4 -8.7 a 166.5 -4.5 -13.6 a a p-value ≤ 0.004 14.2 monotherapy compared to glyburide in a 24-week, double-blind, active-controlled trial, patients with type 2 diabetes who had been on a sulfonylurea for 3 or more months and who had a 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 a 24-week study of nateglinide monotherapy compared to glyburide glyburide 10 mg once daily nateglinide 60 mg three times daily before meal nateglinide 120 mg three times daily before meals hba 1c (%) n=183 n=178 n=179 baseline (mean) 7.8 8.0 7.9 change from baseline (mean) 0.3 1.3 1.1 difference from glyburide 1.0 a 0.9 a fpg (mmol/l) n=184 n=182 n=180 baseline (mean) 9.44 9.67 9.61 change from baseline (mean) 0.19 3.06 2.84 difference from glyburide 2.87 a 2.66 a a p-value < 0.001 14.3 monotherapy and in combination with metformin in a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a 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 2 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 a 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 a 24-week study of nateglinide monotherapy and combination with metformin hba 1c (%) all placebo n=160 nateglinide 120 mg three times daily before meals n=171 metformin 500 mg three times daily n=172 nateglinide 120 mg before meals plus metformin* n=162 baseline (mean) change from baseline (mean) difference from placebo naïve 8.3 +0.4 n=98 8.3 -0.4 bc -0.8 a n=99 8.4 -0.8 c -1.2 a n=98 8.4 -1.5 -1.9 a n=81 baseline (mean) change from baseline (mean) difference from placebo non-naïve 8.2 +0.3 n=62 8.1 -0.7 c -1.0 a n=72 8.3 -0.8 c -1.1 a n=74 8.2 -1.6 -1.9 a n=81 baseline (mean) change from baseline (mean) difference from placebo fpg (mg/dl) all 8.3 +0.6 n=166 8.5 +0.004 bc -0.6 a n=173 8.7 -0.8 c -1.4 a n=174 8.7 -1.4 -2.0 a n=167 baseline (mean) change from baseline (mean) difference from placebo 194.0 +8.0 196.5 -13.1 bc -21.1 a 196.0 -30.0 c -38.0 a 197.7 -44.9 -52.9 a a p-value ≤0.05 vs. placebo b p-value ≤0.03 vs. metformin c p-value ≤0.05 vs. combination * metformin was administered three times daily in another 24-week, double-blind, placebo-controlled trial, patients with type 2 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 1 month) were first entered into a 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 a 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 a 24-week study of nateglinide monotherapy as add-on to metformin hba 1c (%) placebo + metformin n=150 nateglinide 60 mg + metformin n=152 nateglinide 120 mg + metformin n=154 baseline (mean) change from baseline (mean) difference from metformin 8.2 0.01 8.0 -0.4 -0.4 a 8.2 -0.6 -0.6 b a p-value 0.003 vs. metformin b p-value < 0.001 vs. metformin all nateglinide/placebo taken three times daily before meals; all metformin 1000mg twice daily. 14.4 add-on combination therapy with rosiglitazone a 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type 2 diabetes not adequately controlled on rosiglitazone 8 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 a 24-week study of the effect of adding nateglinide or placebo to rosiglitazone hba 1c (%) placebo + rosiglitazone 8 mg once daily n=191 nateglinide 120 mg before meals + rosiglitazone 8 mg once daily n=194 baseline (mean) change from baseline (mean) difference from rosiglitazone (mean) 8.4 0.03 8.3 -0.7 -0.7 a a p-value < 0.0001 14.5 add-on combination therapy with glyburide in a 12-week study of patients with type 2 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 a 12-week study of the effect of adding nateglinide or placebo to glyburide hba 1c (%) placebo + glyburide 10 mg once daily n=58 nateglinide 60 mg before meals + glyburide 10 mg once daily n=55 nateglinide 120 mg before meals + glyburide 10 mg once daily n=54 baseline (mean) change from baseline (mean) difference from glyburide (mean) 8.7 0.3 8.7 0.2 -0.1 a 8.7 -0.02 -0.3 b placebo or nateglinide given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of nateglinide or placebo. a p-value 0.6959 b p-value 0.1246

012 rev. 01/2019 os 984-01-1-09