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)] The most common adverse reactions (5% or greater incidence) among patients treated with repaglinide were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. Repaglinide has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type diabetes have been treated for at least months, 1000 for at least months, and 800 for at least year. The majority of these individuals (1228) received repaglinide in one of five 1-year, active-controlled trials. Over one year, 13% of repaglinide patients were discontinued due to adverse reactions. The most common adverse reactions leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms. Table lists the common adverse reactions for repaglinide patients compared to placebo in trials 12 to 24 weeks duration.Table 1: Adverse Reactions (%) occurring >= 2% in Repaglinide Treated Patients from Pool of 12 to 24 Week Placebo Controlled Trials See trial descriptions in Clinical Trials (14) Repaglinide N=352 PlaceboN=108 Upper Respiratory Infection Headache Sinusitis Arthralgia Nausea Diarrhea Back Pain Rhinitis Constipation Vomiting Paresthesia Chest pain Bronchitis Dyspepsia Urinary tract infection Tooth disorder Allergy 1611665553333322222 810235243233112100 Hypoglycemia In clinical trials with repaglinide, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of repaglinide treated patients and 7% of placebo treated patients [see Warnings and Precautions (5.1)]. Hypoglycemia was reported in 16% of 1228 repaglinide patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1-year controlled trials. Of repaglinide-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization. In 24-week placebo controlled trial, patients who were naive to oral hypoglycemic agent therapy and patients with HbA1c below 8% at baseline had higher frequency of hypoglycemia. Weight Gain There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to repaglinide. The average weight gain in patients treated with repaglinide and not previously treated with sulfonylurea drugs was 3.3%. Cardiovascular Events The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled comparator clinical trials.Table 2: Summary of Serious Cardiovascular Events in Trials Comparing Repaglinide to Sulfonylureas (% of total patients with events) glyburide and glipizide Repaglinide SU Total Exposed Serious CV Events Cardiac Ischemic Events Deaths due to CV Events 12284%2%0.5% 4983%2%0.4% Seven controlled clinical trials included repaglinide combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see Warnings and Precautions (5.3)]. Combination Therapy with Thiazolidinediones Hypoglycemia During 24-week treatment clinical trials of repaglinide-rosiglitazone or repaglinide-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose 50 mg/dL) occurred in 7% of patients in combination therapy compared to 7% for repaglinide monotherapy, and 2% for thiazolidinedione monotherapy. Peripheral Edema and Heart Failure Peripheral edema was reported in 12 out of 250 (4.8%) repaglinide-thiazolidinedione combination therapy patients and out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for repaglinide monotherapy. There were reports in of 250 patients (0.8%) treated with repaglinide-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported. Weight Gain Mean weight increases associated with combination, repaglinide and pioglitazone therapy were 5.5 kg, 0.3 kg, and kg respectively. Mean weight increases associated with combination, repaglinide and rosiglitazone therapy were 4.5 kg, 1.3 kg, and 3.3 kg respectively. Infrequent Adverse Events (<1% of Patients) Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions.. 6.2 Postmarketing Experience. The following additional adverse reactions have been identified during post approval use of repaglinide. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or causal relationship to drug exposure.AlopeciaHemolytic anemiaPancreatitisStevens-Johnson syndromeSevere hepatic dysfunction including jaundice and hepatitis. Alopecia. Hemolytic anemia. Pancreatitis. Stevens-Johnson syndrome. Severe hepatic dysfunction including jaundice and hepatitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ss) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations. Repaglinide closes ATP-dependent potassium channels in the ss-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ss-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.. 12.2 Pharmacodynamics. four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type diabetes using doses ranging from 0.25 (not an approved dose) to mg taken with each of three meals. Repaglinide therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within to weeks. In double-blind, placebo-controlled, 3-month dose titration study, repaglinide or placebo doses for each patient were increased weekly from 0.25 mg (not an approved dose) through 0.5, 1, and mg, to maximum of mg, until fasting plasma glucose (FPG) level <160 mg/dL was achieved or the maximum dose reached. The dose that achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour post-prandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG) (Table 4). Table 4: Repaglinide vs Placebo Mean Change from Baseline after Months of Treatment :p< 0.05 for between group difference Repaglinide Placebo N66 33 Fasting Plasma Glucose (mg/dL) Baseline Change from baseline (at last visit) Post Prandial Glucose (mg/dL) Baseline Change from baseline (at last visit) 220.2 -31.0 261.7 -47.6 215.3 30.3 245.2 56.5 The dosing of repaglinide relative to meal-related insulin release was studied in three trials including 58 patients. Glycemic control was maintained during period in which the meal and dosing pattern was varied (2, or meals per day; before meals 2, 3, or 4) compared with period of regular meals and doses per day (before meals 3). Blood glucose-lowering effect did not differ when repaglinide was administered at the start of meal, 15 minutes before, or 30 minutes before the meal.. 12.3 Pharmacokinetics. The pharmacokinetic parameters of repaglinide obtained from single-dose, crossover study in healthy subjects and from multiple-dose, parallel, dose-proportionality (0.5, 1, and mg) study in patients with type diabetes are summarized in Tables and 6. These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 to mg dose range, indicating linear relationship between dose and plasma drug levels.Table 5: Pharmacokinetic Parameters for Repaglinide in Healthy Subjects CL total body clearance Vss volume of distribution at steady state AbsBio absolute bioavailability Parameter CL (based on i.v.) 38 +- 16 L/hr Vss (based on i.v.) 31 +- 12 AbsBio 56 +- 9% Table 6: Pharmacokinetic Parameters for Repaglinide in Patients with Type Diabetes dosed preprandially with three mealsPharmacokinetic ParameterDose(mg)AUC0-24 hr (ng/mLhr)Mean (SD)Cmax0-5 hr (ng/mL)Mean (SD)0.5 68.9 (154.4) 9.8 (10.2) 125.8 (129.8) 18.3 (9.1) 152.4 (89.60) 26.0 (13.0) 447.4 (211.3) 65.8 (30.1) Tmax0-5 hr Means (SD)T 1/2 Means (Ind Range)0.5 to 1.0 to 1.4 (0.3 to 0.5) hr 1.0 to 1.4 (0.4 to 8.0) hr Absorption After oral administration, repaglinide is completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (Cmax) occur within hour (Tmax). Repaglinide is eliminated from the blood stream with half-life of approximately hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively. Distribution After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%. Metabolism and Elimination Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours after dosing with 14C-repaglinide as single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces. Repaglinide appears to be substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Variability of Exposure Repaglinide AUC after multiple doses of 0.25 to mg with each meal varies over wide range. The intra-individual and inter- individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mLhr, but AUC exposure up to 5417 ng/mLhr was reached in dose escalation studies without apparent adverse consequences. Specific Populations Geriatric Healthy volunteers were treated with regimen of mg repaglinide taken before each of meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and comparably sized group of patients >=65 years of age [see Use in Specific Populations (8.5)]. Gender comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to mg dose range to be 15% to 70% higher in females with type diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. Race No pharmacokinetic studies to assess the effects of race have been performed, but in U.S. 1-year study in patients with type diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33). Renal Impairment Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type diabetes and normal renal function (CrCl 80 mL/min), mild to moderate renal function impairment (CrCl 40 to 80 mL/min), and severe renal function impairment (CrCl 20 to 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mLhr vs 57.2 ng/mLhr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mLhr and 50.7 ng/mL, respectively), but this study showed only weak correlation between repaglinide levels and creatinine clearance. Hepatic Impairment single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mLhr; AUCCLD patients: 368.9 ng/mLhr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Drug-Drug Interactions Drug interaction studies performed in healthy volunteers show that repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with repaglinide did not significantly alter the absorption and disposition of repaglinide. Additionally, the following drugs were studied in healthy volunteers with co-administration of repaglinide.Table 7: Effect of Other Drugs on AUC and Cmax of Repaglinide Unless indicated all drug interactions were observed with single dose of 0.25 mg repaglinide indicates increase indicates decrease Indicates data are from published literature Study DrugDosingRepaglinideDosing1 RepaglinideAUCCmax Clarithromycin250 mg BIDfor days 40% 67% Clopidogrel300 mg (Day 1)75 mg QD (Day to 3) 0.25 mg(Day and 3) (day 1) 5.1 fold (3.9 to 6.6)(day 3) 3.9 fold (2.9 to 5.3) 2.5 fold (1.8 to 3.5)2.0 fold (1.3 to 3.1) Cyclosporine100 mg(2 doses 12 hours apart) 2.5 fold 1.8 fold Deferasirox30 mg/kg QDfor days 0.5 mg 2.3 fold 62% Fenofibrate200 mg QDfor days 0% 0% Gemfibrozil600 mg BIDfor days 8.1 fold 2.4 fold Itraconazole100 mg BIDfor days 1.4 fold 1.5 fold Gemfibrozil Itraconazole Co-administration Gem: 600 mg BID for days Itra: 100 mg BIDfor days 19 fold 2.8 fold Ketoconazole200 mg QDfor days mg 15% 16% Levonorgestrel/ethinyl Estradiol(0.15 mg/0.03 mg)Combination tablet QD for 21 days mg 0% 20% Nifedipine10 mg TIDfor days mg 0% 0% Rifampin600 mg QDfor to days mg 32 to 80% 17 to 79% Simvastatin20 mg QDfor days mg 0% 26% Trimethoprim160 mg BIDfor days160 mg QDfor day 61% 41%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Monotherapy Trials. double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. HbA1c for the repaglinide-treated groups (1 and mg groups combined) at the end of the study was decreased compared to the placebo-treated group in treatment naive patients and in patients previously treated with oral hypoglycemic agents by 2.1% and 1.7%, respectively. In this fixed-dose trial, patients who were treatment naive to oral hypoglycemic agent therapy and patients with HbA1c below 8% at baseline showed greater blood glucose-lowering.. 14.2 Combination Trials. Repaglinide in Combination With Metformin Repaglinide was studied in combination with metformin in 83 patients not satisfactorily controlled on exercise, diet, and metformin alone. Repaglinide dosage was titrated for to weeks, followed by 3-month maintenance period. Combination therapy with repaglinide and metformin resulted in statistically significant improvement in HbA1c and fasting plasma glucose (FPG) compared to repaglinide or metformin monotherapy (Table 8). In this study where metformin dosage was kept constant, the combination therapy of repaglinide and metformin showed dose-sparing effects with respect to repaglinide. The improvement in HbA1c and FPG of the combination group was achieved at lower daily repaglinide dosage than in the repaglinide monotherapy group (Table 8).Table 8: Repaglinide in Combination with Metformin: Mean Change from Baseline after to Months of Treatment1 1: based on intent-to-treat analysis: p< 0.05, for pairwise comparisons with repaglinide and metformin monotherapy. p< 0.05, for pairwise comparison with metformin. Repaglinide Monotherapy Repaglinide Combination Therapywith Metformin MetforminMonotherapy 28 27 27 Median Final Dose (mg/day) 12 (Repaglinide)1500 (metformin) 1500 HbA1c (%) Baseline 8.6 8.3 8.6 Change from baseline -0.38 -1.41 -0.33 Fasting Plasma Glucose (mg/dL) Baseline 174 184 194 Change from baseline 8.8 -39.2 -4.5 Weight (kg) Baseline 87 93 91 Change from baseline 3.0 2.4 -0.90 Repaglinide in Combination With Pioglitazone combination therapy regimen of repaglinide and pioglitazone (N=123) was compared to repaglinide alone (N=61) and pioglitazone alone (N=62) in 24-week trial that enrolled 246 patients previously treated with sulfonylurea or metformin monotherapy (HbA1c 7.0%). repaglinide dosage was titrated during the first 12 weeks, followed by 12-week maintenance period. Combination therapy resulted in statistically significant improvement in HbA1c and FPG compared to monotherapy (Figure 1). The changes from baseline for completers in FPG (mg/dL) and HbA1c (%), respectively were: -39.8 mg/dL and -0.1% for repaglinide, -35.3 mg/dL and -0.1% for pioglitazone and -92.4 mg/dL and -1.9% for the combination. In this study where pioglitazone dosage was kept constant, the combination therapy group showed dose-sparing effects with respect to repaglinide (see Figure Legend). The improvement in HbA1c and FPG of the combination group was achieved at lower daily repaglinide dosage than in the repaglinide monotherapy group. Figure 1: Repaglinide in Combination with Pioglitazone: HbA1c Values LEGEND: HbA1c values by study week for patients who completed study (combination, = 101; repaglinide, = 35, pioglitazone, = 26). Subjects with FPG above 270 mg/dL were withdrawn from the study.Pioglitazone dose: fixed at 30 mg/day; repaglinide median final dose: mg/day for combination and 10 mg/day for monotherapy. Repaglinide in Combination With Rosiglitazone combination therapy regimen of repaglinide and rosiglitazone was compared to monotherapy with either agent alone in 24-week trial that enrolled 252 patients previously treated with sulfonylurea or metformin (HbA1c 7.0%). Combination therapy resulted in statistically significant improvement in HbA1c and FPG compared to monotherapy (Table below). The glycemic effects of the combination therapy were dose-sparing with respect to both total daily repaglinide dosage and total daily rosiglitazone dosage (see Table Legend). The improvement in HbA1c and FPG of the combination therapy group was achieved with lower daily dose of repaglinide and rosiglitazone, as compared to the respective monotherapy groups.Table 9: Repaglinide in Combination with Rosiglitazone: Mean Change from Baseline in 24-Week Study1 1: based on intent-to-treat analysis: p< 0.001 for comparison to either monotherapy p< 0.05 for comparison to repaglinide RepaglinideMonotherapyRepaglinide CombinationTherapywith RosiglitazoneRosiglitazoneMonotherapyN 63 127 62 Median Final Dose (mg/day) 12 (Repaglinide)4 (Rosiglitazone) HbA1c (%) Baseline 9.3 9.1 9.0 Change from baseline -0.17 -1.43 -0.56 Fasting Plasma Glucose (mg/dL) Baseline 269 257 252 Change from baseline -54 -94 -67 Change in Weight (kg) +1.3 +4.5 +3.3 Figure 1: Repaglinide in Combination with Pioglitazone: HbA1c Values.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended starting dose is 0.5 mg orally before each meal if HbA1c is less than 8%; and or mg orally before each meal if HbA1c is 8% or greater. (2.1) The recommended dose range is 0.5 mg to mg before meals, with maximum daily dose of 16 mg. (2.1) The patients dose should be doubled up to mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. (2.1) Instruct patients to skip the dose of repaglinide tablets if meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced. (2.1; 5.1) Instruct patients to take repaglinide tablets within 30 minutes before meals. (2.1) In patients with severe renal impairment (CrCl 20 to 40 mL/min), recommended starting dose is 0.5 mg orally before each meal. (2.2) Dose modifications are required when used concominantly with some medications. (2.3, 7) The recommended starting dose is 0.5 mg orally before each meal if HbA1c is less than 8%; and or mg orally before each meal if HbA1c is 8% or greater. (2.1) The recommended dose range is 0.5 mg to mg before meals, with maximum daily dose of 16 mg. (2.1) The patients dose should be doubled up to mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. (2.1) Instruct patients to skip the dose of repaglinide tablets if meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced. (2.1; 5.1) Instruct patients to take repaglinide tablets within 30 minutes before meals. (2.1) In patients with severe renal impairment (CrCl 20 to 40 mL/min), recommended starting dose is 0.5 mg orally before each meal. (2.2) Dose modifications are required when used concominantly with some medications. (2.3, 7) 2.1 Recommended Dosage and Administration. The recommended starting dose for patients whose HbA1c is less than 8% is 0.5 mg orally before each meal. For patients whose HbA1c is 8% or greater the starting dose is mg or mg orally before each meal. The recommended dose range is 0.5 mg to mg before meals, with maximum daily dose of 16 mg. The patients dose should be doubled up to mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. Instruct patients to take repaglinide tablets within 30 minutes before meals. Repaglinide tablets may be dosed 2, 3, or times day in response to changes in the patients meal pattern. In patients who skip meals, instruct patients to skip the scheduled dose of repaglinide tablets to reduce the risk of hypoglycemia. In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced [see Warnings and Precautions (5.1)].. 2.2 Patients with Severe Renal Impairment. In patients with severe renal impairment (CrCl 20 to 40 mL/min) initiate repaglinide tablets 0.5 mg orally before each meal. Gradually titrate the dose, if needed to achieve glycemic control.. 2.3 Dose Modifications for Drug Interactions. Dosage adjustments are recommended in patients taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Concomitant use with gemfibrozil is contraindicated [see Contraindications (4)].Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed total daily dose of mg [see Drug Interactions (7), Clinical Pharmacology (12.3)].Do not exceed total daily dose of mg of repaglinide tablets in patients receiving cyclosporine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Clinically Important Drug Interactions with Repaglinide Table includes list of drugs with clinically important drug interactions when administered concomitantly with repaglinide and instructions for preventing or managing them.Table 3: Clinically Important Drug Interactions with Repaglinide GemfibrozilClinical Impact:Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)] Intervention:Do not administer repaglinide to patients receiving gemfibrozil [see Contraindications (4)]. ClopidogrelClinical Impact:Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold [see Clinical Pharmacology (12.3)] Intervention:Avoid concomitant use of repaglinide with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed total daily dose of mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use. CyclosporineClinical Impact:Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)] Intervention:Daily maximum repaglinide dose should be limited to mg, and increased frequency of glucose monitoring may be required when repaglinide is co-administered with cyclosporine. CYP2C8 and CYP3A4 InhibitorsIntervention:Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co--administered. Examples:Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel. CYP2C8 and CYP3A4 InducersIntervention:Repaglinide dose increases and increased frequency of glucose monitoring may be required when co--administered. Examples:Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine Drugs That May Increase the Risk of HypoglycemiaIntervention:Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co--administered. Examples:Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics Drugs That May Decrease the Blood Glucose Lowering Effect of RepaglinideIntervention:Repaglinide dose increases and increased frequency of glucose monitoring may be required when co--administered. Examples:Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Drugs That May Blunt Signs and Symptoms of HypoglycemiaIntervention:Increased frequency of glucose monitoring may be required when repaglinide is co-administered with these drugs. Examples:beta-blockers, clonidine, guanethidine, and reserpine Clopidogrel: Avoid concomitant use; if used concomitantly initiate at 0.5 mg before each meal and limit total daily dose to mg (7) Cyclosporine: Limit daily dose of repaglinide to mg and increase frequency of glucose monitoring when co-administered (7)CYP2C8 and CYP3A4 Inhibitors and Drugs That May Increase the Risk of Hypoglycemia: Co-administration may require repaglinide dose reductions and increased frequency of glucose monitoring (7)CYP2C8 and CYP3A4 Inducers and Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide: Co-administration may require repaglinide dose increases and increased frequency of glucose monitoring (7)Drugs That May Blunt Signs and Symptoms of Hypoglycemia: Increased frequency of glucose monitoring may be required when co-administered (7). Clopidogrel: Avoid concomitant use; if used concomitantly initiate at 0.5 mg before each meal and limit total daily dose to mg (7) Cyclosporine: Limit daily dose of repaglinide to mg and increase frequency of glucose monitoring when co-administered (7). CYP2C8 and CYP3A4 Inhibitors and Drugs That May Increase the Risk of Hypoglycemia: Co-administration may require repaglinide dose reductions and increased frequency of glucose monitoring (7). CYP2C8 and CYP3A4 Inducers and Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide: Co-administration may require repaglinide dose increases and increased frequency of glucose monitoring (7). Drugs That May Blunt Signs and Symptoms of Hypoglycemia: Increased frequency of glucose monitoring may be required when co-administered (7).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type diabetes using doses ranging from 0.25 (not an approved dose) to mg taken with each of three meals. Repaglinide therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within to weeks. In double-blind, placebo-controlled, 3-month dose titration study, repaglinide or placebo doses for each patient were increased weekly from 0.25 mg (not an approved dose) through 0.5, 1, and mg, to maximum of mg, until fasting plasma glucose (FPG) level <160 mg/dL was achieved or the maximum dose reached. The dose that achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour post-prandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG) (Table 4). Table 4: Repaglinide vs Placebo Mean Change from Baseline after Months of Treatment :p< 0.05 for between group difference Repaglinide Placebo N66 33 Fasting Plasma Glucose (mg/dL) Baseline Change from baseline (at last visit) Post Prandial Glucose (mg/dL) Baseline Change from baseline (at last visit) 220.2 -31.0 261.7 -47.6 215.3 30.3 245.2 56.5 The dosing of repaglinide relative to meal-related insulin release was studied in three trials including 58 patients. Glycemic control was maintained during period in which the meal and dosing pattern was varied (2, or meals per day; before meals 2, 3, or 4) compared with period of regular meals and doses per day (before meals 3). Blood glucose-lowering effect did not differ when repaglinide was administered at the start of meal, 15 minutes before, or 30 minutes before the meal.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters of repaglinide obtained from single-dose, crossover study in healthy subjects and from multiple-dose, parallel, dose-proportionality (0.5, 1, and mg) study in patients with type diabetes are summarized in Tables and 6. These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 to mg dose range, indicating linear relationship between dose and plasma drug levels.Table 5: Pharmacokinetic Parameters for Repaglinide in Healthy Subjects CL total body clearance Vss volume of distribution at steady state AbsBio absolute bioavailability Parameter CL (based on i.v.) 38 +- 16 L/hr Vss (based on i.v.) 31 +- 12 AbsBio 56 +- 9% Table 6: Pharmacokinetic Parameters for Repaglinide in Patients with Type Diabetes dosed preprandially with three mealsPharmacokinetic ParameterDose(mg)AUC0-24 hr (ng/mLhr)Mean (SD)Cmax0-5 hr (ng/mL)Mean (SD)0.5 68.9 (154.4) 9.8 (10.2) 125.8 (129.8) 18.3 (9.1) 152.4 (89.60) 26.0 (13.0) 447.4 (211.3) 65.8 (30.1) Tmax0-5 hr Means (SD)T 1/2 Means (Ind Range)0.5 to 1.0 to 1.4 (0.3 to 0.5) hr 1.0 to 1.4 (0.4 to 8.0) hr Absorption After oral administration, repaglinide is completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (Cmax) occur within hour (Tmax). Repaglinide is eliminated from the blood stream with half-life of approximately hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively. Distribution After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%. Metabolism and Elimination Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours after dosing with 14C-repaglinide as single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces. Repaglinide appears to be substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Variability of Exposure Repaglinide AUC after multiple doses of 0.25 to mg with each meal varies over wide range. The intra-individual and inter- individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mLhr, but AUC exposure up to 5417 ng/mLhr was reached in dose escalation studies without apparent adverse consequences. Specific Populations Geriatric Healthy volunteers were treated with regimen of mg repaglinide taken before each of meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and comparably sized group of patients >=65 years of age [see Use in Specific Populations (8.5)]. Gender comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to mg dose range to be 15% to 70% higher in females with type diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. Race No pharmacokinetic studies to assess the effects of race have been performed, but in U.S. 1-year study in patients with type diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33). Renal Impairment Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type diabetes and normal renal function (CrCl 80 mL/min), mild to moderate renal function impairment (CrCl 40 to 80 mL/min), and severe renal function impairment (CrCl 20 to 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mLhr vs 57.2 ng/mLhr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mLhr and 50.7 ng/mL, respectively), but this study showed only weak correlation between repaglinide levels and creatinine clearance. Hepatic Impairment single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mLhr; AUCCLD patients: 368.9 ng/mLhr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Drug-Drug Interactions Drug interaction studies performed in healthy volunteers show that repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with repaglinide did not significantly alter the absorption and disposition of repaglinide. Additionally, the following drugs were studied in healthy volunteers with co-administration of repaglinide.Table 7: Effect of Other Drugs on AUC and Cmax of Repaglinide Unless indicated all drug interactions were observed with single dose of 0.25 mg repaglinide indicates increase indicates decrease Indicates data are from published literature Study DrugDosingRepaglinideDosing1 RepaglinideAUCCmax Clarithromycin250 mg BIDfor days 40% 67% Clopidogrel300 mg (Day 1)75 mg QD (Day to 3) 0.25 mg(Day and 3) (day 1) 5.1 fold (3.9 to 6.6)(day 3) 3.9 fold (2.9 to 5.3) 2.5 fold (1.8 to 3.5)2.0 fold (1.3 to 3.1) Cyclosporine100 mg(2 doses 12 hours apart) 2.5 fold 1.8 fold Deferasirox30 mg/kg QDfor days 0.5 mg 2.3 fold 62% Fenofibrate200 mg QDfor days 0% 0% Gemfibrozil600 mg BIDfor days 8.1 fold 2.4 fold Itraconazole100 mg BIDfor days 1.4 fold 1.5 fold Gemfibrozil Itraconazole Co-administration Gem: 600 mg BID for days Itra: 100 mg BIDfor days 19 fold 2.8 fold Ketoconazole200 mg QDfor days mg 15% 16% Levonorgestrel/ethinyl Estradiol(0.15 mg/0.03 mg)Combination tablet QD for 21 days mg 0% 20% Nifedipine10 mg TIDfor days mg 0% 0% Rifampin600 mg QDfor to days mg 32 to 80% 17 to 79% Simvastatin20 mg QDfor days mg 0% 26% Trimethoprim160 mg BIDfor days160 mg QDfor day 61% 41%.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Limited available data from case reports and case series with repaglinide use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Teratogenicity was not observed in rats and rabbits administered repaglinide during organogenesis at approximately 60 and times the maximum daily clinical dose, based on body surface area. No adverse developmental effects were observed in offspring of rats administered repaglinide during late gestation and lactation at approximately times the maximum daily clinical dose (see Data). The estimated background risk of major birth defects is 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 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly 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. Data Animal Data Repaglinide was not teratogenic in rats or rabbits at doses 60 times (rats) and approximately times (rabbit) clinical exposure (on mg/m2 basis) when administered during the period of organogenesis. Offspring of rat dams exposed to repaglinide at >=22 times clinical exposure on mg/m2 basis during days 17 to 22 of gestation and during lactation were less viable and developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to times clinical exposure (on mg/m2 basis).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Repaglinide is not recommended when breastfeeding (8.2). Lactation: Repaglinide is not recommended when breastfeeding (8.2). 8.1 Pregnancy. Risk Summary Limited available data from case reports and case series with repaglinide use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Teratogenicity was not observed in rats and rabbits administered repaglinide during organogenesis at approximately 60 and times the maximum daily clinical dose, based on body surface area. No adverse developmental effects were observed in offspring of rats administered repaglinide during late gestation and lactation at approximately times the maximum daily clinical dose (see Data). The estimated background risk of major birth defects is 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 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly 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. Data Animal Data Repaglinide was not teratogenic in rats or rabbits at doses 60 times (rats) and approximately times (rabbit) clinical exposure (on mg/m2 basis) when administered during the period of organogenesis. Offspring of rat dams exposed to repaglinide at >=22 times clinical exposure on mg/m2 basis during days 17 to 22 of gestation and during lactation were less viable and developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to times clinical exposure (on mg/m2 basis).. 8.2 Lactation. Risk Summary There are no data on the presence of repaglinide 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 of the potential for hypoglycemia in breastfed infants, repaglinide is not recommended for use when breastfeeding. Data In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes [see Use in Specific Populations (8.1)] could be induced in control pups nursed by treated dams, although this occurred to lesser degree than those pups treated in utero . 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.. 8.5 Geriatric Use. In clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age and no patients were greater than 75 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65. There was no increase in frequency or severity of hypoglycemia in older subjects, but greater sensitivity of some older individuals to repaglinide therapy cannot be ruled out.. 8.6 Renal Impairment. Pharmacokinetic studies of repaglinide were conducted in patients with mild to moderate renal function impairment (CrCl 40 to 80 mL/min), and severe renal function impairment (CrCl 20 to 40 mL/min). Initial dose adjustment is not required in patients with mild to moderate renal dysfunction. However, patients with severe renal function impairment should initiate repaglinide therapy with the 0.5 mg dose and be carefully titrated [see Dosage and Administration (2.2)]. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.. 8.7 Hepatic Impairment. single-dose study was conducted 12 patients with chronic liver disease. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations. Therefore, repaglinide should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments may be needed to allow full assessment of response.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypoglycemia: Repaglinide may cause hypoglycemia. Skip the scheduled dose of repaglinide if meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of repaglinide if hypoglycemia occurs. (5.1)Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: Repaglinide is not indicated for use in combination with NPH-insulin. (5.2)Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide. (5.3). Hypoglycemia: Repaglinide may cause hypoglycemia. Skip the scheduled dose of repaglinide if meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of repaglinide if hypoglycemia occurs. (5.1). Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: Repaglinide is not indicated for use in combination with NPH-insulin. (5.2). Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide. (5.3). 5.1 Hypoglycemia. All glinides, including repaglinide, 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 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 co-administered 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)]. Patients should administer repaglinide before meals and be instructed to skip the dose of repaglinide if meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide should be reduced [see Dosage and Administration (2.1)]. 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 Serious Cardiovascular Adverse Reactions with Concomitant Use with NPH-insulin. Across seven controlled trials, there were six serious adverse events of myocardial ischemia in patients treated with repaglinide plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [See Adverse Reactions (6.1)]. Repaglinide is not indicated for use in combination with NPH-insulin.. 5.3 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide.