Repaglinide

1 INDICATIONS AND USAGE Repaglinide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: Repaglinide tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Repaglinide tablets are a glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Limitation of Use : Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)

2 DOSAGE AND ADMINISTRATION The recommended starting dose is 0.5 mg orally before each meal if HbA1c is less than 8%; and 1 or 2 mg orally before each meal if HbA1c is 8% or greater. (2.1) The recommended dose range is 0.5 mg to 4 mg before meals, with a maximum daily dose of 16 mg. (2.1) The patient’s dose should be doubled up to 4 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 a 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 HbA 1c is less than 8% is 0.5 mg orally before each meal. For patients whose HbA 1c is 8% or greater the starting dose is 1 mg or 2 mg orally before each meal. The recommended dose range is 0.5 mg to 4 mg before meals, with a maximum daily dose of 16 mg. The patient’s dose should be doubled up to 4 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 4 times a day in response to changes in the patient’s 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 a total daily dose of 4 mg [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] . Do not exceed a total daily dose of 6 mg of repaglinide tablets in patients receiving cyclosporine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] .

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 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 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 1 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 Placebo N=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 16 11 6 6 5 5 5 3 3 3 3 3 2 2 2 2 2 8 10 2 3 5 2 4 3 2 3 3 1 1 2 1 0 0 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 a 24-week placebo controlled trial, patients who were naïve to oral hypoglycemic agent therapy and patients with a HbA 1c below 8% at baseline had a 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 1228 4% 2% 0.5% 498 3% 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 3 out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for repaglinide monotherapy. There were reports in 2 of 250 patients (0.8%) treated with repaglinide-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a 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 2 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 a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure. Alopecia Hemolytic anemia Pancreatitis Stevens-Johnson syndrome Severe hepatic dysfunction including jaundice and hepatitis

12.3 Pharmacokinetics The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in Tables 5 and 6. These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 to 4 mg dose range, indicating a 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 L AbsBio 56 ± 9% Table 6: Pharmacokinetic Parameters for Repaglinide in Patients with Type 2 Diabetes* *dosed preprandially with three meals Pharmacokinetic Parameter Dose (mg) AUC 0-24 hr (ng/mL*hr) Mean (SD) C max0-5 hr (ng/mL) Mean (SD) 0.5 68.9 (154.4) 9.8 (10.2) 1 125.8 (129.8) 18.3 (9.1) 2 152.4 (89.60) 26.0 (13.0) 4 447.4 (211.3) 65.8 (30.1) T max0-5 hr Means (SD) T½ Means (Ind Range) 0.5 to 4 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 (C max ) occur within 1 hour (T max ). Repaglinide is eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean T max was not changed, but the mean C max 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 (V ss ) 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 14 C-repaglinide as a 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 a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Variability of Exposure Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a 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/mL*hr, but AUC exposure up to 5417 ng/mL*hr was reached in dose escalation studies without apparent adverse consequences. Specific Populations Geriatric Healthy volunteers were treated with a regimen of 2 mg repaglinide taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patients ≥65 years of age [see Use in Specific Populations (8.5) ] . Gender A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females with type 2 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 a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a 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 2 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 C max of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and C max values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Hepatic Impairment A 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 (AUC healthy : 91.6 ng/mL*hr; AUC CLD patients : 368.9 ng/mL*hr; C max , healthy : 46.7 ng/mL; C max , 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 C max of Repaglinide 1 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 Drug Dosing Repaglinide Dosing 1 Repaglinide AUC C max Clarithromycin* 250 mg BID for 4 days 40% ↑ 67% ↑ Clopidogrel* 300 mg (Day 1) 75 mg QD (Day 2 to 3) 0.25 mg (Day 1 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) Cyclosporine 100 mg (2 doses 12 hours apart) 2.5 fold ↑ 1.8 fold ↑ Deferasirox* 30 mg/kg QD for 4 days 0.5 mg 2.3 fold ↑ 62% ↑ Fenofibrate 200 mg QD for 5 days 0% 0% Gemfibrozil* 600 mg BID for 3 days 8.1 fold ↑ 2.4 fold ↑ Itraconazole* 100 mg BID for 3 days 1.4 fold ↑ 1.5 fold ↑ Gemfibrozil + Itraconazole* Co-administration Gem: 600 mg BID for 3 days Itra: 100 mg BID for 3 days 19 fold ↑ 2.8 fold ↑ Ketoconazole 200 mg QD for 4 days 2 mg 15% ↑ 16% ↑ Levonorgestrel/ethinyl Estradiol (0.15 mg/0.03 mg) Combination tablet QD for 21 days 2 mg 0% 20% ↑ Nifedipine* 10 mg TID for 4 days 2 mg 0% 0% Rifampin* 600 mg QD for 6 to 7 days 4 mg 32 to 80% ↓ 17 to 79% ↓ Simvastatin 20 mg QD for 4 days 2 mg 0% 26% ↑ Trimethoprim* 160 mg BID for 2 days 160 mg QD for 1 day 61% ↑ 41% ↑