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 & 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 – 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 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 – 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 (7.1), 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 (7.1), Clinical Pharmacology ( 12.3 )]. Do not exceed a total daily dose of 6 mg of repaglinide tablets in patients receiving cyclosporine [see Drug Interactions (7.1), Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Repaglinide tablets USP, 0.5 mg are white to off white, round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘10’ on other side. Repaglinide tablets USP, 1 mg are yellow colored, round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘11’ on other side. Repaglinide tablets USP, 2 mg are peach colored, mottled round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘12’ on other side. Tablets: 0.5 mg, 1 mg, 2 mg (3)

4 CONTRAINDICATIONS Repaglinide tablets are contraindicated in patients with: • Concomitant use of gemfibrozil [see Drug Interactions ( 7.1 )] • Known hypersensitivity to repaglinide or any inactive ingredients • Concomitant use with gemfibrozil ( 4 ) • Known hypersensitivity to repaglinide or any inactive ingredients ( 4 )

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 tablets were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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 tablets have 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 tablets in one of five 1-year, active-controlled trials. Over one year, 13% of repaglinide tablets 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 tablets patients compared to placebo in trials 12 to 24 weeks duration. Table 1: Adverse Reactions (%) occurring ≥ 2% in Repaglinide Tablets Treated Patients from Pool of 12 to 24 Week Placebo Controlled Trials* Repaglinide Tablets N=352 Placebo N=108 Upper Respiratory Infection 16 8 Headache 11 10 Sinusitis 6 2 Arthralgia 6 3 Nausea 5 5 Diarrhea 5 2 Back Pain 5 4 Rhinitis 3 3 Constipation 3 2 Vomiting 3 3 Paresthesia 3 3 Chest pain 3 1 Bronchitis 2 1 Dyspepsia 2 2 Urinary tract infection 2 1 Tooth disorder 2 0 Allergy 2 0 *See trial descriptions in Clinical Trials ( 14 ) Hypoglycemia In clinical trials with repaglinide tablets, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of repaglinide tablets treated patients and 7% of placebo treated patients [see Warnings and Precautions ( 5.1 ]). Hypoglycemia was reported in 16% of 1228 repaglinide tablets patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1-year controlled trials. Of repaglinide tablets-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 tablets. The average weight gain in patients treated with repaglinide tablets 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 tablets (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 Tablets to Sulfonylureas (% of total patients with events) Repaglinide Tablets SU* Total Exposed 1228 498 Serious CV Events 4% 3% Cardiac Ischemic Events 2% 2% Deaths due to CV Events 0.5% 0.4% * : glyburide and glipizide Seven controlled clinical trials included repaglinide tablets combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide tablets plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide tablets plus NPH-in …

7 DRUG INTERACTIONS Clinically Important Drug Interactions with Repaglinide Tablets Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with repaglinide tablets and instructions for preventing or managing them. Table 3: Clinically Important Drug Interactions with Repaglinide Tablets Gemfibrozil Clinical Impact: Gemfibrozil significantly increased repaglinide tablets exposures by 8.1 fold [see Clinical Pharmacology (12.3) ]. Intervention: Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4) ] . Clopidogrel Clinical Impact: Clopidogrel increased repaglinide tablets exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3) ] Intervention: 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 Dosage and Administration (2.3) ] . Increased frequency of glucose monitoring may be required during concomitant use. Cyclosporine Clinical Impact: Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3) ] Intervention: Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with cyclosporine. CYP2C8 and CYP3A4 Inhibitors Intervention: Repaglinide tablets 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 Inducers Intervention: Repaglinide tablets 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 Hypoglycemia Intervention: Repaglinide tablets 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 Repaglinide Tablets Intervention: Repaglinide tablets 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 Hypoglycemia Intervention: Increased frequency of glucose monitoring may be required when repaglinide tablets 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 4 mg ( 7 ) Cyclosporine : Limit daily dose of repaglinide to 6 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 tablets dose reductions and increased frequency of glucose monitoring ( 7 ) CYP2C8 and CYP3A4 Inducers and Drugs That May D …

8 USE IN SPECIFIC POPULATIONS • Lactation: repaglinide tablets is not recommended when breastfeeding ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data from case reports and case series with repaglinide tablets use in pregnant women have not identified a 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 1 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 4 times the maximum daily clinical dose ( see Data ). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20-25% in women with a HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 1 times (rabbit) clinical exposure (on a mg/m 2 basis) when administered during the period of organogenesis. Offspring of rat dams exposed to repaglinide at ≥22 times clinical exposure on a mg/m 2 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 4 times clinical exposure (on a mg/m 2 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 a 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 tablets 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 a 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 tablets 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 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Initial dose adjustment is not required in p …

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.

11 DESCRIPTION Repaglinide tablets are an oral blood glucose-lowering drug of the glinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown below: Repaglinide is a white to off-white powder with molecular formula C 27 H 36 N 2 O 4 and a molecular weight of 452.6. Repaglinide Tablets, USP contain 0.5 mg, 1 mg, or 2 mg of repaglinide. In addition, each tablet contains the following inactive ingredients: corn starch, dicalcium phosphate anhydrous, glycerin, magnesium stearate, meglumine, microcrystalline cellulose, poloxamer 188, povidone, polacrilin potassium and talc. The 1 mg and 2 mg tablets contain ferric oxide yellow as coloring agent. "Image Description"

10 OVERDOSAGE Severe hypoglycemic reactions with coma, seizure, or other neurological impairment may occur and constitute medical emergencies requiring immediate hospitalization. Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring may continue until the physician is assured that the patient is out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. There is no evidence that repaglinide tablets are dialyzable using hemodialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING Repaglinide Tablets USP, 0.5 mg are white to off white, round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘10’ on other side. Bottles of 100 NDC 65862-670-01 Bottles of 500 NDC 65862-670-05 Bottles of 1,000 NDC 65862-670-99 Repaglinide Tablets USP, 1 mg are yellow colored, round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘11’ on other side. Bottles of 100 NDC 65862-671-01 Bottles of 500 NDC 65862-671-05 Bottles of 1,000 NDC 65862-671-99 Repaglinide Tablets USP, 2 mg are peach colored, mottled round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘12’ on other side. Bottles of 100 NDC 65862-672-01 Bottles of 500 NDC 65862-672-05 Bottles of 1,000 NDC 65862-672-99 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep bottles tightly closed. Dispense in tight containers with safety closures.