Repaglinide 1 mg Tablet, 90-count — NDC 62135-947-90 (Billing 62135-0947-90)

5 WARNINGS AND PRECAUTIONS Hypoglycemia : Repaglinide tablets may cause hypoglycemia. Skip the scheduled dose of repaglinide tablets if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of repaglinide tablets if hypoglycemia occurs.

( 5.1 ) Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin : Repaglinide tablets 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 tablets. ( 5.3 )

5.1Hypoglycemia All glinides, including repaglinide tablets, 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 tablets before meals and be instructed 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 [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.

5.2Serious 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 tablets plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [See Adverse Reactions (6.1) ]. Repaglinide tablets are not indicated for use in combination with NPH-insulin.

5.3Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide tablets.

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 Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 tablets have been administered to 2,931 individuals during clinical trials. Approximately 1,500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1,000 for at least 6 months, and 800 for at least 1 year.

The majority of these individuals (1,228) 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 Sinusits 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 1,228 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 (51/1,228 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 1,228 498 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-insulin from two st… [Excerpted — this section continues on DailyMed.]

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… [Excerpted — this section continues on DailyMed.]