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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypoglycemia : Repaglinide may cause hypoglycemia. Skip the scheduled dose of repaglinide if a 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 a 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.
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