1 INDICATIONS & 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 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 )

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 NorthStar Rx LLC at 1-800-206-7821 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-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 tablets-rosiglitazone or repaglinide tablets-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 tablets monotherapy, and 2% for thiazolidinedione monotherapy.

Peripheral Edema and Heart Failure Peripheral edema was reported in 12 out of 250 (4.8%) repaglinide tablets-thiazolidinedione combination therapy patients and 3 out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for repaglinide tablets monotherapy.

There were reports in 2 of 250 patients (0.8%) treated with repaglinide tablets-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 tablets and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively.

Mean weight increases associated with combination, repaglinide tablets 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 tablets.

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