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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypoglycemia: PRANDIN may cause hypoglycemia. Skip the scheduled dose of PRANDIN if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of PRANDIN if hypoglycemia occurs. (5.1) Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: PRANDIN 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 PRANDIN. (5.3) 5.1 Hypoglycemia All glinides, including PRANDIN, 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 PRANDIN before meals and be instructed to skip the dose of PRANDIN if a meal is skipped. In patients who experience hypoglycemia, the dose of PRANDIN 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 PRANDIN plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see Adverse Reactions (6.1) ] . PRANDIN 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 PRANDIN.
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 PRANDIN were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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. PRANDIN 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 PRANDIN in one of five 1-year, active-controlled trials. Over one year, 13% of PRANDIN 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 PRANDIN patients compared to placebo in trials 12 to 24 weeks duration. Table 1: Adverse Reactions (%) occurring ≥ 2% in PRANDIN Treated Patients from Pool of 12 to 24 Week Placebo Controlled Trials* PRANDIN Placebo N=352 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 PRANDIN, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of PRANDIN treated patients and 7% of placebo treated patients [see Warnings and Precautions (5.1] ) . Hypoglycemia was reported in 16% of 1228 PRANDIN patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1 year controlled trials. Of PRANDIN-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 PRANDIN. The average weight gain in patients treated with PRANDIN 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 PRANDIN (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 PRANDIN to Sulfonylureas (% of total patients with events) PRANDIN 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 PRANDIN combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or PRANDIN plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with PRANDIN 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 PRANDIN-rosiglitazone or PRANDIN-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 PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy. Peripheral Edema and Heart Failure Peripheral edema was reported in 12 out of 250 (4.8%) PRANDIN-thiazolidinedione combination therapy patients and 3 out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for PRANDIN monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN-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, PRANDIN and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively. Mean weight increases associated with combination, PRANDIN 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 PRANDIN. 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