Niacin

5 WARNINGS AND PRECAUTIONS Niacin extended-release preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to niacin extended-release, therapy with niacin extended-release should be initiated with low doses (i.e., 500 mg at bedtime) and the niacin extended-release dose should then be titrated to the desired therapeutic response [see Dosage and Administration (2) ] . Caution should also be used when niacin is used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents. Niacin is rapidly metabolized by the liver, and excreted through the kidneys. Niacin is contraindicated in patients with significant or unexplained hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.3) ] and should be used with caution in patients with renal impairment. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during niacin therapy. Severe hepatic toxicity has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. ( 5.3 ) Myopathy has been reported in patients taking niacin extended-release. The risk for myopathy and rhabdomyolysis are increased among elderly patients; patients with diabetes, renal failure, or uncontrolled hypothyroidism; and patients being treated with a statin. ( 5.2 ) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. ( 5.3 ) Use with caution in patients with unstable angina or in the acute phase of an MI. ( 5 ) Niacin extended-release can increase serum glucose levels. Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use or dose adjustment. ( 5.4 ) 5.1 Mortality and Coronary Heart Disease Morbidity Niacin extended-release has not been shown to reduce cardiovascular morbidity or mortality among patients already treated with a statin. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was a randomized placebo-controlled trial of 3414 patients with stable, previously diagnosed cardiovascular disease. Mean baseline lipid levels were LDL-C 74 mg/dL, HDL-C 35 mg/dL, non-HDL-C 111 mg/dL and median triglyceride level of 163 to 177 mg/dL. Ninety-four percent of patients were on background statin therapy prior to entering the trial. All participants received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40 to 80 mg/dL, and were randomized to receive niacin extended-release 1500 to 2000 mg/day (n=1718) or matching placebo (IR Niacin, 100 to 150 mg, n=1696). On-treatment lipid changes at two years for LDL-C were -12% for the simvastatin plus niacin extended-release group and -5.5% for the simvastatin plus placebo group. HDL-C increased by 25% to 42 mg/dL in the simvastatin plus niacin extended-release group and by 9.8% to 38 mg/dL in the simvastatin plus placebo group (P<0.001). Triglyceride levels decreased by 28.6% in the simvastatin plus niacin extended-release group and by 8.1% in the simvastatin plus placebo group. The primary outcome was an ITT composite of the first study occurrence of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization procedures. The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. The primary outcome occurred in 282 patients in the simvastatin plus niacin extended-release group (16.4%) and in 274 patients in the simvastatin plus placebo group (16.2%) (HR 1.02 [95% CI, 0.87 to 1.21], P=0.79. In an ITT analysis, there were 42 cases of first occurrence of ischemic stroke reported, 27 (1.6%) in the simvastatin plus niacin extended-release group and 15 (0.9%) in the simvastatin plus placebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95 to 3.36], p=0.071). The on-treatment ischemic stroke events were 19 for the simvastatin plus niacin extended-release group and 15 for the simvastatin plus placebo group [see Adverse Reactions (6.1) ] . 5.2 Skeletal Muscle Cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (≥1 g/day) of niacin and statins. Elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism are particularly at risk. Monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration. Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. 5.3 Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Niacin extended-release should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of niacin extended-release. Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily niacin extended-release doses ranging from 500 to 3000 mg, 245 patients received niacin extended-release for a mean duration of 17 weeks. No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than 3 times the upper limit of normal (ULN) during treatment with niacin extended-release. In these studies, fewer than 1% (2/245) of niacin extended-release patients discontinued due to transaminase elevations greater than 2 times the ULN. Liver-related tests should be performed on all patients during therapy with niacin extended-release. Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6-month intervals). Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued. 5.4 Laboratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects. Diabetic patients may experience a dose-related increase in glucose intolerance. Diabetic or potentially diabetic patients should be observed closely during treatment with niacin extended-release, particularly during the first few months of use or dose adjustment; adjustment of diet and/or hypoglycemic therapy may be necessary. Reduction in platelet count: Niacin extended-release has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000 mg). Caution should be observed when niacin extended-release is administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients. Increase in Prothrombin Time (PT): Niacin extended-release has been associated with small but statistically significant increases in prothrombin time (mean of approximately +4%); accordingly, patients undergoing surgery should be carefully evaluated. Caution should be observed when niacin extended-release is administered concomitantly with anticoagulants; prothrombin time should be monitored closely in such patients. Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout. Decrease in Phosphorus: In placebo-controlled trials, niacin extended-release has been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.

6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Most common adverse reactions (incidence >5% and greater than placebo) are flushing, diarrhea, nausea, vomiting, increased cough, and pruritus. ( 6.1 ) Flushing of the skin may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to niacin extended-release dose). (2.2) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or www.avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience In the placebo-controlled clinical trials database of 402 patients (age range 21 to 75 years, 33% women, 89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatment duration of 16 weeks, 16% of patients on niacin extended-release and 4% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with niacin extended-release that led to treatment discontinuation and occurred at a rate greater than placebo were flushing (6% vs. 0%), rash (2% vs. 0%), diarrhea (2% vs. 0%), nausea (1% vs. 0%), and vomiting (1% vs. 0%). The most commonly reported adverse reactions (incidence >5% and greater than placebo) in the niacin extended-release controlled clinical trial database of 402 patients were flushing, diarrhea, nausea, vomiting, increased cough and pruritus. In the placebo-controlled clinical trials, flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions (reported by as many as 88% of patients) for niacin extended-release. Spontaneous reports suggest that flushing may also be accompanied by symptoms of dizziness, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema, which in rare cases may lead to syncope. In pivotal studies, 6% (14/245) of niacin extended-release patients discontinued due to flushing. In comparisons of immediate-release (IR) niacin and niacin extended-release tablets, although the proportion of patients who flushed was similar, fewer flushing episodes were reported by patients who received niacin extended-release. Following 4 weeks of maintenance therapy at daily doses of 1500 mg, the incidence of flushing over the 4-week period averaged 8.6 events per patient for IR niacin versus 1.9 following niacin extended-release. Other adverse reactions occurring in ≥5% of patients treated with niacin extended-release and at an incidence greater than placebo are shown in Table 2 below. Table 2. Treatment-Emergent Adverse Reactions by Dose Level in ≥ 5% of Patients and at an Incidence Greater than Placebo; Regardless of Causality Assessment in Placebo-Controlled Clinical Trials Placebo-Controlled Studies Niacin Extended-release Treatment @ Recommended Daily Maintenance Doses † Placebo (n = 157) 500 mg ‡ (n = 87) 1000 mg (n = 110) 1500 mg (n = 136) 2000 mg (n = 95) % % % % % Gastrointestinal Disorders Diarrhea 13 7 10 10 14 Nausea 7 5 6 4 11 Vomiting 4 0 2 4 9 Respiratory Cough, Increased 6 3 2 < 2 8 Skin and Subcutaneous Tissue Disorders Pruritus 2 8 0 3 0 Rash 0 5 5 5 0 Vascular Disorders Flushing & 19 68 69 63 55 Note: Percentages are calculated from the total number of patients in each column. † Adverse reactions are reported at the initial dose where they occur. @ Pooled results from placebo-controlled studies; for niacin extended-release, n = 245 and median treatment duration = 16 weeks. Number of niacin patients (n) are not additive across doses. ‡ The 500 mg/day dose is outside the recommended daily maintenance dosing range [see Dosage and Administration (2) ] . & 10 patients discontinued before receiving 500 mg, therefore they were not included. In general, the incidence of adverse events was higher in women compared to men. Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) In AIM-HIGH involving 3414 patients (mean age of 64 years, 15% women, 92% Caucasians, 34% with diabetes mellitus) with stable, previously diagnosed cardiovascular disease, all patients received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40 to 80 mg/dL, and were randomized to receive niacin extended-release 1500 to 2000 mg/day (n=1718) or matching placebo (IR Niacin, 100 to 150 mg, n=1696). The incidence of the adverse reactions of “blood glucose increased” (6.4% vs. 4.5%) and “diabetes mellitus” (3.6% vs. 2.2%) was significantly higher in the simvastatin plus niacin extended-release group as compared to the simvastatin plus placebo group. There were 5 cases of rhabdomyolysis reported, 4 (0.2%) in the simvastatin plus niacin extended-release group and one (<0.1%) in the simvastatin plus placebo group [see Warnings and Precautions (5.1) ] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of niacin extended-release. Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: tachycardia, palpitations, atrial fibrillation, other cardiac arrhythmias Eye disorders: blurred vision, macular edema Gastrointestinal disorders: peptic ulcers, eructation, flatulence Hepatobiliary disorders: hepatitis, jaundice Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus and vesiculobullous rash) Metabolism and nutrition disorders: decreased glucose tolerance, gout Musculoskeletal and connective tissue disorders: myalgia, myopathy Nervous system disorders: dizziness, insomnia, asthenia, nervousness, paresthesia, migraine Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: maculopapular rash, dry skin, sweating, burning sensation/skin burning sensation, skin discoloration, acanthosis nigricans Vascular disorders: syncope, hypotension, postural hypotension Clinical Laboratory Abnormalities Chemistry: Elevations in serum transaminases, LDH, fasting glucose, uric acid, total bilirubin, amylase and creatine kinase, and reduction in phosphorus. Hematology: Slight reductions in platelet counts and prolongation in prothrombin time. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table border="1" cellpadding="0" cellspacing="0" width="696px"><col width="4in"/><col width="4in"/><col width="4in"/><col width="4in"/><col width="4in"/><col width="4in"/><tbody><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> </td><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Placebo-Controlled Studies Niacin Extended-release Treatment ^@</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> </td><td styleCode=" Botrule Toprule Lrule Rrule "> </td><td colspan="3" styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Recommended Daily Maintenance Doses ^&#x2020;</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "> </td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Placebo</paragraph><paragraph>(n = 157)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>500 mg ^&#x2021;</paragraph><paragraph>(n = 87)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>1000 mg</paragraph><paragraph>(n = 110)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>1500 mg (n = 136)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>2000 mg</paragraph><paragraph>(n = 95)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "> </td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>%</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>%</paragraph></td></tr><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Gastrointestinal Disorders </content></paragraph></td><td colspan="4" styleCode=" Botrule Toprule Lrule Rrule "> </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Diarrhea </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>13</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>10</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>14</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Nausea </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>7</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>11</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Vomiting </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>4</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>9</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Respiratory </content></paragraph></td><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Cough, Increased </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>6</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>&lt; 2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>8</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders </content></paragraph></td><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Pruritus </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>2</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>8</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>3</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Rash </paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>5</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph><content styleCode="bold">Vascular Disorders </content></paragraph></td><td colspan="5" styleCode=" Botrule Toprule Lrule Rrule "> </td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Flushing ^&amp;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>19</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>68</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>69</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>63</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule "><paragraph>55</paragraph></td></tr><tr><td colspan="6" styleCode=" Botrule Toprule Lrule Rrule "><paragraph>Note: Percentages are calculated from the total number of patients in each column. </paragraph><paragraph>^&#x2020; Adverse reactions are reported at the initial dose where they occur. </paragraph><paragraph>^@ Pooled results from placebo-controlled studies; for niacin extended-release, n = 245 and median treatment duration = 16 weeks. Number of niacin patients (n) are not additive across doses. </paragraph><paragraph>^&#x2021; The 500 mg/day dose is outside the recommended daily maintenance dosing <content styleCode="italics">range [see <linkHtml href="#ID_be8b4ecc-d0e2-4007-abdd-7528c3ae5310">Dosage and Administration (2)</linkHtml>] </content>. </paragraph><paragraph>^&amp; 10 patients discontinued before receiving 500 mg, therefore they were not included. </paragraph></td></tr></tbody></table>