1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hyperlipidemia.

Niacin therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

Niacin extended-release tablets are indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.

In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.

In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.

Niacin extended-release tablets in combination with a bile acid binding resin is indicated to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.

Niacin is also indicated as adjunctive therapy for treatment of adult patients with severe hypertriglyceridemia who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.

Limitations of Use Addition of niacin extended-release tablets did not reduce cardiovascular morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial (AIM-HIGH) [see Warnings and Precautions (5.1) ] .

Niacin extended-release tablets contain extended-release niacin (nicotinic acid) and are indicated: To reduce elevated TC, LDL-C, Apo B and TG, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.

( 1 ) To reduce the risk of recurrent nonfatal myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia.

( 1 ) In combination with a bile acid binding resin: Slows progression or promotes regression of atherosclerotic disease in patients with a history of coronary artery disease (CAD) and hyperlipidemia.

( 1 ) As an adjunct to diet to reduce elevated TC and LDL-C in adult patients with primary hyperlipidemia.

( 1 ) To reduce TG in adult patients with severe hypertriglyceridemia.

( 1 ) Limitations of use: Addition of niacin extended-release tablets did not reduce cardiovascular morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial.

( 5.1 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Mortality and Coronary Heart Disease Morbidity [see Warnings and Precautions (5.1) ] Skeletal Muscle (rhabdomyolysis) [see Warnings and Precautions (5.2) ] Liver Dysfunction [see Warnings and Precautions (5.3) ] Laboratory Abnormalities [see Warnings and Precautions (5.4) ] 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience 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.

In the placebo-controlled clinical trials database of 402 patients (age range 21 years 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 1,500 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) 1,000 mg (n = 110) 1,500 mg (n = 136) 2,000 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 (2.2)] .

& 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 3,414 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 mg/dL to 80 mg/dL, and were randomized to receive niacin extended-release 1,500 mg/day to 2,000 mg/day (n=1,718) or matching placebo (IR Niacin, 100 mg to 150 mg, n=1,696).

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.

6.2 Post-marketing 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.