niacin 250 MG Oral Capsule

INDICATIONS AND USAGE I. Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Nicotinic acid, alone or in combination with a bile-acid binding resin, is indicated as an adjunct to diet for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia (Types IIa and IIb) † , when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate (see also the NCEP treatment guidelines 6 ). Prior to initiating therapy with nicotinic acid, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total cholesterol, HDL cholesterol, and triglycerides. II. Nicotinic acid is also indicated as adjunctive therapy for the treatment of adult patients with very high serum triglyceride levels (Types IV and V hyperlipidemia)† who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them. Such patients typically have serum triglyceride levels over 2,000 mg/dL and have elevations of VLDL cholesterol as well as fasting chylomicrons (Type V hyperlipidemia) † . Subjects who consistently have total serum or plasma triglycerides below 1,000 mg/dL are unlikely to develop pancreatitis. Therapy with nicotinic acid may be considered for those subjects with triglyceride elevations between 1,000 and 2,000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. Some Type IV patients with triglycerides under 1,000 mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern with massive triglyceride elevations accompanying fasting chylomicronemia, but the influence of nicotinic acid therapy on the risk of pancreatitis in such situations has not been adequately studied. Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL. Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia 7 . † Classification of Hyperlipoproteinemias Lipoproteins Lipid Elevations Type Elevated Major Minor C = cholesterol, TG = triglycerides LDL = low-density lipoprotein VLDL = very low-density lipoprotein IDL = intermediate-density lipoprotein I (rare) Chylomicrons TG ↑→ C IIa LDL C ..... IIb LDL, VLDL C TG III (rare) IDL C/TG ..... IV VLDL TG ↑→ C V (rare) Chylomicrons, VLD TG ↑→ C

DOSAGE AND ADMINISTRATION Niacin extended-release tablets should be taken at bedtime with a low-fat snack. ( 2.1 ) Dose range: 500 mg to 2,000 mg once daily. ( 2.1 ) Therapy with niacin extended-release tablets must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy and should not be increased by more than 500 mg in any 4-week period. ( 2.1 ) Maintenance dose: 1,000 to 2,000 mg once daily. ( 2.2 ) Doses greater than 2,000 mg daily are not recommended. ( 2.2 ) 2.1 Initial Dosing Niacin extended-release tablets should be taken at bedtime, after a low-fat snack and doses should be individualized according to patient response. Therapy with niacin extended-release tablets must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. The recommended dose escalation is shown in Table 1 below. Table 1. Recommended Dosing Week(s) Daily dose Niacin Extended-Release Tablets Dosage INITIAL TITRATION 1 to 4 500 mg 1 Niacin extended-release tablet 500 mg at bedtime SCHEDULE 5 to 8 1,000 mg 1 Niacin extended-release tablet 1,000 mg or 2 Niacin extended-release tablets 500 mg at bedtime * 1,500 mg 2 Niacin extended-release tablets 750 mg or 3 Niacin extended-release tablets 500 mg at bedtime * 2,000 mg 2 Niacin extended-release tablets 1,000 mg or 4 Niacin extended-release tablets 500 mg at bedtime * After Week 8, titrate to patient response and tolerance. If response to 1,000 mg daily is inadequate, increase dose to 1,500 mg daily; may subsequently increase dose to 2,000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2,000 mg daily are not recommended. Women may respond at lower doses than men. 2.2 Maintenance Dose The daily dosage of niacin extended-release tablets should not be increased by more than 500 mg in any 4–week period. The recommended maintenance dose is 1,000 mg (two 500 mg tablets or one 1,000 mg tablets) to 2,000 mg (two 1,000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2,000 mg daily are not recommended. Women may respond at lower niacin extended-release tablets doses than men [see Clinical Studies (14.2) ] . Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1,000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable. Flushing of the skin [see Adverse Reactions (6.1) ] 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 tablets dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of niacin extended-release tablets ingestion. Equivalent doses of niacin extended-release tablets should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions (5) ] . Patients previously receiving other niacin products should be started with the recommended niacin extended-release tablets titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response. If niacin extended-release tablets therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1). Niacin extended-release tablets should be taken whole and should not be broken, crushed or chewed before swallowing. 2.3 Dosage in Patients with Renal or Hepatic Impairment Use of niacin extended-release tablets in patients with renal or hepatic impairment has not been studied. Niacin extended-release tablets are contraindicated in patients with significant or unexplained hepatic dysfunction. Niacin extended-release tablets should be used with caution in patients with renal impairment [see Warnings and Precautions (5) ] . 2.1 Initial Dosing Niacin extended-release tablets should be taken at bedtime, after a low-fat snack and doses should be individualized according to patient response. Therapy with niacin extended-release tablets must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. The recommended dose escalation is shown in Table 1 below. Table 1. Recommended Dosing Week(s) Daily dose Niacin Extended-Release Tablets Dosage INITIAL TITRATION 1 to 4 500 mg 1 Niacin extended-release tablet 500 mg at bedtime SCHEDULE 5 to 8 1,000 mg 1 Niacin extended-release tablet 1,000 mg or 2 Niacin extended-release tablets 500 mg at bedtime * 1,500 mg 2 Niacin extended-release tablets 750 mg or 3 Niacin extended-release tablets 500 mg at bedtime * 2,000 mg 2 Niacin extended-release tablets 1,000 mg or 4 Niacin extended-release tablets 500 mg at bedtime * After Week 8, titrate to patient response and tolerance. If response to 1,000 mg daily is inadequate, increase dose to 1,500 mg daily; may subsequently increase dose to 2,000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2,000 mg daily are not recommended. Women may respond at lower doses than men. 2.2 Maintenance Dose The daily dosage of niacin extended-release tablets should not be increased by more than 500 mg in any 4–week period. The recommended maintenance dose is 1,000 mg (two 500 mg tablets or one 1,000 mg tablets) to 2,000 mg (two 1,000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2,000 mg daily are not recommended. Women may respond at lower niacin extended-release tablets doses than men [see Clinical Studies (14.2) ] . Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1,000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable. Flushing of the skin [see Adverse Reactions (6.1) ] 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 tablets dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of niacin extended-release tablets ingestion. Equivalent doses of niacin extended-release tablets should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions (5) ] . Patients previously receiving other niacin products should be started with the recommended niacin extended-release tablets titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response. If niacin extended-release tablets therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1). Niacin extended-release tablets should be taken whole and should not be broken, crushed or chewed before swallowing. 2.3 Dosage in Patients with Renal or Hepatic Impairment Use of niacin extended-release tablets in patients with renal or hepatic impairment has not been studied. Niacin extended-release tablets are contraindicated in patients with significant or unexplained hepatic dysfunction. Niacin extended-release tablets shou

WARNINGS AND PRECAUTIONS Niacin extended-release tablet preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to niacin extended-release tablets, therapy with niacin extended-release tablets should be initiated with low doses (i.e., 500 mg at bedtime) and the niacin extended-release tablets dose should then be titrated to the desired therapeutic response [see Dosage and Administration (2.1) ] . Caution should also be used when niacin extended-release tablets are 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 extended-release tablets are 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 extended-release tablets 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 tablets. 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 tablets 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 tablets have 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 tablets 1,500 to 2,000 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 -12.0% for the simvastatin plus niacin extended-release tablets group and -5.5% for the simvastatin plus placebo group. HDL-C increased by 25.0% to 42 mg/dL in the simvastatin plus niacin extended-release tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets. Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily niacin extended-release tablets doses ranging from 500 to 3,000 mg, 245 patients received niacin extended-release tablets 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 tablets. In these studies, fewer than 1% (2/245) of niacin extended-release tablets 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 tablets. 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 tablets, 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 tablets have been associated

CONTRAINDICATIONS Niacin extended-release tablets are contraindicated in the following conditions: • Active liver disease or unexplained persistent elevations in hepatic transaminases [see Warnings and Precautions ( 5.3 )] • Patients with active peptic ulcer disease • Patients with arterial bleeding • Hypersensitivity to niacin or any component of this medication [see Adverse Reactions ( 6.1 )] Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. ( 4 , 5.3 ) Active peptic ulcer disease. ( 4 ) Arterial bleeding. ( 4 ) Known hypersensitivity to product components. ( 4 , 6.1 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism by which niacin alters lipid profiles has not been well defined. It may involve several actions including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma. Niacin decreases the rate of hepatic synthesis of VLDL and LDL, and does not appear to affect fecal excretion of fats, sterols, or bile acids. 12.3 Pharmacokinetics Absorption Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Time to reach the maximum niacin plasma concentrations was about 5 hours following niacin extended-release tablets. To reduce the risk of gastrointestinal (GI) upset, administration of niacin extended-release tablets with a low-fat meal or snack is recommended. Single-dose bioavailability studies have demonstrated that the 500 mg and 1000 mg tablet strengths are dosage form equivalent but the 500 mg and 750 mg tablet strengths are not dosage form equivalent. Metabolism The pharmacokinetic profile of niacin is complicated due to extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidemia, these metabolic pathways are saturable, which explains the nonlinear relationship between niacin dose and plasma concentrations following multiple-dose niacin extended-release tablets administration. Nicotinamide does not have hypolipidemic activity; the activity of the other metabolites is unknown. Elimination Following single and multiple doses, approximately 60 to 76% of the niacin dose administered as niacin extended-release tablets was recovered in urine as niacin and metabolites; up to 12% was recovered as unchanged niacin after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered. Pediatric Use No pharmacokinetic studies have been performed in this population (≤16 years) [see Use in Specific Populations ( 8.4 )] . Geriatric Use No pharmacokinetic studies have been performed in this population (>65 years) [see Use in Specific Populations ( 8.5 )] . Renal Impairment No pharmacokinetic studies have been performed in this population. Niacin extended-release tablets should be used with caution in patients with renal disease [see Warnings and Precautions ( 5 )] . Hepatic Impairment No pharmacokinetic studies have been performed in this population. Active liver disease, unexplained transaminase elevations and significant or unexplained hepatic dysfunction are contraindications to the use of niacin extended-release tablets [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] . Gender Steady-state plasma concentrations of niacin and metabolites after administration of niacin extended-release tablets are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. This gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders [see Gender ( 8.8 )] . Drug interactions Fluvastatin Niacin did not affect fluvastatin pharmacokinetics [see Drug Interactions ( 7.1 )] . Lovastatin When niacin extended-release tablets 2000 mg and lovastatin 40 mg were co-administered, niacin extended-release tablets increased lovastatin C max and AUC by 2% and 14%, respectively, and decreased lovastatin acid C max and AUC by 22% and 2%, respectively. Lovastatin reduced niacin extended-release tablets bioavailability by 2-3% [see Drug Interactions ( 7.1 )] . Simvastatin When niacin extended-release tablets 2000 mg and simvastatin 40 mg were co-administered, niacin extended-release tablets increased simvastatin C max and AUC by 1% and 9%, respectively, and simvastatin acid C max and AUC by 2% and 18%, respectively. Simvastatin reduced niacin extended-release tablets bioavailability by 2% [see Drug Interactions ( 7.1 )] . Bile Acid Sequestrants An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine [see Drug Interactions ( 7.2 )] .