NIASPAN^®
niacin extended-release tablets

Rx ONLY

NIASPAN^® (niacin extended-release tablets), contains niacin, which at therapeutic doses is an antihyperlipidemic agent. Niacin (nicotinic acid, or 3-pyridinecarboxylic acid) is a white, crystalline powder, very soluble in water, with the following structural formula:

NIASPAN^® is an unscored, medium-orange, film-coated tablet for oral administration and is available in three tablet strengths containing 500, 750, and 1000mg niacin. NIASPAN^® tablets also contain the inactive ingredients hypromellose, povidone, stearic acid, and polyethylene glycol, and the following coloring agents: FD&C yellow #6/sunset yellow FCF Aluminum Lake, synthetic red and yellow iron oxides, and titanium dioxide.

Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. Niacin (but not nicotinamide) in gram doses reduces total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in total HDL-C is associated with an increase in apolipoprotein A-I (Apo A-I) and a shift in the distribution of HDL subfractions. These shifts include an increase in the HDL₂:HDL₃ ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL particle containing only Apo A-I). Niacin treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant form of LDL independently associated with coronary risk.¹ In addition, preliminary reports suggest that niacin causes favorable LDL particle size transformations, although the clinical relevance of this effect requires further investigation. The effect of niacin-induced changes in lipids/lipoproteins on cardiovascular morbidity or mortality in individuals without pre-existing coronary disease has not been established.

A variety of clinical studies have demonstrated that elevated levels of TC, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of TC and LDL-C, and inversely with the level of HDL-C.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG have not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

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.

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 hypercholesterolemia. 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 (see also Table 10 and the NCEP treatment guidelines⁸). Prior to initiating therapy with niacin, 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 obtained to measure TC, HDL-C, and TG.

• NIASPAN^® is indicated as an adjunct to diet for reduction of elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb; Table 11), when the response to an appropriate diet has been inadequate.
• NIASPAN^® in combination with lovastatin is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb; Table 11) in:
  • Patients treated with lovastatin who require further TG-lowering or HDL-raising who may benefit from having niacin added to their regimen
  • Patients treated with niacin who require further LDL-lowering who may benefit from having lovastatin added to their regimen

  Combination therapy is not indicated as initial therapy. (See DOSAGE AND ADMINISTRATION.)

• In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.
• In patients with a history of coronary artery disease (CAD) and hypercholesterolemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.
• NIASPAN^® in combination with a bile acid binding resin is indicated as an adjunct to diet for reduction of elevated TC and LDL-C levels in adult patients with primary hypercholesterolemia (Type IIa; Table 11), when the response to an appropriate diet, or diet plus monotherapy, has been inadequate.
• Niacin is also indicated as adjunctive therapy for treatment of adult patients with very high serum triglyceride levels (Types IV and V hyperlipidemia; Table 11) 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 TG levels over 2000 mg/dL and have elevations of VLDL-C as well as fasting chylomicrons (Type V hyperlipidemia; Table 11). Patients who consistently have total serum or plasma TG below 1000 mg/dL are unlikely to develop pancreatitis. Therapy with niacin may be considered for those patients with TG elevations between 1000 and 2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. Some Type IV patients with TG under 1000 mg/dL may, through dietary or alcohol indiscretion, convert to a Type V pattern with massive TG elevations accompanying fasting chylomicronemia, but the influence of niacin therapy on 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 TG, but who have normal levels of VLDL-C. Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia.⁹

After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (TC minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

NIASPAN^® is contraindicated in patients with a known hypersensitivity to niacin or any component of this medication, significant or unexplained hepatic dysfunction, active peptic ulcer disease, or arterial bleeding.

NIASPAN^® preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to NIASPAN^®, therapy with NIASPAN ^®  should be initiated with low doses (i.e., 500mg qhs) and the NIASPAN^® dose should then be titrated to the desired therapeutic response (see DOSAGE AND ADMINISTRATION).

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.

NIASPAN ^® 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 NIASPAN^®.

Niacin preparations, like some other lipid-lowering therapies, have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily NIASPAN^® doses ranging from 500 to 3000mg, 245 patients received NIASPAN^® 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 NIASPAN^®. In these studies, fewer than 1% (2/245) of NIASPAN^® patients discontinued due to transaminase elevations greater than 2 times the ULN.

In three safety and efficacy studies with a combination tablet of NIASPAN^® and lovastatin involving titration to final daily doses (expressed as mg of niacin/ mg of lovastatin) 500mg/10mg to 2500mg/40mg, ten of 1028 patients (1.0%) experienced reversible elevations in AST/ALT to more than 3 times the upper limit of normal (ULN). Three of ten elevations occurred at doses outside the recommended dosing limit of 2000mg/40mg; no patient receiving 1000mg/20mg had 3-fold elevations in AST/ALT.

In the placebo-controlled clinical trials and the long-term extension study, elevations in transaminases did not appear to be related to treatment duration; elevations in AST levels did appear to be dose related. Transaminase elevations were reversible upon discontinuation of NIASPAN^®.

Liver tests should be performed on all patients during therapy with NIASPAN^®. 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.

Rare cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (≥1 g/day) of niacin and HMG-CoA reductase inhibitors. In clinical studies with a combination tablet of NIASPAN^® and lovastatin, no cases of rhabdomyolysis and one suspected case of myopathy have been reported in 1079 patients who were treated with doses up to 2000mg of NIASPAN^® and 40mg of lovastatin daily for periods up to 2 years. Physicians contemplating combined therapy with HMG-CoA reductase inhibitors and NIASPAN ^® should carefully weigh the potential benefits and risks and should carefully 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 of either drug. 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.

Before instituting therapy with NIASPAN^® an attempt should be made to control hyperlipidemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE).

Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during NIASPAN^® therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycemic therapy may be necessary.

Caution should also be used when NIASPAN^® 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.

Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout.

NIASPAN^® has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000mg). In addition, NIASPAN^® 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 NIASPAN^® is administered concomitantly with anticoagulants; prothrombin time and platelet counts should be monitored closely in such patients.

In placebo-controlled trials, NIASPAN^® has been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000mg). Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.

Niacin is rapidly metabolized by the liver, and excreted through the kidneys. NIASPAN^® is contraindicated in patients with significant or unexplained hepatic dysfunction (see CONTRAINDICATIONS and WARNINGS) and should be used with caution in patients with renal dysfunction.

Patients should be advised:

• to take NIASPAN^® at bedtime, after a low-fat snack. Administration on an empty stomach is not recommended;
• to carefully follow the prescribed dosing regimen, including the recommended titration schedule, in order to minimize side effects (see DOSAGE AND ADMINISTRATION);
• that flushing is a common side effect of niacin therapy that usually subsides after several weeks of consistent niacin use. Flushing may vary in severity, may last for several hours after dosing, and will, by taking NIASPAN^® at bedtime, most likely occur during sleep; however, if awakened by flushing at night, to get up slowly, especially if feeling dizzy, feeling faint, or taking blood pressure medications;
• that taking aspirin (approximately 30 minutes before taking NIASPAN^®) or a nonsteroidal anti-inflammatory drug (e.g., ibuprofen) may minimize flushing;
• to avoid ingestion of alcohol or hot drinks around the time of NIASPAN^® administration, to minimize flushing;
• that if NIASPAN^® therapy is discontinued for an extended length of time, their physician should be contacted prior to re-starting therapy; re-titration is recommended (see DOSAGE AND ADMINISTRATION; Table 13);
• to notify their physician if they are taking vitamins or other nutritional supplements containing niacin or related compounds such as nicotinamide (see Drug Interactions);
• to notify their physician if symptoms of dizziness occur;
• if diabetic, to notify their physician of changes in blood glucose;
• that NIASPAN^® tablets should not be broken, crushed or chewed, but should be swallowed whole.

HMG-CoA Reductase Inhibitors: See WARNINGS, Skeletal Muscle.

Antihypertensive Therapy: Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.

Aspirin: Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear.

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. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of NIASPAN^®.

Other: Concomitant alcohol or hot drinks may increase the side effects of flushing and pruritus and should be avoided around the time of NIASPAN^® ingestion. Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as nicotinamide may potentiate the adverse effects of NIASPAN^®.

Niacin may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines. Niacin may also give false-positive reactions with cupric sulfate solution (Benedict's reagent) in urine glucose tests.

Niacin administered to mice for a lifetime as a 1% solution in drinking water was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m² basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed. No studies have been conducted with NIASPAN^® regarding carcinogenesis, mutagenesis, or impairment of fertility.

Niacin has been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with NIASPAN^® in nursing mothers.

Safety and effectiveness of niacin therapy in pediatric patients (≤16 years) have not been established. No studies in patients under 21 years of age have been conducted with NIASPAN^®.

Of 979 patients in clinical studies of NIASPAN^®, 21% of the patients were age 65 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

NIASPAN^® is generally well tolerated; adverse reactions have been mild and transient. In the placebo-controlled clinical trials, flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events (reported by as many as 88% of patients) for NIASPAN^®. Spontaneous reports suggest that flushing may also be accompanied by symptoms of dizziness, tachycardia, palpitations, shortness of breath, sweating, chills, and/or edema, which in rare cases may lead to syncope. In pivotal studies, fewer than 6% (14/245) of NIASPAN^® patients discontinued due to flushing. In comparisons of immediate-release (IR) niacin and NIASPAN^®, although the proportion of patients who flushed was similar, fewer flushing episodes were reported by patients who received NIASPAN^®. Following 4 weeks of maintenance therapy at daily doses of 1500mg, the incidence of flushing over the 4-week period averaged 8.56 events per patient for IR niacin versus 1.88 following NIASPAN^®.

Other adverse events occurring in 5% or greater of patients treated with NIASPAN^®, at least remotely related to NIASPAN^®, are shown in Table 12 below.

In general, the incidence of adverse events was higher in women compared to men.

The following adverse events have also been reported with NIASPAN^® or other niacin products, either during clinical trials or in routine patient management.

Body as a Whole:  generalized edema; face edema; peripheral edema; asthenia; chills

Cardiovascular:  atrial fibrillation and other cardiac arrhythmias; tachycardia; palpitations; orthostasis; syncope; hypotension

Eye:  toxic amblyopia; cystoid macular edema

Gastrointestinal:  activation of peptic ulcers and peptic ulceration; jaundice; eructation; flatulence

Metabolic:  decreased glucose tolerance; gout

Musculoskeletal:  myalgia; myasthenia

Nervous:  dizziness; insomnia; leg cramps; nervousness; paresthesia

Respiratory:   dyspnea

Skin:   hyper-pigmentation; acanthosis nigricans; maculopapular rash; urticaria; dry skin; sweating

Other:   migraine

Niacin is a non-narcotic drug. It has no known addiction potential in humans.

Supportive measures should be undertaken in the event of an overdose.

NIASPAN^® should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with NIASPAN^® must be initiated at 500mg 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 13 below.

The daily dosage of NIASPAN^® should not be increased by more than 500mg in any 4-week period. The recommended maintenance dose is 1000mg (two 500mg tablets or one 1000mg tablet) to 2000mg (two 1000mg tablets or four 500mg tablets) once daily at bedtime. Doses greater than 2000mg daily are not recommended. Women may respond at lower NIASPAN^® doses than men (see CLINICAL PHARMACOLOGY, Gender Effect).

Single-dose bioavailability studies have demonstrated that two of the 500mg and one of the 1000mg tablet strengths are interchangeable but three of the 500mg and two of the 750mg tablet strengths are not interchangeable.

If lipid response to NIASPAN^® alone is insufficient (see NCEP treatment guidelines; Table 10), or if higher doses of NIASPAN^® are not well tolerated, some patients may benefit from combination therapy with a bile acid binding resin or an HMG-CoA reductase inhibitor (see WARNINGS, PRECAUTIONS, Drug Interactions,Concomitant Therapy below, and CLINICAL PHARMACOLOGY, NIASPAN Clinical Studies).

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by pretreatment with aspirin (taken 30 minutes prior to NIASPAN^® dose) or non-steroidal anti-inflammatory drugs. 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.

Equivalent doses of NIASPAN^® should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin (see WARNINGS). Patients previously receiving other niacin products should be started with the recommended NIASPAN^® titration schedule (see Table 13), and the dose should subsequently be individualized based on patient response.

If NIASPAN^® therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 13).

NIASPAN^® tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

Use of NIASPAN^® in patients with renal or hepatic insufficiency has not been studied. NIASPAN^® is contraindicated in patients with significant or unexplained hepatic dysfunction. NIASPAN^® should be used with caution in patients with renal insufficiency (see WARNINGS,PRECAUTIONS).

NIASPAN^® tablets are supplied as unscored, medium-orange, film-coated, capsule-shaped tablets containing 500, 750 or 1000mg of niacin in an extended-release formulation. Tablets are debossed KOS on one side and the tablet strength (500, 750 or 1000) on the other side. Tablets are supplied in bottles of 100 as shown below.

500mg tablets:    bottles of 100 - NDC# 60598-140-01

750mg tablets:    bottles of 100 - NDC# 60598-141-01

1000mg tablets:  bottles of 100 - NDC# 60598-142-01

Store at room temperature (20 to 25°C or 68 to 77°F).

• Bostom AG et al. JAMA 1996; 276:544-548.
• The Coronary Drug Project Research Group, JAMA 1975; 231:360-381.
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• Brown G et al. N Engl J Med 1990; 323:1289-1298.
• Pasternak RC et al. Annals Int Med 1996; 125:529-540.
• Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), JAMA 2001; 285:2486-2497.
• Nikkila EA, In: The Metabolic Basis of Inherited Disease, 5th ed., Chap. 30, 622-642. 1983.

Manufactured for:
Kos Pharmaceuticals, Inc.
Cranbury, NJ 08512

^©2007 Kos Pharmaceuticals, Inc., Cranbury, NJ 08512, USA Printed in U.S.A

U.S. Patent Nos. 6,080,428; 6,129,930; 6,406,715 B1; 6,676,967; 6,746,691; 6,818,229; 7,011,848; 6,469,035 and other patents pending.

03–5572

Rev. April 2007