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.

1. 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.
2. 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) when treatment with both NIASPAN® and lovastatin is appropriate and as an adjunct to diet.
3. In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.
4. 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.
5. 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.
6. 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

Table 10. NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories

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.

Table 11. Classification of Hyperlipoproteinemias

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.

Table 13. Recommended Dosing

Maintenance Dose

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.

Concomitant Therapy

Concomitant Therapy with Lovastatin

Patients already receiving a stable dose of lovastatin who require further TG-lowering or HDL-raising (e.g., to achieve NCEP non-HDL-C goals), may receive concomitant dosage titration with NIASPAN® per NIASPAN® recommended initial titration schedule (see Table 13, DOSAGE AND ADMINISTRATION section). For patients already receiving a stable dose of NIASPAN® who require further LDL-lowering (e.g., to achieve NCEP LDL-C goals; Table 10), the usual recommended starting dose of lovastatin is 20mg once a day. Dose adjustments should be made at intervals of 4 weeks or more. Combination therapy with NIASPAN® and lovastatin should not exceed doses of 2000mg and 40mg daily, respectively.

Dosage in Patients with Renal or Hepatic Insufficiency

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.

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

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

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

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

REFERENCES

8.  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.

9.  Nikkila EA, In: The Metabolic Basis of Inherited Disease, 5th ed., Chap. 30, 622- 642. 1983.

Manufactured for: Kos Pharmaceuticals, Inc., Cranbury, NJ 08512. FDA rev date: 12/18/2007

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