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).

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.

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.

Skeletal Muscle

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.

General

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

Pregnancy Category C.

Animal reproduction studies have not been conducted with niacin or with NIASPAN®. It is also not known whether niacin at doses typically used for lipid disorders can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. If a woman receiving niacin for primary hypercholesterolemia (Types IIa or IIb) becomes pregnant, the drug should be discontinued. If a woman being treated with niacin for hypertriglyceridemia (Types IV or V) conceives, the benefits and risks of continued therapy should be assessed on an individual basis.

Nursing Mothers

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.

Pediatric Use

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®.

Geriatric Use

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.

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