Overview

In controlled clinical studies, 40/214 (19%) of patients randomized to ADVICOR discontinued therapy prior to study completion. Of the 214 patients enrolled 18 (8%) discontinued due to flushing. In the same controlled studies, 9/94 (10%) of patients randomized to lovastatin and 19/92 (21%) of patients randomized to NIASPAN also discontinued treatment prior to study completion secondary to adverse events. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events, and occurred in 53% to 83% of patients treated with ADVICOR. Spontaneous reports with NIASPAN and clinical studies with ADVICOR suggest that flushing may also be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, chills, and/or edema.

Adverse Reactions Information

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice.

The adverse reaction information from clinical studies does, however provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described in this section reflect the exposure to ADVICOR in two double-blind, controlled clinical studies of 400 patients. The population was 28 to 86 years-of-age, 54% male, 85% Caucasian, 9% Black, and 7% Other, and had mixed dyslipidemia (Frederickson Types IIa and IIb).

In addition to flushing, other adverse events occurring in 5% or greater of patients treated with ADVICOR are shown in Table 8 below.

Table 8. Treatment-Emergent Adverse Events in ≥ 5% of Patients (Events Irrespective of Causality; Data from Controlled, Double-Blind Studies)

The following adverse events have also been reported with niacin, lovastatin, and/or other HMG-CoA reductase inhibitors, but not necessarily with ADVICOR, either during clinical studies or in routine patient management.

Clinical Laboratory Abnormalities

Chemistry

Elevations in serum transaminases (see WARNINGS - Liver Dysfunction), CPK and fasting glucose, and reductions in phosphorus. Niacin extended-release tablets have been associated with slight elevations in LDH, uric acid, total bilirubin, and amylase. Lovastatin and/or HMG-CoA reductase inhibitors have been associated with elevations in alkaline phosphatase, γ-glutamyl transpeptidase and bilirubin, and thyroid function abnormalities.

Hematology

Niacin extended-release tablets have been associated with slight reductions in platelet counts and prolongation in PT (see WARNINGS).

Drug Abuse And Dependence

Neither niacin nor lovastatin is a narcotic drug. ADVICOR has no known addiction potential in humans.

Niacin

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 niacin. 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 ADVICOR.

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

Lovastatin

Serious skeletal muscle disorders, e.g., rhabdomyolysis, have been reported during concomitant therapy of lovastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors. (See WARNINGS, Skeletal Muscle).

Coumarin Anticoagulants - In a small clinical study in which lovastatin was administered to warfarin-treated patients, no effect on PT was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two seconds increase in PT in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased PT have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, PT be determined before starting ADVICOR and frequently enough during early therapy to insure that no significant alteration of PT occurs. Once a stable PT has been documented, PT can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of ADVICOR is changed, the same procedure should be repeated.

Antipyrine - Lovastatin had no effect on the pharmacokinetics of antipyrine or its metabolites. However, since lovastatin is metabolized by the cytochrome P450 isoform 3A4 enzyme system, this does not preclude an interaction with other drugs metabolized by the same isoform.

Propranolol - In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.

Digoxin - In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

Oral Hypoglycemic Agents - In pharmacokinetic studies of lovastatin in hypercholesterolemic, non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.

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