Advicor^®
(niacin extended-release/lovastatin tablets)

Annotated Final Package Insert
Advicor CBE-0 Labeling Supplement:
Additional Safety Information

Rx ONLY

ADVICOR contains niacin extended-release and lovastatin in combination. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and niacin are both lipid-altering agents.

Niacin is nicotinic acid, or 3-pyridinecarboxylic acid. Niacin is a white, nonhygroscopic crystalline powder that is very soluble in water, boiling ethanol and propylene glycol. It is insoluble in ethyl ether. The empirical formula of niacin is C₆H₅NO₂ and its molecular weight is 123.11. Niacin has the following structural formula:

Lovastatin is [1S -[1(alpha)(R *), 3(alpha), 7(beta), 8(beta)(2S *, 4S *), 8a(beta)]]-1,2,3, 7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1-naphthalenyl 2-methylbutanoate. Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. The empirical formula of lovastatin is C₂₄H₃₆O₅ and its molecular weight is 404.55. Lovastatin has the following structural formula:

ADVICOR tablets contain the labeled amount of niacin and lovastatin and have the following inactive ingredients: hypromellose, povidone, stearic acid, polyethylene glycol, titanium dioxide, polysorbate 80.

The individual tablet strengths (expressed in terms of mg niacin/mg lovastatin) contain the following coloring agents:

ADVICOR 500 mg/20 mg - synthetic red and yellow iron oxides.
ADVICOR 750 mg/20 mg – FD&C yellow #6 Aluminum Lake.
ADVICOR 1000 mg/20 mg - synthetic red, yellow, and black iron oxides.
ADVICOR 1000 mg/40 mg – red iron oxide.

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B-100 (Apo B) promote human atherosclerosis. Similarly, decreased levels of high-density lipoprotein cholesterol (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.

Cholesterol-enriched triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma triglycerides (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.

As an adjunct to diet, the efficacy of niacin and lovastatin in improving lipid profiles (either individually, or in combination with each other, or niacin in combination with other statins) for the treatment of dyslipidemia has been well documented. The effect of combined therapy with niacin and lovastatin on cardiovascular morbidity and mortality has not been determined.

In a multi-center, randomized, double-blind, parallel, 28-week, active-comparator study in patients with Type IIa and IIb hyperlipidemia, ADVICOR was compared to each of its components (NIASPAN and lovastatin). Using a forced dose-escalation study design, patients received each dose for at least 4 weeks. Patients randomized to treatment with ADVICOR initially received 500 mg/20 mg. The dose was increased at 4-week intervals to a maximum of 1000 mg/20 mg in one-half of the patients and 2000 mg/40 mg in the other half. The NIASPAN monotherapy group underwent a similar titration from 500 mg to 2000 mg. The patients randomized to lovastatin monotherapy received 20 mg for 12 weeks titrated to 40 mg for up to 16 weeks. Up to a third of the patients randomized to ADVICOR or NIASPAN discontinued prior to Week 28. In this study, ADVICOR decreased LDL-C, TG and Lp(a), and increased HDL-C in a dose-dependent fashion (Tables 2, 3, 4 and 5 below). Results from this study for LDL-C mean percent change from baseline (the primary efficacy variable) showed that:

• LDL-lowering with ADVICOR was significantly greater than that achieved with lovastatin 40 mg only after 28 weeks of titration to a dose of 2000 mg/40 mg (p<.0001)
• ADVICOR at doses of 1000 mg/20 mg or higher achieved greater LDL-lowering than NIASPAN (p<.0001) The LDL-C results are summarized in Table 2.

ADVICOR achieved significantly greater HDL-raising compared to lovastatin and NIASPAN monotherapy at all doses (Table 3).

In addition, ADVICOR achieved significantly greater TG-lowering at doses of 1000 mg/20 mg or greater compared to lovastatin and NIASPAN monotherapy (Table 4).

The Lp(a) lowering effects of ADVICOR and NIASPAN were similar, and both were superior to lovastatin (Table 5). The independent effect of lowering Lp(a) with NIASPAN or ADVICOR on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

ADVICOR is a fixed-dose combination product and is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION). 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. Initial medical therapy is indicated with a single agent 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 7 and the NCEP treatment guidelines¹).

ADVICOR is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types IIa and IIb; Table 6) 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.

Prior to initiating therapy with a lipid-lowering agent, 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 TC, HDL-C, and TG. For patients with TG < 400 mg/dL, LDL-C can be estimated using the following equation:

•  LDL-C = TC – [(0.20 x TG) + HDL-C]

For TG levels > 400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. Lipid determinations should be performed at intervals of no less than 4 weeks and dosage adjusted according to the patient's response to therapy. The NCEP Treatment Guidelines are summarized in Table 7.

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.

ADVICOR is contraindicated in patients with a known hypersensitivity to niacin, lovastatin or any component of this medication, active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS), active peptic ulcer disease, or arterial bleeding.

ADVICOR 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., 500 mg once daily at bedtime) 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.

ADVICOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of ADVICOR.

Niacin preparations and lovastatin preparations have been associated with abnormal liver tests. In studies using NIASPAN alone, 0.8% of patients were discontinued for transaminase elevations. In studies using lovastatin alone, 0.2% of patients were discontinued for transaminase elevations.² In three safety and efficacy studies involving titration to final daily ADVICOR doses ranging from 500 mg/10 mg to 2500 mg/40 mg, 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 2000 mg/40 mg; no patient receiving 1000 mg/20 mg had 3-fold elevations in AST/ALT.

In clinical studies with ADVICOR, elevations in transaminases did not appear to be related to treatment duration; elevations in AST and ALT levels did appear to be dose related. Transaminase elevations were reversible upon discontinuation of ADVICOR.

Liver function tests should be performed on all patients during therapy with ADVICOR. Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first 6 months, 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, if confirmed, 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.

Before instituting therapy with a lipid-altering medication, an attempt should be made to control dyslipidemia 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 ADVICOR 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 fasting blood sugar (FBS). In three clinical studies, which included 1028 patients exposed to ADVICOR (6 to 22% of whom had diabetes type II at baseline), increases in FBS above normal occurred in 46 to 65% of patients at any time during study treatment with ADVICOR. Fourteen patients (1.4%) were discontinued from study treatment: 3 patients for worsening diabetes, 10 patients for hyperglycemia and 1 patient for a new diagnosis of diabetes. In the studies in which lovastatin and NIASPAN were used as active controls, 24 to 41% of patients receiving lovastatin and 43 to 58% of patients receiving NIASPAN also had increases in FBS above normal. One patient (1.1%) receiving lovastatin was discontinued for hyperglycemia. Diabetic or potentially diabetic patients should be observed closely during treatment with ADVICOR, and adjustment of diet and/or hypoglycemic therapy may be necessary.

In one long-term study of 106 patients treated with ADVICOR, elevations in prothrombin time (PT) >3 times ULN occurred in 2 patients (2%) during study drug treatment. In a long-term study of 814 patients treated with ADVICOR, 7 patients were noted to have platelet counts <100,000 during study drug treatment. Four of these patients were discontinued, and one patient with a platelet count <100,000 had prolonged bleeding after a tooth extraction. Prior studies have shown that NIASPAN can be associated with dose-related reductions in platelet count (mean of –11% with 2000 mg) and increases of PT (mean of approximately +4%). Accordingly, patients undergoing surgery should be carefully evaluated. In controlled studies, ADVICOR has been associated with small but statistically significant dose-related reductions in phosphorus levels (mean of -10% with 2000 mg/40 mg). Phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia. In clinical studies with ADVICOR, hypophosphatemia was more common in males than in females. The clinical relevance of hypophosphatemia in this population is not known.

Caution should also be used when ADVICOR is used in patients with unstable angina or in the acute phase of 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, in patients predisposed to gout, niacin therapy should be used with caution. Niacin is rapidly metabolized by the liver, and excreted through the kidneys. ADVICOR 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.

Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.

Patients should be advised of the following:

• -to report promptly unexplained muscle pain, tenderness, or weakness (see WARNINGS, Skeletal Muscle);
• -to take ADVICOR at bedtime, with a low-fat snack. Administration on an empty stomach is not recommended;
• -to carefully follow the prescribed dosing regimen (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 last for several hours after dosing, may vary in severity, and will, by taking ADVICOR at bedtime, most likely occur during sleep. If awakened by flushing, especially if taking antihypertensives, rise slowly to minimize the potential for dizziness and/or syncope;
• -that taking aspirin (up to approximately 30 minutes before taking ADVICOR) or another non-steroidal antiinflammatory drug (e.g., ibuprofen) may minimize flushing;
• - to avoid ingestion of alcohol or hot drinks around the time of ADVICOR administration, to minimize flushing;
• -should not be administered with grapefruit juice;
• -that if ADVICOR 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);
• -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 ADVICOR tablets should not be broken, crushed, or chewed, but should be swallowed whole.

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.

No studies have been conducted with ADVICOR regarding carcinogenesis, mutagenesis, or impairment of fertility.

No studies have been conducted on the effect of ADVICOR, niacin or lovastatin on the mother or the fetus during labor or delivery, on the duration of labor or delivery, or on the growth, development, and functional maturation of the child.

No studies have been conducted with ADVICOR in nursing mothers.

Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of niacin and lovastatin (see CONTRAINDICATIONS), ADVICOR should not be taken while a woman is breastfeeding.

Niacin has been reported to be excreted in human milk. It is not known whether lovastatin is excreted in human milk. A small amount of another drug in this class is excreted in human breast milk.

No studies in patients under 18 years-of-age have been conducted with ADVICOR. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug or its active ingredients is limited, treatment of pediatric patients with ADVICOR is not recommended at this time.

Of the 214 patients who received ADVICOR in double-blind clinical studies, 37.4% were 65 years-of-age and older, and of the 814 patients who received ADVICOR in open-label clinical studies, 36.2% were 65 years-of-age and older. Responses in LDL-C, HDL-C, and TG were similar in geriatric patients. No overall differences in the percentage of patients with adverse events were observed between older and younger patients. No overall differences were observed in selected chemistry values between the two groups except for amylase which was higher in older patients.

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.

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.

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.

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

Information on acute overdose with ADVICOR in humans is limited. Until further experience is obtained, no specific treatment of overdose with ADVICOR can be recommended. The patient should be carefully observed and given supportive treatment.

The s.c. LD50 of niacin is 5 g/kg in rats.

The signs and symptoms of an acute overdose of niacin can be anticipated to be those of excessive pharmacologic effect: severe flushing, nausea/vomiting, diarrhea, dyspepsia, dizziness, syncope, hypotension, possibly cardiac arrhythmias and clinical laboratory abnormalities. Insufficient information is available on the potential for the dialyzability of niacin.

After oral administration of lovastatin to mice the median lethal dose observed was >15 g/m².

Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdose have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 to 6 g. The dialyzability of lovastatin and its metabolites in man is not known at present.

The usual recommended starting dose for NIASPAN is 500 mg qhs. NIASPAN must be titrated and the dose should not be increased by more than 500 mg every 4 weeks up to a maximum dose of 2000 mg a day, to reduce the incidence and severity of side effects. Patients already receiving a stable dose of NIASPAN may be switched directly to a niacin-equivalent dose of ADVICOR.

The usual recommended starting dose of lovastatin is 20 mg once a day. Dose adjustments should be made at intervals of 4 weeks or more. Patients already receiving a stable dose of lovastatin may receive concomitant dosage titration with NIASPAN, and switch to ADVICOR once a stable dose of NIASPAN has been reached.

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by pretreatment with aspirin (taken up to approximately 30 minutes prior to ADVICOR dose) or other non-steroidal anti-inflammatory drugs. 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 ADVICOR may be substituted for equivalent doses of NIASPAN but should not be substituted for other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin preparations (see WARNINGS). Patients previously receiving niacin products other than NIASPAN should be started on NIASPAN with the recommended NIASPAN titration schedule, and the dose should subsequently be individualized based on patient response. A relative bioavailability study results indicated that ADVICOR tablet strengths (i.e., two tablets of 500 mg/20 mg and one tablet of 1000 mg/40 mg) are not interchangeable.

ADVICOR should be taken at bedtime, with a low-fat snack. ADVICOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing. The lowest initial ADVICOR dose is a single 500 mg/20 mg tablet once daily at bedtime. The dose of ADVICOR should not be increased by more than 500 mg daily (based on the NIASPAN component) every 4 weeks. The dose of ADVICOR should be individualized based on targeted goals for cholesterol and triglycerides, and on patient response. Doses of ADVICOR greater than 2000 mg/40 mg daily are not recommended. If ADVICOR therapy is discontinued for an extended period (>7 days), reinstitution of therapy should begin with the lowest dose of ADVICOR.

ADVICOR is an unscored capsule-shaped tablet containing either 500, 750, or 1000 mg of extended-release niacin, and 20 mg of immediate-release lovastatin (ADVICOR 500 mg/20 mg, 750 mg/20 mg, 1000 mg/20 mg), or 1000 mg of extended-release niacin and 40 mg of immediate-release lovastatin (ADVICOR 1000 mg/40 mg). Tablets are color-coated and debossed with “KOS” on one side and the tablet strength code on the other side. ADVICOR 500 mg/20 mg tablets are light yellow, code “502”. ADVICOR 750 mg/20 mg tablets are light orange, code “752”. ADVICOR 1000 mg/20 mg tablets are dark pink/light purple, code “1002”. ADVICOR 1000 mg/40 mg tablets are reddish brown, code “1004.” Tablets are supplied in bottles of 90 tablets as shown below.

500 mg/20 mg tablets: bottles of 90 - NDC# 60598-006-90

750 mg/20 mg tablets: bottles of 90 - NDC# 60598-007-90

1000 mg/20 mg tablets: bottles of 90 - NDC# 60598-008-90

1000 mg/40 mg tablets: bottles of 90 - NDC# 60598-009-90

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

NIASPAN is a registered trademark of Kos Pharmaceuticals, Inc., and Mevacor is a registered trademark of Merck & Co., Inc.

• 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.
• Downs JR, et al. JAMA 1998; 279:1615-1622.
• Bradford RH, et al. Arch Intern Med 1991;151:43-49.
• Bradford RH, et al. Am J Cardiol 1994; 74:667-673.
• Manson JM, et al. Reprod Toxicol 1996; 10(6): 439-446.

Mfr. for:
KOS PHARMACEUTICALS, INC.
Cranbury, NJ 08512

400169/0506 ©2006 Kos Pharmaceuticals, Inc., Cranbury, NJ 08512

Printed in USA

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; and other patents pending.