ADVICOR niacin and lovastatin tablet extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
NIACIN (UNII: 2679MF687A) (NIACIN - UNII:2679MF687A)
Available from:
AbbVie Inc.
INN (International Name):
NIACIN
Composition:
NIACIN 500 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application

ADVICOR- niacin and lovastatin tablet, extended release

AbbVie Inc.

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Advicor

(niacin extended-release/lovastatin tablets)

DESCRIPTION

ADVICOR (niacin extended-release and lovastatin) is intended to facilitate the daily administration of

its individual components, Niaspan and lovastatin, when used together for the intended patient

population (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).

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 C H NO 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

H O 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

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

coloring agents:

ADVICOR 500 mg/20 mg - Iron Oxide Yellow, Iron Oxide Red.

ADVICOR 750 mg/20 mg - FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake.

®

ADVICOR 1000 mg/20 mg - Iron Oxide Red, Iron Oxide Yellow, Iron Oxide Black.

ADVICOR 1000 mg/40 mg - Iron Oxide Red.

CLINICAL PHARMACOLOGY

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.

Effects on lipids

ADVICOR

ADVICOR reduces LDL-C, TC, and TG, and increases HDL-C due to the individual actions of niacin

and lovastatin. The magnitude of individual lipid and lipoprotein responses may be influenced by the

severity and type of underlying lipid abnormality.

Niacin

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 LDL-C, Apo B, Lp(a), TG, and

TC, and increases HDL-C. The increase in 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

HDL :HDL ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particle containing only Apo

A-I). In addition, preliminary reports suggest that niacin causes favorable LDL particle size

transformations, although the clinical relevance of this effect is not yet clear.

Lovastatin

Lovastatin has been shown to reduce both normal and elevated LDL-C concentrations. Apo B also falls

substantially during treatment with lovastatin. Since each LDL-C particle contains one molecule of Apo

B, and since little Apo B is found in other lipoproteins, this strongly suggests that lovastatin does not

merely cause cholesterol to be lost from LDL-C, but also reduces the concentration of circulating LDL

particles. In addition, lovastatin can produce increases of variable magnitude in HDL-C, and modestly

reduces VLDL-C and plasma TG. The effects of lovastatin on Lp(a), fibrinogen, and certain other

independent biochemical risk markers for coronary heart disease are not well characterized.

Mechanism of Action

Niacin

The mechanism by which niacin alters lipid profiles is not completely understood and 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-C and LDL-C, and does not

appear to affect fecal excretion of fats, sterols, or bile acids.

Lovastatin

Lovastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase,

the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to

mevalonate is an early step in the biosynthetic pathway for cholesterol. Lovastatin is a prodrug and has

little, if any, activity until hydrolyzed to its active beta-hydroxyacid form, lovastatin acid. The

mechanism of the LDL-lowering effect of lovastatin may involve both reduction of VLDL-C

concentration and induction of the LDL receptor, leading to reduced production and/or increased

catabolism of LDL-C.

Pharmacokinetics

Absorption and Bioavailability

ADVICOR

In single-dose studies of ADVICOR, rate and extent of niacin and lovastatin absorption were

bioequivalent under fed conditions to that from NIASPAN (niacin extended-release tablets) and

Mevacor

(lovastatin) tablets, respectively. After administration of two ADVICOR 1000 mg/20 mg

tablets, peak niacin concentrations averaged about 18 mcg/mL and occurred about 5 hours after dosing;

about 72% of the niacin dose was absorbed according to the urinary excretion data. Peak lovastatin

concentrations averaged about 11 ng/mL and occurred about 2 hours after dosing.

The extent of niacin absorption from ADVICOR was increased by administration with food. The

administration of two ADVICOR 1000 mg/20 mg tablets under low-fat or high-fat conditions resulted in

a 22 to 30% increase in niacin bioavailability relative to dosing under fasting conditions. Lovastatin

bioavailability is affected by food. Lovastatin C

was increased 48% and 21% after a high- and a

low-fat meal, respectively, but the lovastatin AUC was decreased 26% and 24% after a high- and a low-

fat meal, respectively, compared to those under fasting conditions.

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.

Niacin

Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are

dose dependent and highly variable. Peak steady-state niacin concentrations were 0.6, 4.9, and 15.5

mcg/mL after doses of 1000, 1500, and 2000 mg NIASPAN once daily (given as two 500 mg, two 750

mg, and two 1000 mg tablets, respectively).

Lovastatin

Lovastatin appears to be incompletely absorbed after oral administration. Because of extensive hepatic

extraction, the amount of lovastatin reaching the systemic circulation as active inhibitors after oral

administration is low (<5%) and shows considerable inter-individual variation. Peak concentrations of

active and total inhibitors occur within 2 to 4 hours after Mevacor

administration.

Lovastatin absorption appears to be increased by at least 30% by grapefruit juice; however, the effect is

dependent on the amount of grapefruit juice consumed and the interval between grapefruit juice and

lovastatin ingestion. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a

dosing interval achieved a steady-state between the second and third days of therapy and were about 1.5

times those following a single dose of Mevacor

Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of

HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably

due, in part, to inhibition of CYP3A4.

Distribution

Niacin

Niacin is less than 20% bound to human serum proteins and distributes into milk. Studies using

radiolabeled niacin in mice show that niacin and its metabolites concentrate in the liver, kidney, and

adipose tissue.

Lovastatin

Both lovastatin and its beta-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.

Distribution of lovastatin or its metabolites into human milk is unknown; however, lovastatin distributes

into milk in rats. In animal studies, lovastatin concentrated in the liver, and crossed the blood-brain and

placental barriers.

Metabolism

Niacin

Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses

used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with

glycine to form nicotinuric acid (NUA). NUA is then excreted, although there may be a small amount of

reversible metabolism back to niacin. The other pathway results in the formation of NAD. It is unclear

whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is

further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is

further metabolized to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-

4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans.

Lovastatin

Lovastatin undergoes extensive first-pass extraction and metabolism by cytochrome P450 3A4 in the

liver, its primary site of action. The major active metabolites present in human plasma are the beta-

hydroxyacid of lovastatin (lovastatin acid), its 6'-hydroxy derivative, and two additional metabolites.

Elimination

ADVICOR

Niacin is primarily excreted in urine mainly as metabolites. After a single dose of ADVICOR, at least

60% of the niacin dose was recovered in urine as unchanged niacin and its metabolites. The plasma

half-life for lovastatin was about 4.5 hours in single-dose studies.

Niacin

The plasma half-life for niacin is about 20 to 48 minutes after oral administration and dependent on dose

administered. Following multiple oral doses of NIASPAN, up to 12% of the dose was recovered in

urine as unchanged niacin depending on dose administered. The ratio of metabolites recovered in the

urine was also dependent on the dose administered.

Lovastatin

Lovastatin is excreted in urine and bile, based on studies of Mevacor

. Following an oral dose of

radiolabeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter

represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug.

Special Populations

Hepatic

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either niacin

or lovastatin (see WARNINGS, Liver Dysfunction).

Renal

No information is available on the pharmacokinetics of niacin in patients with renal insufficiency.

In a study of patients with severe renal insufficiency (creatinine clearance 10 to 30 mL/min), the plasma

concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher

than those in healthy volunteers.

ADVICOR should be used with caution in patients with renal disease.

Gender

Plasma concentrations of niacin and metabolites after single- or multiple-dose administration of niacin

are generally higher in women than in men, with the magnitude of the difference varying with dose and

metabolite. Recovery of niacin and metabolites in urine, however, is generally similar for men and

women, indicating similar absorption for both genders. The gender differences observed in plasma

niacin and metabolite levels may be due to gender-specific differences in metabolic rate or volume of

distribution. Data from clinical trials suggest that women have a greater hypolipidemic response than

men at equivalent doses of NIASPAN and ADVICOR.

In a multiple-dose study, plasma concentrations of active and total HMG-CoA reductase inhibitors were

20 to 50% higher in women than in men. In two single-dose studies with ADVICOR, lovastatin

concentrations were about 30% higher in women than men, and total HMG-CoA reductase inhibitor

concentrations were about 20 to 25% greater in women.

In a multi-center, randomized, double-blind, active-comparator study in patients with Type IIa and IIb

hyperlipidemia, ADVICOR was compared to single-agent treatment (NIASPAN and lovastatin). The

treatment effects of ADVICOR compared to lovastatin and NIASPAN differed for males and females

with a significantly larger treatment effect seen for females. The mean percent change from baseline at

endpoint for LDL-C, TG, and HDL-C by gender are as follows (Table 1):

Table 1. Mean percent change from baseline at endpoint for LDL-C, HDL-C and TG by gender

ADVICOR 2000 mg/40 mg

NIASPAN 2000 mg

Lovastatin 40 mg

Women

(n=22)

(n=30)

Women

(n=28)

(n=28)

Women

(n=21)

(n=38)

LDL-C

-47%

-34%

-12%

-31%

-31%

HDL-C

+33%

+24%

+22%

+15%

-48%

-35%

-25%

-15%

-15%

-23%

Drug-drug Interactions

Table 2. The Effects of Other Drugs on Lovastatin Exposure When Both Were Co-administered

Drug

N

Dose of

Co-administered Drug or

Grapefruit Juice

Dosing of

Lovas tatin

AUC Ratio*

(with / without

co-adminis tered

drug)

Lovas tatin Lovas tatin

Acid

Gemfibrozil

600 mg BID for 3 days

40 mg

0.96

2.80

* Results based on a chemical assay.

Lovastatin acid refers to the β-hydroxyacid of lovastatin.

The mean total AUC of lovastatin without itraconazole phase could not be determined accurately.

Results could be representative of strong CYP3A4 inhibitors such as ketoconazole, posaconazole,

clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone.

Estimated minimum change.

The effect of amounts of grapefruit juice between those used in these two studies on lovastatin

pharmacokinetics has not been studied.

Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was

administered TID for 2 days, and 200 mL together with single dose lovastatin and 30 and 90 minutes

following single dose lovastatin on Day 3.

Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was

administered with breakfast for 3 days, and lovastatin was administered in the evening on Day 3.

Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable

graft function, transplanted at least 9 months prior to study.

ND = Analyte not determined.

Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid

and lactone.

Gemfibrozil

600 mg BID for 3 days

40 mg

0.96

2.80

Itraconazole

200 mg QD for 4 days

40 mg on Day

> 36

100 mg QD for 4 days

40 mg on Day

> 14.8

15.4

Grapefruit

Juice

(high dose)

200 mL of double-strength TID

80 mg single

dose

15.3

Grapefruit

Juice

(low dose)

8 oz (about 250 mL) of single-

strength for 4 days

40 mg single

dose

1.94

1.57

Cyclos porine

Not described

10 mg QD for

10 days

5- to 8-

fold

Number of

Subjects

Dosing of Coadministered Drug

or Grapefruit Juice

Dosing of

Lovas tatin

AUC Ratio*

(with / without

co-adminis tered

drug)

No Effect = 1.00

Total Lovastatin

Acid

Diltiazem

120 mg BID for 14 days

20 mg

3.57

Clinical Studies

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 3, 4, 5 and 6 below). Results from this study for LDL-C

mean percent change from baseline (the primary efficacy variable) showed that:

è

1. 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)

2. 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 3.

Table 3. LDL-C mean percent change from baseline

Week

ADVICOR

NIASPAN

Lovastatin

Dose

(mg/mg)

Dose

(mg)

Dose

(mg)

Baseline

190.9 mg/dL

189.7 mg/dL

185.6 mg/dL

1000/20

-30%

1000

-29%

1000/40

-36%

1000

-31%

1500/40

-37%

1500

-12%

-34%

2000/40

-42%

2000

-14%

-32%

*n = number of patients remaining in the trial at each timepoint

ADVICOR achieved significantly greater HDL-raising compared to lovastatin and NIASPAN

monotherapy at all doses (Table 4).

Table 4. HDL-C mean percent change from baseline

Week

ADVICOR

NIASPAN

Lovastatin

Dose

(mg/mg)

Dose

(mg)

Dose

(mg)

Baseline

45 mg/dL

47 mg/dL

43 mg/dL

1000/20

+20%

1000

+14%

1000/40

+20%

1000

+15%

1500/40

+27%

1500

+22%

2000/40

+30%

2000

+24%

*n = number of patients remaining in the trial at each timepoint

In addition, ADVICOR achieved significantly greater TG-lowering at doses of 1000 mg/20 mg or

greater compared to lovastatin and NIASPAN monotherapy (Table 5).

Table 5. TG median percent change from baseline

Week

ADVICOR

NIASPAN

Lovastatin

Dose

(mg/mg)

Dose

(mg)

Dose

(mg)

Baseline

174 mg/dL

186 mg/dL

171 mg/dL

1000/20

-32%

1000

-22%

-20%

1000/40

-39%

1000

-23%

-17%

1500/40

-44%

1500

-31%

-21%

2000/40

-44%

2000

-31%

-20%

*n = number of patients remaining in the trial at each timepoint

The Lp(a) lowering effects of ADVICOR and NIASPAN were similar, and both were superior to

lovastatin (Table 6). 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.

Table 6. Lp(a) median percent change from baseline

Table 6. Lp(a) median percent change from baseline

Week

ADVICOR

NIASPAN

Lovastatin

Dose

(mg/mg)

Lp(a)

Dose

(mg)

Lp(a)

Dose

(mg)

Lp(a)

Baseline

34 mg/dL

41 mg/dL

42 mg/dL

1000/20

1000

1000/40

1000

-12%

1500/40

-17%

1500

-22%

2000/40

-22%

2000

-32%

*n = number of patients remaining in the trial at each timepoint

ADVICOR Long-Term Study

A total of 814 patients were enrolled in a long-term (52-week), open-label, single-arm study of

ADVICOR. Patients were force dose-titrated to 2000 mg/40 mg over 16 weeks. After titration, patients

were maintained on the maximum tolerated dose of ADVICOR for a total of 52 weeks. Five hundred-

fifty (550) patients (68%) completed the study, and fifty-six percent (56%) of all patients were able to

maintain a dose of 2000 mg/40 mg for the 52 weeks of treatment. The lipid-altering effects of

ADVICOR peaked after 4 weeks on the maximum tolerated dose, and were maintained for the duration

of treatment. These effects were comparable to what was observed in the double-blind study of

ADVICOR (Tables 3-5).

INDICATIONS AND USAGE

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. Drug 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 8 and the NCEP treatment guidelines ).

ADVICOR

ADVICOR (niacin extended-release and lovastatin) is indicated for use when treatment with both

NIASPAN and lovastatin is appropriate. As described in the labeling for Niaspan and lovastatin below,

the components of ADVICOR are both indicated for the treatment of hypercholesterolemia. Patients

receiving treatment with ADVICOR should be on a standard cholesterol-lowering diet and should

continue on this diet during treatment.

NIASPAN (niacin extended-release)

Hypercholesterolemia

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 (Table 7), when the response to an appropriate diet has been

inadequate.

Secondary Prevention of Cardiovascular Events

In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to

reduce the risk of recurrent nonfatal myocardial infarction.

Hypertriglyceridemia

Niacin is also indicated as adjunctive therapy for treatment of adult patients with very high serum

triglyceride levels (Table 7) 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 (Table 7). 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

patients with TG under 1000 mg/dL may, through dietary or alcohol indiscretion, convert to a 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 hyperlipoproteinemia, who have elevations of chylomicrons and plasma TG, but who

have normal levels of VLDL-C.

Lovas tatin

Hypercholesterolemia

Lovastatin is indicated as an adjunct to diet for the reduction of elevated TC and LDL-C levels in

patients with primary hypercholesterolemia (Table 7), when the response to diet restricted in saturated

fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

Primary Prevention of Cardiovascular Events

In individuals without symptomatic cardiovascular disease, average to moderately elevated TC and

LDL-C, and below average HDL-C, lovastatin is indicated to reduce the risk of:

Myocardial infarction

Unstable angina

Coronary revascularization procedures

Secondary Prevention of Cardiovascular Events

Lovastatin is also indicated to slow the progression of coronary atherosclerosis in patients with

coronary heart disease as part of a treatment strategy to lower TC and LDL-C to target levels.

The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:

TC = total cholesterol; TG = triglycerides; LDL = low-density lipoprotein; VLDL = very low-density

lipoprotein; IDL = intermediate-density lipoprotein ↑→ = increased or no change

Table 7. Classification of Hyperlipoproteinemias

Type

Lipoproteins Elevated

Lipid Elevations

I (rare)

Chylomicrons

Major

Minor

↑→TC

LDL,VLDL

III (rare)

VLDL

TC/TG

V (rare)

Chylomicrons, VLDL

↑→TC

General Recommendations

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 8.

Table 8. NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle

Changes and Drug Therapy in Different Risk Categories

Risk Category

LDL Goal

(mg/dL)

LDL Level at Which to Initiate

Therapeutic Lifestyle Changes

(mg/dL)

LDL Level at Which to

Consider Drug

Therapy (mg/dL)

CHD or CHD

risk equivalents

(10-year risk >20%)

<100

≥ 100

≥ 130

(100-129:drug optional)

2+ Risk factors

(10-year risk ≤20%)

<130

≥ 130

10-year risk 10%-20%: ≥ 130

10-year risk <10%: ≥ 160

0-1 Risk factor

<160

≥ 160

≥ 190

(160-189:LDL-lowering

drug optional)

CHD, coronary heart disease

Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of

<100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that

primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may

call for deferring drug therapy in this subcategory.

Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in

people with 0-1 risk factor is not necessary.

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.

CONTRAINDICATIONS

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.

Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,

posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin,

telithromycin and nefazodone) (see WARNINGS, Myopathy/Rhabdomyolysis).

Pregnancy and lactation - Atherosclerosis is a chronic process and the discontinuation of lipid-

lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of

primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol

biosynthesis pathway are essential components for fetal development, including synthesis of steroids

and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase, such as lovastatin, to

decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis

pathway, ADVICOR is contraindicated in women who are pregnant and in lactating mothers. ADVICOR

may cause fetal harm when administered to pregnant women. ADVICOR should be administered to

women of childbearing age only when such patients are highly unlikely to conceive. If the patient

becomes pregnant while taking this drug, ADVICOR should be discontinued immediately and the patient

should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS

††

†††

††

†††

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).

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.

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.

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.

It is recommended that liver enzyme tests be obtained prior to initiating therapy with ADVICOR and

repeated as clinically indicated.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking

statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or

jaundice occurs during treatment with ADVICOR, promptly interrupt therapy. If an alternate etiology is

not found do not restart ADVICOR.

Myopathy/Rhabdomyolysis

Lovastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is

manifested as muscle pain or weakness associated with grossly elevated creatine kinase (> 10 times

ULN). Rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, has been

reported rarely and can occur at any time. In a large, long-term, clinical safety and efficacy study

(the EXCEL study)

with lovastatin, myopathy occurred in up to 0.2% of patients treated with

lovastatin 20 to 80 mg for up to 2 years. When drug treatment was interrupted or discontinued in these

patients, muscle symptoms and creatine kinase (CK) increases promptly resolved. The risk of myopathy

is increased by concomitant therapy with certain drugs, some of which were excluded by the EXCEL

study design.

The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the

following:

Strong inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-

CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform

3A4. Certain drugs which share this metabolic pathway can raise the plasma levels of lovastatin and may

increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the

macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV

protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or large quantities of

grapefruit juice (>1 quart daily). Combination of these drugs with lovastatin is contraindicated. If

treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable,

therapy with lovastatin should be suspended during the course of treatment.

Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro

(human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of

lovastatin. It is recommended that dose adjustment of lovastatin be considered during coadministration.

Increased lovastatin concentration in plasma has been associated with an increased risk of

myopathy/rhabdomyolysis.

Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.

Other fibrates: Caution should be used when prescribing other fibrates with lovastatin, as these agents

can cause myopathy when given alone. The benefit of further alterations in lipid levels by the

combined use of lovastatin with other fibrates should be carefully weighed against the potential

risks of this combination.

Cyclosporine: The use of lovastatin with cyclosporine should be avoided.

Danazol, diltiazem or verapamil with higher doses of lovastatin: In patients taking concomitant

danazol, diltiazem or verapamil, the dose of lovastatin should not exceed 20 mg (see DOSAGE

AND ADMINISTRATION), as the risk of myopathy increases at higher doses. The benefits of the

use of lovastatin in patients receiving danazol, diltiazem, or verapamil should be carefully weighed

against the risks of these combinations.

Amiodarone: In patients taking concomitant amiodarone, the dose of lovastatin should not

exceed 40 mg (see DOSAGE AND ADMINISTRATION), as the risk of myopathy increases at

higher doses.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin

coadministered with colchicine, and caution should be exercised when prescribing lovastatin with

colchicine.

Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant

administration of ranolazine. Dose adjustment of lovastatin may be considered during co-administration

with ranolazine.

Prescribing recommendations for interacting agents are summarized in Table 9.

Table 9

Drug Interactions Associated with Increased

Risk of Myopathy/Rhabdomyolysis

Interacting Agents

Prescribing Recommendations

Strong CYP3A4 inhibitors, e.g.:

Ketoconazole

Itraconazole

Posaconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Contraindicated with lovastatin

Gemfibrozil

Cyclosporine

Avoid with lovastatin

Danazol

Do not exceed 20 mg lovastatin daily

Diltiazem

Verapamil

Amiodarone

Do not exceed 40 mg lovastatin daily

Grapefruit juice

Avoid large quantities of grapefruit juice (>1 quart daily)

ADVICOR

Myopathy and/or rhabdomyolysis have been reported when lovastatin is used in combination with

lipid-altering doses (≥1g/day) of niacin. Physicians contemplating the use of ADVICOR, a

combination of lovastatin and niacin, should 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 month of treatment or during any period of upward dosage titration

of either drug. Periodic CK determinations may be considered in such situations, but there is no

assurance that such monitoring will prevent myopathy.

In clinical studies, no cases of rhabdomyolysis and one suspected case of myopathy have been reported

in 1079 patients who were treated with ADVICOR at doses up to 2000 mg/40 mg for periods up to 2

years.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy

showing necotizing myopathy without significant inflammation; improvement with immunosuppressive

agents.

All patients starting therapy with ADVICOR, or whose dose of ADVICOR is being increased,

should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain,

tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and

symptoms persist after discontinuing ADVICOR. A CK level above 10 times ULN in a patient

with unexplained muscle symptoms indicates myopathy. ADVICOR therapy should be

discontinued immediately if myopathy is diagnosed or suspected.

In patients with complicated medical histories predisposing to rhabdomyolysis, such as preexisting

renal insufficiency, dose escalation requires caution. ADVICOR therapy should be discontinued if

markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ADVICOR therapy should

also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to

the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;

trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

PRECAUTIONS

General

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.

Niacin

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.

Lovas tatin

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.

Endocrine function - Increases in HbA1c and fasting serum glucose levels have been reported with

HMG-CoA reductase inhibitors, including lovastatin.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically

blunt adrenal and/or gonadal steroid production. Results of clinical studies with drugs in this class have

been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical

studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal

reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase

inhibitor has been shown to reduce the plasma testosterone response to human chorionic gonadotropin

(HCG). In the same study, the mean testosterone response to HCG was slightly but not significantly

reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA

reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The

effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with

lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately.

Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower

cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone,

cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

CNS toxicity - Lovastatin produced optic nerve degeneration (Wallerian degeneration of

retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a

dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans

taking the highest recommended dose (as measured by total enzyme inhibitory activity).

Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen

in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level

) similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell

infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were

seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug

levels (C

) which were about 30 times higher than the mean values in humans taking 80 mg/day.

Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.

Cataracts were seen in dogs treated with lovastatin for 11 and 28 weeks at 180 mg/kg/day and 1 year at

60mg/kg/day.

Information for Patients

Patients should be advised of the following:

to report promptly unexplained muscle pain, tenderness, or weakness particularly if accompanied by

malaise or fever or if muscle signs and symptoms persist after discontinuing ADVICOR (see

WARNINGS, Myopathy/Rhabdomyolysis);

to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right

upper abdominal discomfort, dark urine or jaundice (see WARNINGS, Liver Dysfunction);

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) may minimize flushing;

to avoid ingestion of alcohol, hot beverages and spicy foods 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.

Drug Interactions

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

Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not

expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors

of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV

protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and large quantities of

grapefruit juice (>1 quart daily) increase the risk of myopathy by reducing the elimination of lovastatin

(see WARNINGS, Myopathy/Rhabdomyolysis).

In vitro studies have demonstrated that voriconazole inhibits the metabolism of lovastatin. Adjustment of

the lovastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if

voriconazole must be used concomitantly with lovastatin.

Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong

CYP3A4 inhibitors, but which can cause myopathy when given alone (see WARNINGS,

Myopathy/Rhabdomyolysis).

Gemfibrozil

Other fibrates

Other Drug Interactions

Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of

cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis).

Danazol, Diltiazem, or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant

administration of danazol, diltiazem, or verapamil particularly with higher doses of lovastatin (see

WARNINGS, Myopathy/Rhabdomyolysis and CLINICAL PHARMACOLOGY, Pharmacokinetics).

Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly

with a closely related member of the HMGCoA reductase inhibitor class (see WARNINGS,

Myopathy/Rhabdomyolysis).

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.

Colchicine - Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin

coadministered with colchicine.

Ranolazine - The risk of myopathy, including rhabdomyolysis, may be increased by concomitant

administration of ranolazine.

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.

Drug/Laboratory Test Interactions

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

of fertility.

Niacin

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/m basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of

fertility have been performed.

Lovastatin

In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence

of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose

produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose

of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted

plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures

of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary

adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice

were given 300 times the human dose on a mg/kg body weight basis, plasma levels of total inhibitory

activity were only 4 times higher in mice than in humans given 80 mg of lovastatin.)

There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice

beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The

human stomach contains only glandular mucosa.

In a 24-month carcinogenicity study in rats, there was a positive dose-response relationship for

hepatocellular carcinogenicity in males at drug exposures between 2 to 7 times that of human exposure

at 80 mg/day (doses in rats were 5, 30, and 180 mg/kg/day).

An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with

other HMG-CoA reductase inhibitors.

A drug in this class chemically similar to lovastatin was administered to mice for 72 weeks at 25, 100,

and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times

higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral

dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose

males, with a maximum incidence of 90% in males. The incidence of adenomas of the liver was

significantly increased in mid- and high-dose females. Drug treatment also significantly increased the

incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland

(a gland of the eye of rodents) were significantly higher in high-dose mice than in controls.

No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of

Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence

of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse

hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in

CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell

formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in

this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in

studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks

at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this

same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal

maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule

degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes

were observed in the testes from rats of either study. The clinical significance of these findings is

unclear.

Pregnancy

Pregnancy Category X

— See CONTRAINDICATIONS.

ADVICOR should be administered to women of childbearing potential only when such patients are

highly unlikely to conceive and have been informed of the potential hazard. Safety in pregnant women

has not been established and there is no apparent benefit to therapy with ADVICOR during pregnancy

(see CONTRAINDICATIONS). Treatment should be immediately discontinued as soon as pregnancy is

recognized.

Niacin

Animal reproduction studies have not been conducted with niacin or with ADVICOR. 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 or

ADVICOR for primary hypercholesterolemia becomes pregnant, the drug should be discontinued.

Lovastatin

Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-

CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in

women exposed to lovastatin or another structurally related HMG-CoA reductase inhibitor, the

incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed

what would be expected in the general population. The number of cases is adequate only to exclude a 3-

to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively

followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some

point in the first trimester when pregnancy was identified.

Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human

exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m surface area

(doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8

times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits

at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose).

Labor and Delivery

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.

functional maturation of the child.

Nursing Mothers

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.

Pediatric Use

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.

Geriatric Use

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.

ADVERSE REACTIONS

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, burning sensation/skin burning sensation, 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.

In addition to flushing, other adverse events occurring in 5% or greater of patients treated with

ADVICOR are shown in Table 10 below.

Table 10. Treatment-Emergent Adverse Events in ≥ 5% of Patients (Events Irrespective of

Causality; Data from Controlled, Double-Blind Studies)

Adverse Event

ADVICOR

NIASPAN

Lovastatin

Total Number of Patients

Cardiovas cular

163 (76%)

66 (72%)

24 (26%)

Flushing

152 (71%)

60 (65%)

17 (18%)

Body as a Whole

104 (49%)

50 (54%)

42 (45%)

Asthenia

10 ( 5%)

6 ( 7%)

5 ( 5%)

Flu Syndrome

12 ( 6%)

7 ( 8%)

4 ( 4%)

Headache

20 ( 9%)

12 (13%)

5 ( 5%)

Infection

43 (20%)

14 (15%)

19 (20%)

Pain

18 ( 8%)

3 ( 3%)

9 (10%)

Pain, Abdominal

9 ( 4%)

1 ( 1%)

6 ( 6%)

Pain, Back

10 ( 5%)

5 ( 5%)

5 ( 5%)

Digestive System

51 (24%)

26 (28%)

16 (17%)

Diarrhea

13 ( 6%)

8 ( 9%)

2 ( 2%)

Dyspepsia

6 ( 3%)

5 ( 5%)

4 ( 4%)

Nausea

14 ( 7%)

11 (12%)

2 ( 2%)

Vomiting

7 ( 3%)

5 ( 5%)

Metabolic and Nutrit. System

37 (17%)

18 (20%)

13 (14%)

Hyperglycemia

8 ( 4%)

6 ( 7%)

6 ( 6%)

Musculoskeletal System

19 ( 9%)

9 (10%)

17 (18%)

Myalgia

6 ( 3%)

5 ( 5%)

8 ( 9%)

Skin and Appendages

38 (18%)

19 (21%)

11 (12%)

Pruritus

14 ( 7%)

7 ( 8%)

3 ( 3%)

Rash

11 ( 5%)

11 (12%)

3 ( 3%)

Note: Percentages are calculated from the total number of patients in each column.

See also the full prescribing information for niacin extended release (Niaspan) and lovastatin products.

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.

Body as a Whole:

chest pain; abdominal pain; edema; chills; malaise

Cardiovascular:

atrial fibrillation; tachycardia; palpitations, and

other cardiac arrhythmias; postural hypotension,

orthostasis; hypotension; syncope

Eye:

toxic amblyopia; cystoid macular edema;

ophthalmoplegia; eye irritation, blurred vision,

progression of cataracts

Gastrointestinal:

activation of peptic ulcers and peptic ulceration;

dyspepsia; vomiting; anorexia; constipation;

flatulence, pancreatitis; hepatitis; fatty change in

liver; jaundice; and rarely, cirrhosis, fulminant

hepatic necrosis, and hepatoma, eructation, fatal and

non-fatal hepatic failure

Metabolic:

gout, decreased glucose tolerance

Musculoskeletal:

muscle cramps; myopathy; rhabdomyolysis;

arthralgia, myalgia.

There have been rare reports of immune-mediated

necrotizing myopathy with statin use (see

WARNINGS).

Nervous:

dizziness; insomnia; dry mouth; paresthesia; anxiety;

tremor; vertigo; peripheral neuropathy; psychic

disturbances; dysfunction of certain cranial nerves,

nervousness, burning sensation/skin burning

sensation, peripheral nerve palsy

Psychiatric

depression

Skin:

hyper-pigmentation; acanthosis nigricans; urticaria;

alopecia; dry skin; sweating; and a variety of skin

changes (e.g., nodules, discoloration, dryness of

mucous membranes, changes to hair/nails),

vesiculobullous rash, maculopapular rash

Respiratory:

dyspnea; rhinitis

Urogenital:

gynecomastia; loss of libido; erectile dysfunction

Hypersensitivity reactions:

An apparent hypersensitivity syndrome has been

reported rarely, which has included one or more of

the following features: anaphylaxis, angioedema,

tongue edema, larynx edema, face edema,

peripheral edema, laryngismus, lupus

erythematous-like syndrome, polymyalgia

rheumatica, vasculitis, purpura, thrombocytopenia,

leukopenia, hemolytic anemia, positive ANA, ESR

increase, eosinophilia, arthritis, arthralgia,

urticaria, asthenia, photosensitivity, fever, chills,

flushing, malaise, dyspnea, toxic epidermal

necrolysis, erythema multiforme, including

Stevens-Johnson syndrome, dermatomyositis

Other:

migraine

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been

reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

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, amylase and creatine kinase. 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.

OVERDOSAGE

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.

Niacin

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.

Lovas tatin

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

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.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receiving ADVICOR or

its individual active components and should continue on this diet during treatment with lipid-altering

therapy (see NCEP Treatment Guidelines for details on dietary therapy).

ADVICOR

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. Patients not currently on NIASPAN

must start ADVICOR at the lowest initial ADVICOR dose, 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.

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by

pretreatment with aspirin up to the recommended dose of 325 mg (taken up to approximately 30 minutes

prior to ADVICOR dose). 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.

NIASPAN

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. 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. The recommended dose escalation is shown in Table 11 below.

Patients already receiving a stable dose of NIASPAN may be switched directly to a niacin-equivalent

dose of ADVICOR.

Table 11. Recommended Dosing

Maintenance Dose:

The daily dosage of NIASPAN should not be increased by more than 500 mg in any 4-week

period. The recommended maintenance dose is 1000 mg (two 500 mg tablets) to 2000 mg (two

1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily

are not recommended. Women may respond at lower NIASPAN doses than men.

Flushing of the skin (see ADVERSE REACTIONS) may be reduced in frequency or severity by

pretreatment with aspirin up to the recommended dose of 325 mg (taken 30 minutes prior to NIASPAN

dose). 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. Concomitant alcoholic, hot drinks or spicy foods may

increase the side effects of flushing and pruritus and should be avoided around the time of ADVICOR

ingestion.

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 11), and the dose should subsequently be individualized based on patient response.

Single-dose bioavailability studies have demonstrated that NIASPAN tablet strengths are not

interchangeable.

If NIASPAN therapy is discontinued for an extended period, reinstitution of therapy should include a

titration phase (see Table 11).

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 10, 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 8), 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. Combination therapy with NIASPAN and lovastatin should not exceed doses of 2000 mg and 40

mg 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 (see WARNINGS,

PRECAUTIONS. NIASPAN should be used with caution in patients with renal insufficiency (see

CLINICAL PHARMACOLOGY).

Lovastatin

The usual recommended starting dose is 20 mg once a day given with the evening meal. The

recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended

dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see

NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL

cholesterol of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be

started on 20 mg/day of lovastatin. A starting dose of 10 mg may be considered for patients requiring

smaller reductions. Adjustments should be made at intervals of 4 weeks or more.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the

dosage of lovastatin if cholesterol levels fall significantly below the targeted range.

Dosage in Patients taking Danazol, Diltiazem or Verapamil

In patients taking danazol, diltiazem, or verapamil concomitantly with lovastatin (see WARNINGS,

Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of lovastatin and should not exceed 20

mg/day.

Dosage in Patients taking Amiodarone

In patients taking amiodarone concomitantly with lovastatin, the dose should not exceed 40 mg/day (see

WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug

interactions).

Concomitant Lipid-Lowering Therapy

Use of lovastatin with gemfibrozil should be avoided.

Caution should be used when prescribing other fibrates with lovastatin, as fibrates can cause myopathy

when given alone.

Dosage in Patients with Renal Insufficiency

In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above

20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see

CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).

HOW SUPPLIED

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 printed with the “a” logo and a code number

specific to the tablet strength on the same 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# 0074-3005-90

750 mg/20 mg tablets: bottles of 90 - NDC# 0074-3072-90

1000 mg/20 mg tablets: bottles of 90 - NDC# 0074-3007-90

1000 mg/40 mg tablets: bottles of 90 - NDC# 0074-3010-90

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

NIASPAN is a registered trademark of AbbVie Inc., and Mevacor is a registered trademark of Merck &

Co., Inc.

REFERENCES

1. 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.

2. Downs JR, et al. JAMA 1998; 279:1615-1622.

3. Bradford RH, et al. Arch Intern Med 1991;151:43-49.

4. Bradford RH, et al. Am J Cardiol 1994; 74:667-673.

5. Manson JM, et al. Reprod Toxicol 1996; 10(6): 439-446.

Manufactured by AbbVie LTD, Barceloneta, PR 00617

for AbbVie Inc., North Chicago, IL 60064, U.S.A.

© 2013 AbbVie Inc.

03-A745 February, 2013

NDC 0074–3005–90

Advicor

Niacin Extended-Release/Lovastatin

500 mg / 20 mg

90 Tablets

Rx only abbvie

NDC 0074–3072–90

Advicor

Niacin Extended-Release/Lovastatin

750 mg / 20 mg

90 Tablets

Rx only abbvie

NDC 0074–3007–90

Advicor

Niacin Extended-Release/Lovastatin

1000 mg / 20 mg

90 Tablets

Rx only abbvie

NDC 0074–3010–90

Advicor

Niacin Extended-Release/Lovastatin

1000 mg / 40 mg

90 Tablets

Rx only abbvie

ADVICOR

niacin and lovastatin tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 74-30 0 5

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

NIACIN (UNII: 26 79 MF6 8 7A) (NIACIN - UNII:26 79 MF6 8 7A)

NIACIN

50 0 mg

LO VASTATIN (UNII: 9 LHU78 OQFD) (LOVASTATIN - UNII:9 LHU78 OQFD)

LOVASTATIN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

PO VIDO NES (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

YELLOW (LIGHT YELLOW)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

17mm

Flavor

Imprint Code

A;50 2

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 0 74-30 0 5-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/17/20 0 1

0 3/31/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21249

12/17/20 0 1

0 3/31/20 18

ADVICOR

niacin and lovastatin tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 74-30 72

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

NIACIN (UNII: 26 79 MF6 8 7A) (NIACIN - UNII:26 79 MF6 8 7A)

NIACIN

750 mg

LO VASTATIN (UNII: 9 LHU78 OQFD) (LOVASTATIN - UNII:9 LHU78 OQFD)

LOVASTATIN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

PO VIDO NES (UNII: FZ9 8 9 GH9 4E)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

ORANGE (LIGHT ORANGE)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

19 mm

Flavor

Imprint Code

A;752

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 0 74-30 72-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/17/20 0 1

0 4/30 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21249

12/17/20 0 1

0 4/30 /20 17

ADVICOR

niacin and lovastatin tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 74-30 0 7

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

NIACIN (UNII: 26 79 MF6 8 7A) (NIACIN - UNII:26 79 MF6 8 7A)

NIACIN

10 0 0 mg

LO VASTATIN (UNII: 9 LHU78 OQFD) (LOVASTATIN - UNII:9 LHU78 OQFD)

LOVASTATIN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STEARIC ACID (UNII: 4ELV7Z6 5AP)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

PO VIDO NES (UNII: FZ9 8 9 GH9 4E)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

PINK (DARK PINK/LIGHT PURPLE)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

19 mm

Flavor

Imprint Code

A;10 0 2

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 0 74-30 0 7-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/17/20 0 1

11/30 /20 17

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21249

12/17/20 0 1

11/30 /20 17

ADVICOR

niacin and lovastatin tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 0 74-30 10

Route of Administration

ORAL

Active Ingredient/Active Moiety

AbbVie Inc.

Ingredient Name

Basis of Strength

Stre ng th

NIACIN (UNII: 26 79 MF6 8 7A) (NIACIN - UNII:26 79 MF6 8 7A)

NIACIN

10 0 0 mg

LO VASTATIN (UNII: 9 LHU78 OQFD) (LOVASTATIN - UNII:9 LHU78 OQFD)

LOVASTATIN

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STEARIC ACID (UNII: 4ELV7Z6 5AP)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

PO VIDO NES (UNII: FZ9 8 9 GH9 4E)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

Product Characteristics

Color

BROWN (REDDISH BROWN)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

19 mm

Flavor

Imprint Code

A;10 0 4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 0 74-30 10 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/17/20 0 1

0 1/31/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21249

12/17/20 0 1

0 1/31/20 18

Labeler -

AbbVie Inc. (078458370)

Revised: 3/2017

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