Advicor

Flushing (warmth/redness/itching/tingling of the skin, especially of the face/neck), sweating, headache, dizziness, or chills may occur within 2 to 4 hours after taking this medication. Flushing may persist for a few hours. These effects should improve or go away after several weeks as your body adjusts to the medication. Stomach upset, nausea, vomiting, or diarrhea may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.A very small number of people taking lovastatin may have mild memory problems or confusion. If these rare effects occur, talk to your doctor.Tell your doctor immediately if any of these unlikely but serious side effects occur: toe/joint pain, fainting, swelling ankles/feet/hands, shortness of breath, fast heartbeat, easy bruising/bleeding, black/tarry stools, vomit that looks like coffee grounds.This drug may infrequently cause muscle problems (which can rarely lead to very serious conditions called rhabdomyolysis and autoimmune myopathy). Tell your doctor right away if you develop any of these symptoms during treatment and if these symptoms persist after your doctor stops this drug: muscle pain/tenderness/weakness (especially with fever or unusual tiredness), change in the amount of urine.This medication may rarely cause liver problems. If you notice any of the following rare but serious side effects, tell your doctor immediately: yellowing eyes/skin, dark urine, persistent nausea/vomiting, severe stomach/abdominal pain.A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Advicor is a prescription medication used to lower cholesterol.  It is a single product containing 2 medications: lovastatin and niacin extended-release.

Lovastatin belongs to a group of medications called HMG-CoA reductase inhibitors. Niacin is a nicotinic acid. Together, these medications lower cholesterol.

This medication comes in tablet form and is usually taken once a day at bedtime with a low-fat snack.  Advicor tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.

Common side effects of Advicor include flushing, nausea, and diarrhea.

If you take too much Advicor, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Advicor is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur.  However, if overdose is suspected, seek emergency medical attention.

In the U.S.

• Advicor

Available Dosage Forms:

• Tablet
• Tablet, Extended Release

Therapeutic Class: Antihyperlipidemic

Pharmacologic Class: Vitamin B (class)

Chemical Class: Nicotinic Acid (class)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

The use of niacin and lovastatin combination is not recommended in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of niacin and lovastatin combination in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir
• Atazanavir
• Boceprevir
• Clarithromycin
• Cobicistat
• Darunavir
• Erythromycin
• Fosamprenavir
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Mibefradil
• Mifepristone
• Nefazodone
• Nelfinavir
• Posaconazole
• Ritonavir
• Saquinavir
• Telaprevir
• Telithromycin
• Tipranavir
• Voriconazole

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Atorvastatin
• Bezafibrate
• Ceritinib
• Cerivastatin
• Ciprofibrate
• Clofibrate
• Colchicine
• Conivaptan
• Cyclosporine
• Dabigatran Etexilate
• Dalfopristin
• Danazol
• Daptomycin
• Delavirdine
• Diltiazem
• Dronedarone
• Fenofibrate
• Fenofibric Acid
• Fluconazole
• Gemfibrozil
• Lomitapide
• Lovastatin
• Lumacaftor
• Niacin
• Pitavastatin
• Quinupristin
• Ranolazine
• Rosuvastatin
• Simvastatin
• Verapamil

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Azithromycin
• Bosentan
• Clopidogrel
• Oat Bran
• Pectin
• St John's Wort
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Liver disease, history of—Use with caution. May cause side effects to become worse.

• Angina (severe chest pain), unstable or
• Diabetes or
• Gout or
• Heart attack, acute—Use with caution. May make these conditions worse.

• Bleeding, arterial (coming from an artery) or
• Liver disease, active or
• Liver enzymes, elevated or
• Peptic ulcer disease, active—Should not be used in patients with these conditions.

• Electrolyte disorders, severe or
• Endocrine disorders, severe or
• Epilepsy (seizures), not well-controlled or
• Hypotension (low blood pressure) or
• Metabolic disorders, severe or
• Sepsis (severe infection in the blood)—Patients with these conditions may be at risk of developing muscle and kidney problems.

• Kidney disease—Use with caution. The effects this medicine may be increased because of slower removal of the medicine from the body.

It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly to lower your cholesterol and triglyceride (fats) levels. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Do not use lovastatin/niacin if you are also using the following medicines: boceprevir (Victrelis®), nefazodone (Serzone®), telaprevir (Incivek®), certain antibiotics (such as clarithromycin, erythromycin, itraconazole, ketoconazole, posaconazole, telithromycin, Nizoral®), or certain medicines to treat HIV/AIDS (such as atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, Crixivan®, Kaletra®, Lexiva®, Norvir®, Prezista®, Reyataz®). Using these medicines together can cause serious side effects.

Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness. These may be symptoms of serious muscle problems such as myopathy or immune-mediated necrotizing myopathy (IMNM).

Call your doctor right away if you have dark-colored urine, have a fever, have muscle cramps or spasms, have muscle pain or stiffness, feel very tired or weak, or have diarrhea. These could be symptoms of a serious muscle problem called rhabdomyolysis, which can cause kidney problems.

Stop using this medicine and check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of liver damage.

This medicine may affect blood sugar levels. This is important if you are diabetic or prediabetic. If you notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

This medicine may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert. Change positions slowly when getting up from a sitting or lying position.

This medicine should not be taken with vitamins containing niacin or nicotinamide.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine if you have major surgery, a major injury, or you develop other serious health problems. It may also affect the result of certain medical tests.

This medicine may cause a side effect called flushing. Flushing is a feeling of warmth or redness on the face, neck, arms, and occasionally, on the upper chest. To avoid flushing, alcohol, hot beverages, and spicy foods should be avoided around the time you take this medicine. Additionally, your doctor may recommend that you take aspirin 30 minutes before taking this medicine to prevent flushing.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flushing. Taking aspirin 30 minutes before taking Advicor may help. If you wake up at night with flushing, get up slowly if you feel like passing out or you are dizzy.
• Headache.
• Upset stomach.
• Loose stools (diarrhea).
• Itching.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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 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 - 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.

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 HDL2:HDL3 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 Cmax 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)	Men (n=30)	Women (n=28)	Men (n=28)	Women (n=21)	Men (n=38)
LDL-C	-47%	-34%	-12%	-9%	-31%	-31%
HDL-C	+33%	+24%	+22%	+15%	+3%	+7%
TG	-48%	-35%	-25%	-15%	-15%	-23%

Drug-drug Interactions

* 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. Þ 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. ß Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9 months prior to study. à ND = Analyte not determined. è Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.
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 Lovastatin	AUC Ratio* (with / without co-administered drug)
				Lovastatin	Lovastatin Acid
Gemfibrozil	11	600 mg BID for 3 days	40 mg	0.96	2.80
Itraconazole‡	12	200 mg QD for 4 days	40 mg on Day 4	> 36§	22
	10	100 mg QD for 4 days	40 mg on Day 4	> 14.8§	15.4
Grapefruit Juice¶ (high dose)	10	200 mL of double-strength TID#	80 mg single dose	15.3	5.0
Grapefruit Juice¶ (low dose)	16	8 oz (about 250 mL) of single-strengthÞ for 4 days	40 mg single dose	1.94	1.57
Cyclosporine	16	Not describedß	10 mg QD for 10 days	5- to 8-fold	NDà
	Number of Subjects	Dosing of Coadministered Drug or Grapefruit Juice	Dosing of Lovastatin	AUC Ratio* (with / without co-administered drug) No Effect = 1.00
				Total Lovastatin Acid è
Diltiazem	10	120 mg BID for 14 days	20 mg	3.57è

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:

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
	n*	Dose (mg/mg)	LDL	n*	Dose (mg)	LDL	n*	Dose (mg)	LDL
Baseline	57	-	190.9 mg/dL	61	-	189.7 mg/dL	61	-	185.6 mg/dL
12	47	1000/20	-30%	46	1000	-3%	56	20	-29%
16	45	1000/40	-36%	44	1000	-6%	56	40	-31%
20	42	1500/40	-37%	43	1500	-12%	54	40	-34%
28	42	2000/40	-42%	41	2000	-14%	53	40	-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
	n*	Dose (mg/mg)	HDL	n*	Dose (mg)	HDL	n*	Dose (mg)	HDL
Baseline	57	-	45 mg/dL	61	-	47 mg/dL	61	-	43 mg/dL
12	47	1000/20	+20%	46	1000	+14%	56	20	+3%
16	45	1000/40	+20%	44	1000	+15%	56	40	+5%
20	42	1500/40	+27%	43	1500	+22%	54	40	+6%
28	42	2000/40	+30%	41	2000	+24%	53	40	+6%
*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
	n*	Dose (mg/mg)	TG	n*	Dose (mg)	TG	n*	Dose (mg)	TG
Baseline	57	-	174 mg/dL	61	-	186 mg/dL	61	-	171 mg/dL
12	47	1000/20	-32%	46	1000	-22%	56	20	-20%
16	45	1000/40	-39%	44	1000	-23%	56	40	-17%
20	42	1500/40	-44%	43	1500	-31%	54	40	-21%
28	42	2000/40	-44%	41	2000	-31%	53	40	-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
Week	Advicor			NIASPAN			Lovastatin
	n*	Dose (mg/mg)	Lp(a)	n*	Dose (mg)	Lp(a)	n*	Dose (mg)	Lp(a)
Baseline	57	-	34 mg/dL	61	-	41 mg/dL	60	-	42 mg/dL
12	47	1000/20	-9%	46	1000	-8%	55	20	+8%
16	45	1000/40	-9%	44	1000	-12%	55	40	+8%
20	42	1500/40	-17%	43	1500	-22%	53	40	+6%
28	42	2000/40	-22%	41	2000	-32%	52	40	0%
*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).

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).

Lovastatin-niacin has been assigned to pregnancy category X by the FDA. Animal studies for the combination product have not been reported, however lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (mice) and 80 times the human exposure (rats). There are no controlled data in human pregnancy. Lovastatin-niacin use is considered contraindicated during pregnancy.