Advicor

Name: Advicor

What else should I know about niacin and lovastatin?

What preparations of niacin and lovastatin are available?

Tablets (niacin/lovastatin): 500/20, 750/20, 1000/20, 1000/40 mg

How should I keep niacin and lovastatin stored?

Advicor should be stored at room temperature, between 20 C - 25 C (68 F - 77 F).

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 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-pyridone5-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

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 coadministered drug)
No Effect = 1.00
Lovastatin Lovastatin Acid†
Gemfibrozil 11 600 mg BID for 3 days 40 mg 0.96 2.8
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
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 describedβ 10 mg QD for 10 days 5- to 8-fold NDa
  Number of Subjects Dosing of Coadministered Drug or Grapefruit Juice Dosing of Lovastatin AUC Ratio* (with / without coadministered drug) No Effect = 1.00
Total Lovastatin Acid e
Diltiazem 10 120 mg BID for 14 days 20 mg 3.57e
* 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.
β Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9 months prior to study.
aND = Analyte not determined.
eLactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.

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 (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).

Manufacturer

  • AbbVie Inc.

Advicor and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant. The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to clarify the possible risks to an unborn baby when a medication is taken during pregnancy.

Advicor falls into category X. It has been shown that women taken Advicor during pregnancy may have babies born with problems. There are no situations where the benefits of the medication for the mother outweigh the risks of harm to the baby. These medicines should never be used by pregnant women.

What do I need to tell my doctor BEFORE I take Advicor?

  • If you have an allergy to lovastatin, niacin, or any other part of Advicor (niacin and lovastatin).
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.
  • If you are breast-feeding. Do not breast-feed while you take Advicor.
  • If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for HIV, infections, or depression. There are many drugs that must not be taken with Advicor. Your doctor or pharmacist can tell you if you are taking a drug that must not be taken with this medicine.
  • If you have any of these health problems: Bleeding problems, liver problems or rise in liver enzymes, or ulcer disease.

This is not a list of all drugs or health problems that interact with Advicor.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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.2 In three safety and efficacy studies involving titration to final daily Advicor doses ranging from 500 mg/10 mg to 2500 mg/40 mg, ten of 1028 patients (1.0%) experienced reversible elevations in AST/ALT to more than 3 times the upper limit of normal (ULN). Three of ten elevations occurred at doses outside the recommended dosing limit of 2000 mg/40 mg; no patient receiving 1000 mg/20 mg had 3-fold elevations in AST/ALT.

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

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)3,4 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
Diltiazem
Verapamil
Do not exceed 20 mg lovastatin daily
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.

US Brand Name

  1. Advicor

What is lovastatin and niacin (advicor)?

Niacin, also called nicotinic acid, is a B vitamin (vitamin B3). It occurs naturally in plants and animals, and is also added to many foods as a vitamin supplement. Niacin is also present in many multivitamins and nutritional supplements.

Lovastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." Lovastatin reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

The combination of lovastatin and niacin is used to lower cholesterol and triglycerides (types of fat) in the blood.

Lovastatin and niacin may also be used for other purposes not listed in this medication guide.

What should i avoid while taking lovastatin and niacin (advicor)?

If you also take cholestyramine (Prevalite, Questran) or colestipol (Colestid), avoid taking them within 4 to 6 hours before or after you take lovastatin and niacin.

Avoid eating foods that are high in fat or cholesterol. Lovastatin and niacin will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

Grapefruit and grapefruit juice may interact with lovastatin and niacin and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

For Healthcare Professionals

Applies to lovastatin / niacin: oral tablet extended release

Musculoskeletal

Lovastatin has been associated with rare cases of severe myopathy and rhabdomyolysis, manifested as elevations in creatine kinase, myoglobinuria, proteinuria, and renal failure. These conditions appear to be dose related, usually occurring with doses greater than 30 mg per day.

Concomitant use of lovastatin-niacin and potent inhibitors of CYP450 3A4 (i.e., cyclosporine, antifungal azoles, macrolide antibiotics, ketolide antibiotics, HIV protease inhibitors, large amounts of grapefruit juice) or other drugs known to cause myopathy (i.e., gemfibrozil) is associated with an increased risk of myotoxicity.

Myopathy and/or rhabdomyolysis have also been reported when lovastatin is used in combination with lipid-altering doses (greater than or equal to 1 g/day) of niacin.

Patients should be instructed to report promptly symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if markedly elevated, lovastatin should be discontinued. The value of routine monitoring of creatine kinase is not known. In some studies up to 11% of patients experienced elevations in creatine kinase while on lovastatin. In most cases these elevations were mild, transient, and not associated with clinical symptoms.

Itraconazole used concomitantly with lovastatin has led to one reported case of severe rhabdomyolysis in a 63-year-old woman. Caution should be exercised when HMG-CoA reductase inhibitors and azole antifungals are prescribed concurrently.[Ref]

Musculoskeletal side effects associated with the administration of lovastatin have included elevations in creatine kinase, muscle cramps, myopathy, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia and myalgia.

In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.[Ref]

Dermatologic

Dermatologic side effects associated with the administration of lovastatin have included rash and pruritus. Other dermatologic side effects reported with HMG-CoA reductase inhibitors have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, dermatomyositis, purpura, and alopecia. These effects may be manifestations of a hypersensitivity reaction.

Dermatologic side effects associated with the administration of niacin have included flushing (facial and whole body) and pruritus. Rare cases of hyperpigmentation and acanthosis nigricans have been reported.[Ref]

Niacin-related flushing (facial and whole body) and pruritus occur as a result of stimulation and release of prostaglandins and have been major drawbacks of this drug. These symptoms have occurred in up to 78% of patients and usually resolved after 2 weeks of continued therapy. Flushing can be minimized with use of an extended release form of the drug, gradual dosage titration (over 2 to 3 months), and by administering the dosage during or within 30 minutes after meals. Aspirin (325 mg), if not otherwise contraindicated), taken within 30 minutes of niacin ingestion and avoidance of hot beverages and alcohol which can aggravate flushing by causing peripheral vasodilation may be recommended to reduce flushing.[Ref]

Endocrine

Endocrine side effects of lovastatin have included hypospermia. Other endocrine side effects of HMG-CoA reductase inhibitors have included gynecomastia and thyroid dysfunction.

Rare incidences of altered thyroid function tests associated with the use of niacin have been reported. Changes appeared to be due to decreased thyroid binding capacity and concentration of thyroid binding globulin.[Ref]

Gastrointestinal

Gastrointestinal side effects associated with the administration of lovastatin have included flatulence (to 6%), abdominal pain (to 6%), diarrhea (to 6%), constipation (to 5%), nausea (to 5%), dyspepsia, and heartburn. Other gastrointestinal side effects of HMG-CoA reductase inhibitors have included pancreatitis, anorexia, and vomiting.

Gastrointestinal side effects associated with the administration of niacin have included exacerbation of peptic ulcer disease, nausea, vomiting, diarrhea, and dyspepsia. Persistent fatigue, nausea or anorexia may be a sign of hepatotoxicity.[Ref]

Gastrointestinal side effects are among the most common complaints in patients on lovastatin. These effects tend to be mild and transient in nature and will often dissipate with continued therapy.[Ref]

Cardiovascular

Niacin has been shown to increase plasma homocysteine levels. Homocysteine is an independent risk factor for arterial occlusive disease. Clinical implications of these increases and the influence of folic acid supplementation as a means to decrease homocysteine levels remain to be determined.[Ref]

Cardiovascular side effects associated with the administration of niacin generally have been rare and have included transient tachycardia, hypotension and dizziness. The Coronary Drug Project (1975) reported a significant increase in cardiac arrhythmias associated with the use of niacin; some experts consider preexisting arrhythmias or angina pectoris contraindications to its use.

Niacin have been shown to increase plasma homocysteine levels. Homocysteine is an independent risk factor for arterial occlusive disease. Clinical implications of these increases and the influence of folic acid supplementation as a means to decrease homocysteine levels remain to be determined.[Ref]

Genitourinary

Genitourinary side effects associated with the administration of HMG-CoA reductase inhibitors, including lovastatin, have included erectile dysfunction.

Genitourinary side effects associated with the administration of niacin have included decreased sexual function in up to 3% and 22% of male patients who have taken unmodified and timed release niacin, respectively.[Ref]

Halkin, et al report a case in which use of both lovastatin and pravastatin on different occasions in the same patient led to reversible impotence. The impotence resolved within 2 weeks after discontinuation of the HMG-CoA reductase inhibitor.[Ref]

Hematologic

Hematologic side effects associated with the administration of HMG-CoA reductase inhibitors have included hemolytic anemia, thrombocytopenia, and leukopenia. These effects may be manifestations of a hypersensitivity reaction.

Hematologic side effects associated with the administration of niacin have included coagulopathies associated with elevations of liver function enzymes.[Ref]

Hypersensitivity

Hypersensitivity side effects associated with the administration of lovastatin have been reported rarely with HMG-CoA reductase inhibitors and have included anaphylaxis, angioedema, urticaria, fever (including severe hyperthermia), chills, flushing, malaise, and dyspnea.[Ref]

Hepatic

Hepatic side effects associated with the administration of lovastatin have included elevations in liver function enzyme tests (to 2%). Other hepatic side effects reported with HMG-CoA reductase inhibitors have included hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in the liver, cirrhosis, and fulminant hepatic necrosis.

Hepatic side effects associated with the administration of niacin have included hepatic toxicity.[Ref]

Persistent elevations in liver function tests to three times normal values have been reported in up to 2% of patients on lovastatin in clinical trials. Overall, 1.5% of patients were withdrawn from study due to elevations in serum transaminases. While most patients remained asymptomatic with these elevations, cases of cholestatic jaundice and hepatitis have been reported.

Liver function tests should be closely monitored. Lovastatin should be discontinued in patients with persistent, significant elevations (three times the upper limit of normal) in liver function parameters.

Hepatotoxicity has been reported in 2% to 3% of patients who have taken larger doses (3 grams or more daily) of niacin or who have used timed release preparations. Hepatotoxicity usually reverses within one week after drug discontinuation, but sometimes can be avoided with dosage reductions or switching to crystalline niacin (if hepatotoxicity developed while using a timed release preparation). Clinical monitoring of patient response and tolerance, including laboratory evaluation of liver function tests is generally recommended.

Dose-related increases in aspartate aminotransferase and alkaline phosphatase have been associated with dosage increases greater than 2.5 grams over 1 month. Computerized tomography has revealed changes consistent with focal fatty liver in some cases. Although these changes usually resolve with dose reduction, continued routine monitoring of liver function tests is recommended. Rare cases of fulminant, even fatal, hepatic failure have been reported.

In one retrospective analysis of 969 predominantly elderly male veterans treated for dyslipoproteinemia with controlled release niacin (average dose 3.1 grams/day), the incidences of possible and probable hepatotoxicity (biochemical criteria) were 2.2% and 4.7%, respectively. Predisposing risk factors included high dose, alcohol use, preexisting liver disease, and concurrent oral sulfonylurea use. The incidence of hepatotoxicity was significantly less among patients who were taking an average daily dose of 2.1 grams.[Ref]

Immunologic

Immunologic side effects associated with the administration of lovastatin have included a lupus-like syndrome with positive ANA and elevated ESR. Other immunologic side effects of HMG-CoA reductase inhibitors have included polymyalgia rheumatica and vasculitis.[Ref]

Metabolic

Nicotinic acid competes with uric acid for excretion by the kidneys. Hyperuricemia associated with niacin appears to be more common in men.[Ref]

Metabolic side effects associated with the administration of lovastatin have included a case report of hyperkalemia in a patient with mild renal insufficiency on concomitant lisinopril. A positive rechallenge implicated lovastatin as a confounding factor in this case.

Metabolic changes associated with niacin have included hyperuricemia and hyperglycemia. Clinical monitoring of patient response and tolerance, including laboratory evaluations of serum uric acid and blood glucose levels, is recommended in patients with a history of gout or diabetes mellitus.[Ref]

Nervous system

Nervous system side effects associated with the administration of lovastatin have included headache (9%) and dizziness (2%). In addition, one study demonstrated an increase in sleep latency and total wake time in patients treated with lovastatin as compared to patients treated with pravastatin. Other nervous system side effects reported with HMG-CoA reductase inhibitors have included cranial nerve dysfunction, tremor, vertigo, memory loss, paresthesias, peripheral neuropathy, and peripheral nerve palsy.

Nervous system side effects associated with the administration of niacin have included paresthesias, headache, fatigue, and insomnia.[Ref]

Ocular

Ocular side effects associated with the administration of HMG-CoA reductase inhibitors have included progression of cataracts and ophthalmoplegia. There is no evidence to support adverse effects of lovastatin on the human lens.

Ocular side effects associated with the administration of niacin have included amblyopia, sicca syndromes, blurred vision, eyelid edema, and macular edema. In this study, 7% of 102 patients taking niacin discontinued therapy due to adverse ocular side effects.[Ref]

Niacin appears to cause a reversible toxic cystoid maculopathy in approximately 0.7% of patients taking at least 1.5 grams daily. The maculopathy typically has been reversible upon discontinuation of therapy.[Ref]

Psychiatric

Psychiatric side effects associated with the administration of HMG-CoA reductase inhibitors have included anxiety, depression, insomnia, and decreased libido.[Ref]

Renal

Renal side effects associated with the administration of lovastatin have included acute renal failure secondary to rhabdomyolysis.[Ref]

Other

Other side effects associated with the administration of lovastatin-niacin have included headache, back pain, and migraine. Fatigue, cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion), depression, peripheral nerve palsy, dermatomyositis, and progression of cataracts have been reported in postmarketing experience with lovastatin.[Ref]

Some side effects of Advicor may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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