Advicor (Lovastatin; niacin) (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 and ).

Advicor (Lovastatin; niacin) 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.

Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) 500 mg/20 mg - synthetic red and yellow iron oxides.Advicor (Lovastatin; niacin) 750 mg/20 mg – FD&C yellow #6 Aluminum Lake.Advicor (Lovastatin; niacin) 1000 mg/20 mg - synthetic red, yellow, and black iron oxides.Advicor (Lovastatin; niacin) 1000 mg/40 mg – red iron oxide.

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B-100 (Apo B) promote human atherosclerosis. Similarly, decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of TC and LDL-C, and inversely with the level of HDL-C.

Cholesterol-enriched triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma triglycerides (TG) are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG have not consistently been shown to be an independent risk factor for CHD.

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

Advicor (Lovastatin; niacin) 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 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 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.

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 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.

In single-dose studies of Advicor (Lovastatin; niacin) , 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 (Lovastatin; niacin) 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 (Lovastatin; niacin) was increased by administration with food. The administration of two Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) tablet strengths (i.e., two tablets of 500 mg/20 mg and one tablet of 1000 mg/40 mg) are not interchangeable.

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 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 (less than 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.

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.

Both lovastatin and its beta-hydroxyacid metabolite are highly bound (greater than 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.

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 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.

Niacin is primarily excreted in urine mainly as metabolites. After a single dose of Advicor (Lovastatin; niacin) , 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.

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 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.

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either niacin or lovastatin (see ).

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 (Lovastatin; niacin) should be used with caution in patients with renal disease.

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 (Lovastatin; niacin) .

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; niacin) , 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 (Lovastatin; niacin) was compared to single-agent treatment (NIASPAN and lovastatin). The treatment effects of Advicor (Lovastatin; niacin) 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 ():

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 and the NCEP treatment guidelines).

Advicor (Lovastatin; niacin) (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 (Lovastatin; niacin) are both indicated for the treatment of hypercholesterolemia. Patients receiving treatment with Advicor (Lovastatin; niacin) should be on a standard cholesterol-lowering diet and should continue on this diet during treatment.

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 (Frederickson Types IIa and IIb; ), when the response to an appropriate diet has been inadequate.

In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.

Niacin is also indicated as adjunctive therapy for treatment of adult patients with very high serum triglyceride levels (Types IV and V hyperlipidemia; ) 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 (Type V hyperlipidemia; ). 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 Type IV patients with TG under 1000 mg/dL may, through dietary or alcohol indiscretion, convert to a Type V 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 Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma TG, but who have normal levels of VLDL-C. Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia.

Lovastatin is indicated as an adjunct to diet for the reduction of elevated TC and LDL-C levels in patients with primary hypercholesterolemia (Frederickson Types IIa and IIb; ), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.

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:

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:

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 less than 400 mg/dL, LDL-C can be estimated using the following equation:

LDL-C = TC – [(0.20 x TG) + HDL-C]

After the LDL-C goal has been achieved, if the TG is still greater than or equal to 200 mg/dL, non-HDL-C (TC minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

Advicor (Lovastatin; niacin) 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 ), active peptic ulcer disease, or arterial bleeding.

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 (Lovastatin; niacin) 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 (Lovastatin; niacin) , 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 (Lovastatin; niacin) .

Liver function tests should be performed on all patients during therapy with Advicor (Lovastatin; niacin) . Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and, if confirmed, then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued.

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). 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.

In clinical studies, no cases of rhabdomyolysis and one suspected case of myopathy have been reported in 1079 patients who were treated with Advicor (Lovastatin; niacin) at doses up to 2000 mg/40 mg for periods up to 2 years.

In patients with complicated medical histories predisposing to rhabdomyolysis, such as preexisting renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with Advicor (Lovastatin; niacin) should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes.

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 ).

Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) (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 (Lovastatin; niacin) . 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 (Lovastatin; niacin) , and adjustment of diet and/or hypoglycemic therapy may be necessary.

In one long-term study of 106 patients treated with Advicor (Lovastatin; niacin) , elevations in prothrombin time (PT) greater than 3 times ULN occurred in 2 patients (2%) during study drug treatment. In a long-term study of 814 patients treated with Advicor (Lovastatin; niacin) , 7 patients were noted to have platelet counts less than 100,000 during study drug treatment. Four of these patients were discontinued, and one patient with a platelet count less than 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 (Lovastatin; niacin) 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 (Lovastatin; niacin) , hypophosphatemia was more common in males than in females. The clinical relevance of hypophosphatemia in this population is not known.

Caution should also be used when Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) is contraindicated in patients with significant or unexplained hepatic dysfunction (see and ) and should be used with caution in patients with renal dysfunction.

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

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.

Patients should be advised of the following:

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

Niacin may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines. Niacin may also give false-positive reactions with cupric sulfate solution (Benedict's reagent) in urine glucose tests.

No studies have been conducted with Advicor (Lovastatin; niacin) regarding carcinogenesis, mutagenesis, or impairment of fertility.

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.

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 with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an chromosome aberration study in CHO cells, or an 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.

— See .

Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) during pregnancy (see ). Treatment should be immediately discontinued as soon as pregnancy is recognized.

Animal reproduction studies have not been conducted with niacin or with Advicor (Lovastatin; niacin) . 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 (Lovastatin; niacin) for primary hypercholesterolemia (Types IIa or IIb) becomes pregnant, the drug should be discontinued.

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).

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

No studies have been conducted with Advicor (Lovastatin; niacin) in nursing mothers.

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

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

No studies in patients under 18 years-of-age have been conducted with Advicor (Lovastatin; niacin) . 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 (Lovastatin; niacin) is not recommended at this time.

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

In controlled clinical studies, 40/214 (19%) of patients randomized to Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) . Spontaneous reports with NIASPAN and clinical studies with Advicor (Lovastatin; niacin) suggest that flushing may also be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, chills, and/or edema.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The adverse reaction information from clinical studies does, however provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

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

In addition to flushing, other adverse events occurring in 5% or greater of patients treated with Advicor (Lovastatin; niacin) are shown in below.

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

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

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

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

Neither niacin nor lovastatin is a narcotic drug. Advicor (Lovastatin; niacin) has no known addiction potential in humans.

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

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

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

After oral administration of lovastatin to mice the median lethal dose observed was greater than 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.

The patient should be placed on a standard cholesterol-lowering diet before receiving Advicor (Lovastatin; niacin) or its individual active components and should continue on this diet during treatment with lipid-altering therapy (see ).

Advicor (Lovastatin; niacin) should be taken at bedtime, with a low-fat snack. Advicor (Lovastatin; niacin) tablets should be taken whole and should not be broken, crushed, or chewed before swallowing. Patients not currently on Niaspan must start Advicor (Lovastatin; niacin) at the lowest initial Advicor (Lovastatin; niacin) dose, a single 500 mg/20 mg tablet once daily at bedtime. The dose of Advicor (Lovastatin; niacin) should not be increased by more than 500 mg daily (based on the NIASPAN component) every 4 weeks. The dose of Advicor (Lovastatin; niacin) should be individualized based on targeted goals for cholesterol and triglycerides, and on patient response. Doses of Advicor (Lovastatin; niacin) greater than 2000 mg/40 mg daily are not recommended.

Flushing of the skin (see ) may be reduced in frequency or severity by pretreatment with aspirin (taken up to approximately 30 minutes prior to Advicor (Lovastatin; niacin) dose) or other non-steroidal anti-inflammatory drugs. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach.

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 qhs 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 below. Patients already receiving a stable dose of NIASPAN may be switched directly to a niacin-equivalent dose of Advicor (Lovastatin; niacin) .

Flushing of the skin (see ) may be reduced in frequency or severity by pretreatment with aspirin (taken 30 minutes prior to NIASPAN dose) or non-steroidal anti-inflammatory drugs. 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.

Equivalent doses of NIASPAN should be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin (see ). Patients previously receiving other niacin products should be started with the recommended NIASPAN titration schedule (see ), 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 ).

NIASPAN tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

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 , section). For patients already receiving a stable dose of NIASPAN who require further LDL-lowering (e.g., to achieve NCEP LDL-C goals; ), 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.

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

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 and ). Patients requiring reductions in LDL cholesterol of 20% or more to achieve their goal (see ) 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.

In patients taking cyclosporine or danazol concomitantly with lovastatin (see ), therapy should begin with 10 mg of lovastatin and should not exceed 20 mg/day.

In patients taking amiodarone or verapamil concomitantly with lovastatin, the dose should not exceed 40 mg/day (see and ).

In patients with severe renal insufficiency (creatinine clearance less than 30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see and ).

Advicor (Lovastatin; niacin) 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 (Lovastatin; niacin) 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 (Lovastatin; niacin) 1000 mg/40 mg). Tablets are color-coated and printed with the Abbott ‘A’ logo and a code number specific to the tablet strength on the same side. Advicor (Lovastatin; niacin) 500 mg/20 mg tablets are light yellow, code “502”. Advicor (Lovastatin; niacin) 750 mg/20 mg tablets are light orange, code “752”. Advicor (Lovastatin; niacin) 1000 mg/20 mg tablets are dark pink/light purple, code “1002”. Advicor (Lovastatin; niacin) 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:

750 mg/20 mg tablets:

1000 mg/20 mg tablets:

1000 mg/40 mg tablets:

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

NIASPAN is a registered trademark of Abbott Laboratories, and Mevacor is a registered trademark of Merck & Co., Inc.

Mfr. for:Abbott LaboratoriesNorth Chicago, IL 60064, U.S.A.

2007 Abbott Laboratories, North Chicago, IL 60064, U.S.A.Printed in U.S.A.

U.S. Patent Nos. 6,080,428; 6,129,930; 6,406,715 B1; 6,676,967;6,746,691; 6,818,229; 7,011,848; and other patents pending.

Advicor (Lovastatin; niacin) , Niacin extended-Release/Lovastatin Tablets

Advicor (Lovastatin; niacin) , Niacin extended-Release/Lovastatin Tablets

Advicor (Lovastatin; niacin) , Niacin extended-Release/Lovastatin Tablets

Advicor (Lovastatin; niacin) , Niacin extended-Release/Lovastatin Tablets