Niacin and Lovastatin (Systemic)


VA CLASSIFICATION
Primary: CV359

Commonly used brand name(s): Advicor.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihyperlipidemic —

Indications

Accepted

Hyperlipidemia (treatment)—Niacin and lovastatin combination therapy is indicated for treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types IIa and IIb) in patients who require further triglyceride lowering or HDL raising effects and have been previously treated with lovastatin and may benefit from having niacin added to their regimen, or in patients who require further LDL lowering effects and have been previously treated with niacin and may benefit from having lovastatin added to their regimen.{01}

Unaccepted
Niacin and lovastatin combination therapy is not indicated for initial treatment of hypercholesterolemia and mixed dyslipidemia.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Niacin: 123.11
    Lovastatin: 404.55
{01}
Mechanism of action/Effect:

Niacin's mechanism of lipid alteration 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. Niacin functions after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. Niacin, (in gram doses) reduces low density lipoprotein cholesterol (LDL-C), apolipoprotein B-100 (Apo B), Lp(a), triglyceride (TG), and total cholesterol (TC), and increases high density lipoprotein cholesterol (HDL-C). The increase in HDL-C is associated with an increase in apolipoprotein A-1.{01}

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, a precursor to cholesterol. Lovastatin is a prodrug and has little, if any activity until hydrolyzed to the 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. Apo B also decreases substantially and there is a modest decrease in triglyceride levels. Lovastatin produces increases in HDL-C of variable magnitude.{01}

Absorption:

Niacin—After administration of two niacin and lovastatin, 1000 mg / 20 mg tablets approximately 72% of the niacin dose was absorbed according to urinary excretion data. Niacin absorption rate increases when administered with food. Under low-fat or high-fat conditions there is a 22 to 30% increase in niacin bioavailability relative to dosing under fasting conditions.{01}

Lovastatin—is incompletely absorbed after oral administration. Lovastatin's bioavailability is affected when administered with food. The AUC was decreased 26% and 24% after a high-fat and low-fat meal, respectively, compared to fasting conditions.
Note: Lovastatin absorption appears to be increased by at least 30% by grapefruit juice, however, the effect is dependent on the amount of juice consumed and the interval between juice and lovastatin ingestion.

{01}

Distribution:

Niacin—is distributed into breastmilk.{01}

Lovastatin— it is unknown if lovastatin or its metabolites are distributed into human breastmilk. However, lovastatin distributes into the breastmilk in rats. In animal studies, lovastatin concentrated in the liver, and crossed the blood-brain and placental barriers.{01}

Protein binding:

Niacin—Low (less than 20%), human serum proteins {01}

Lovastatin—Very high (greater than 95%), human plasma proteins{01}

Biotransformation:

Niacin undergoes rapid and extensive first pass metabolism that is dose-specific and at the doses used to treat dyslipidemia, saturable. One pathway is a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted and there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). Nicotinamide (a precursor to NAD or a product of synthesis of NAD) is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to N-methyl-2-pyridone-5-carboxamide (2PY) predominantly and to N-methyl-4-pyridone-5-carboxamide (4PY).{01}

Lovastatin undergoes extensive first-pass extraction and metabolism by cytochrome P450 3A4 in the liver, its primary site of action. The amount of drug reaching the systemic circulation is less than 5%, due to the extensive hepatic first-pass metabolism. The major active metabolites present in human plasma are the beta-hydroxyacid of lovastatin (lovastatin acid), its 6'-hydroxy derivative, and two additional metabolites.{01}


Elimination

Niacin plasma half-life—approximately 20 to 48 minutes after oral administration and dependent on the dose administered. {01}

Lovastatin plasma half-life—approximately 4.5 hours in single dose studies.{01}

Time to peak concentration:

Niacin—5 hours following oral administration of two niacin and lovastatin, 1000 mg / 20 mg tablets.{01}

Lovastatin—2 hours following oral administration of two niacin and lovastatin, 1000 mg / 20 mg tablets.{01}

Peak plasma and steady-state concentration:

Niacin peak plasma— 18 micrograms per mL following oral administration of two niacin and lovastatin 1000 mg / 20 mg tablets. .

Niacin plasma concentration—in the general circulation is dose dependent and highly variable.{01}

Niacin peak steady-state—0.6, 4.9, and 15.5 micrograms per mL after oral divided daily doses of 1000, 1500 and 2000 mg of extended release niacin. Peak steady-state niacin concentrations are dose dependent and highly variable.{01}

Lovastatin peak plasma—11 micrograms per mL following administration of two niacin and lovastatin 1000 mg / 20 mg tablets. The amount of lovastatin reaching the systemic circulation as active inhibitors after oral administration is low (less than 5%) and shows inter-individual variation. Peak concentration of active and total inhibitors occur within 2 to 4 hours. {01}Lovastatin Cmax was increased 48% and 21% after a high-fat and low-fat meal, respectively

In severe renal insufficiency (creatine clearance of 10 to 30 mL per minute), the plasma concentration after a single dose of lovastatin were approximately two-fold higher.{01}

Elimination:
    Niacin—primarily excreted in urine mainly as metabolites. After a single dose of niacin and lovastatin, at least 60% of the niacin dose was recovered in the urine as unchanged niacin and its metabolites. 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 is dependent on the dose administered{01}
    Lovastatin— is excreted in urine and bile. Following an oral dose of radiolabeled lovastatin in patients, 10% of the dose was excreted in urine and 83% of the dose was excreted in feces (representing absorbed drug equivalents excreted as well as any unabsorbed drug). {01}


Precautions to Consider

Note: No carcinogenesis, mutagenesis or impairment of fertility studies have been conducted with the combination of niacin and lovastatin.{01}


Carcinogenicity

Niacin, administered to mice for a lifetime as a 1% solution in drinking water, was not carcinogenic. In this study, mice received approximately 6 to 8 times a human dose of 3000 mg per day as determined on a mg per m2 basis.{01}

Lovastatin, administered to mice in a 21-month carcinogenic study, demonstrated a significant increase in the incidence of hepatocellular carcinomas and adenomas in both male and female mice at 500 mg per kg body weight per day. This dose produced a total plasma drug exposure 3 to 4 time that of humans given the highest recommended dose of lovastatin.{01}

Lovastatin, administered to mice, demonstrated a statistically significant increase in pulmonary adenomas in female mice at approximately 4 times the human drug exposure. There was an increase in the incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at lovastatin exposures of 1 to 2 times that of humans, however the human stomach does not contain non-glandular mucosa.{01}

Lovastatin, administered to rats in a 24-month carcinogenic study, demonstrated a positive dose-response relationship for hepatocellular carcinogenicity in males at exposures between 2 to 7 times that of human exposure at 80 mg per day (doses in rats were 5, 30 and 180 mg per kg body weight per day).{01}

Mutagenicity

Niacin was negative for mutagenicity in a microbiological Ames test.{01}

Lovastatin showed no evidence of mutagenicity in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. No evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.{01}

Pregnancy/Reproduction
Fertility—
Niacin—No studies on impairment of fertility have been performed. {01}

Lovastatin—Male dogs administered 20 mg per kg body weight per day experienced drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation.{01}

Pregnancy—
Niacin and lovastatin is contraindicated in women who are pregnant. It may cause fetal harm when administered to pregnancy women . Safety in pregnant woman has not been established and there is no apparent benefit to therapy in pregnancy. If a woman receiving niacin and lovastatin for primary hypercholesterolemia (Types IIa or IIb) becomes pregnant, the drug should be discontinued and the patient should be apprised of the potential hazard to the fetus. Niacin and lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive.{01}

In humans, rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a prospective study in 100 pregnant women exposed to lovastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths or stillbirths did not exceed what would be expected in the general population. In 89% of the prospectively followed pregnancies, drug treatments was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. The number of cases is adequate only to exclude a 3 to 4 fold increase in congenital anomalies over the background incidence.{01}

Animal studies, have not been conducted with niacin or with the combination of niacin and lovastatin. It is not know whether niacin at doses typically used for lipid disorders can cause fetal harm.

Animal studies with 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 at a dose of 800 mg per kg body weight per day. No evidence of malformations was noted in rabbits at exposure up to 3 times the human exposure at a maximum dose of 15 mg per kg body weight per day.{01}

FDA Pregnancy Category X


Labor and delivery—

No studies have been conducted on the effect of niacin and 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.{01}

Breast-feeding

Because of the potential for serious adverse reactions in nursing infants from lipid altering doses of niacin and lovastatin, the combination of niacin and lovastatin should not be taken while a women is breast-feeding.{01}

Niacin has been reported to be distributed into breast milk. It is not known whether lovastatin is distributed into breast milk. A small amount of another drug in this class is distributed into breast milk. No studies have been be conducted on nursing mothers with the administration of niacin and lovastatin combination therapy{01}

Pediatrics

No studies have been conducted on the relationship of age to the effects of niacin and lovastatin in the pediatric population. Safety and efficacy have not been established for patients under the age of 18.{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of niacin and lovastatin in the elderly{01}

In double-blind clinical studies of 214 patients, as well as in open-label clinical studies of 814 patients, respectively 37.4% and 36.2% were 65 years of age and older. 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, except for amylase which was higher in older patients. Responses in LDL-C, HDL-C and TG were similar in geriatric patients.{01}


Pharmacogenetics

Women have a greater hypolipidemic response than men at equivalent doses. There was a higher plasma concentration of niacin and metabolites in women than in men, a magnitude varying with dose and metabolite, which may be due to differences in metabolic rate or volume of distribution. Recovery of niacin and metabolites in urine are similar for men and women indicating similar absorption for both genders.{01}

In two single dose studies with niacin and lovastatin combination, the lovastatin concentrations were about 30% higher in women than in men and the total HMG-CoA reductase inhibitor concentrations were about 20 to 25% greater in women.{01}

In a multi-center randomized, double-blind active comparator study, following a 2000 mg / 40 mg dose of niacin and lovastatin combination, resulted in a 47% reduction in LDL-C in women, compared to 34% reduction in men; a 33% increase in HDL-C in women compared to a 24% increase in men; and a 48% decrease in TG in women compared to a 35% decrease in men.{01}


Dental

Treatment with niacin and lovastatin should be stopped a few days before dental surgery{01}

Surgical

In patients undergoing elective major surgery, or have acute medical or surgical conditions, their treatment with niacin and lovastatin should be stopped a few days before thier surgery or when any major acute medical or surgical condition supervenes.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol, substantial use of{01}    (Elevations in transaminase values may occur, caution should be used. The use of alcohol also increases the flushing side effect produced by the niacin component.{01})


» Anticoagulants, coumarin derivatives{01}    (bleeding and/or increased prothrombin time have been reported in patients taking coumarin anticoagulants concomitantly with lovastatin{01})


» Antihypertensive agents{01}    (niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension{01})


Aspirin{01}    (concomitant with niacin and lovastatin may decrease the metabolic clearance of niacin. The clinical significance of this is unclear{01})


Cholestyramine{01}or
Colestipol    (in anin-vitro study the amount of available niacin bound by bile acid sequestrants was 98 % bound for colestipol and 10 to 30% bound for cholestyramine. Therefore, it is recommended that four to six hours, or as great an interval as possible should elapse between the ingestion of bile acid-binding resins and niacin and lovastatin combination therapy{01})


» Clarithromycin{01}or
» Cyclosporine,{01} or
» Erythromycin{01} or
» Grapefruit juice (> 1 quart per day){01} or
» HIV protease inhibitors{01} or
» Itraconazole, {01}or
» Ketoconazole{01}or
» Nefazodone{01}    (lovastatin and certain other food or drugs which share the metabolic pathway of cytochrome P450 isoform 3A4 have an increased risk of myopathy when coadministered. Lovastatin had no effect on the pharmacokinetics of antipyrine or its metabolites. However, since lovastatin is metabolized by the cytochrome P450 isoform 3A4 enzyme system, this does not preclude an interaction with other drugs metabolized by the same isoform{01})


» Gemfibrozil or
» Clofibrate or
» Fenofibrate    (concomitant use with gemfibrozil or other fibrates increases the incidence and severity of myopathy{01})


» Niacin containing vitamins or supplements{01}    (large doses of niacin or related compounds such as nicotinamide may potentiate adverse effects of niacin and lovastatin combination therapy.{01}
Note: The substitution of the sustained release niacin formulation in the niacin and lovastatin combination for equivalent doses of immediate release (crystalline) niacin has resulted in severe hepatic toxicity, including fulminant hepatic necrosis.{01}

)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Catecholamine Fluorometry, {01}    (niacin may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines {01} )


» Urine glucose tests{01}    (niacin may produce false-positive reactions in urine glucose tests with cupric sulfate solution (Benedict's reagent){01} )

With physiology/laboratory test values
Blood sugar, fasting{01}    (there may be a dose-related rise in fasting blood glucose levels{01})


» Creatine kinase{01}    (elevations in creatine kinase may be indicative of myopathy in patients on niacin and lovastatin therapy.{01})


Liver function tests{01}    (niacin and lovastatin preparation have been associated with abnormal liver tests; elevations in transaminases does not appear to be related to treatment duration; elevations in AST and ALT levels appear to be dose related; transaminase elevations were reversible upon discontinuation of niacin and lovastatin therapy{01})


Phosphorous{01}    (niacin and lovastatin has been associated with reductions in phosphorous levels.{01})


Platelet count    (niacin and lovastatin has been associated with a decrease in platelet count.{01})


Prothrombin time{01}    (elevations in prothrombin time (PT) have occurred, in patients receiving niacin and lovastatin therapy.{01})


Uric acid{01}    (niacin may elevate uric acid levels{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Bleeding, arterial{01}    (niacin and lovastatin therapy may cause reduction in platelet counts resulting in bleeding episodes)


» Hepatic disease, acute or{01}
» Hepatic dysfunction, significant or unexplained, or{01}
» Serum transaminases, persistently elevated{01}    (niacin and lovastatin therapy use is not recommended.)


» Hypersensitivity to niacin or lovastatin{01}
» Peptic ulcer disease, active{01}    (niacin and lovastatin therapy use is not recommended in patients with active peptic ulcer disease.{01})

{01}
Risk-benefit should be considered when the following medical problems exist
Angina, unstable or{01}
Myocardial infarction, acute phase{01}    (caution should be used in patients experiencing unstable angina or who are in the acute phase of an MI and who are coadministered vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.{01})


Diabetes    (diabetic patients may experience a dose related rise in fasting blood sugar (FBS). Patients should be monitored closely as adjustments in hypoglycemic therapy may be necessary.{01})


Endocrine function, impaired{01}    (caution should be used in patients with impaired endocrine function, especially if receiving other drugs such as cimetidine, ketoconazole or spironolactone that may decrease the levels or activity of endogenous steroid hormones{01}.)


Liver disease, history of{01}    (patients with a past history of jaundice, or hepatobiliary disease should be observed closely.{01})


Gout{01}    (niacin may elevate uric acid levels, so patients predisposed to gout should be monitored closely.{01})


Peptic ulcer disease, history of{01}    (patients with a peptic ulcer disease should be observed closely.{01})


Renal disease{01}    (niacin is excreted through the kidneys, so caution should be exercised in patients with existing renal disease.{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Lipid profile    (Triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and total triglyceride should be performed prior to initiating therapy and at intervals of no less than 4 weeks. For patients with TG < 400 mg per dL, low-density lipoprotein cholesterol (LDL-C) can be estimated using this equation: LDL-C = TC - [(0.02 x TG)] + HDL-C. For TG levels > 400 mg per dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. {01})


» Liver function tests {01}    (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 approximately every 6 months, thereafter. In patients who develop elevated serum transaminases, measurements should be repeated promptly and if confirmed then performed more frequently. If 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.{01})


» Glucose monitoring{01}    (diabetic patients may experience a dose related rise in fasting blood sugar. Diabetic or potentially diabetic patients should be monitored closely during treatment with niacin and lovastatin, and adjustment of diet and hypoglycemic therapy may be necessary{01})


» Creatine kinase (CK), serum{01}    (increases in CK values to > 10 times the upper limit of normal [ULN] have been reported. Niacin and lovastatin treatment should be discontinued if marked elevations of creatine kinase occur. If these elevations are accompanied by diffuse muscle aches, tenderness, or weakness, myopathy should be considered and therapy discontinued.{01})


» Phosphorous monitoring    (levels should be monitored periodically in patients at risk for hypophosphatemia.{01})


» Platelet monitoring    (platelet levels should be monitored periodically in patients at risk of bleeding episodes{01})


» Prothrombin time{01}    (in patients taking anticoagulants, PT should be determined before starting niacin and lovastatin and frequently during early therapy to insure that no significant alteration of PT occurs. Once a stable PT has been observed, the normal course of monitoring may be resumed. If the dose of niacin and lovastatin is changed, the same procedure should be repeated.{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Clinical studies of single product niacin, or lovastatin did not result in any significantly different treatment-emergent adverse events from the combination product of niacin and lovastatin{01}.


Those indicating need for medical attention
Incidence more frequent
    
Asthenia (lack or loss of strength)
    
infection (cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination)
    
pain — generalized or back pain
{01}
Incidence less frequent
    
Abdominal pain (stomach pain)
    
hyperglycemia (abdominal pain; blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; nausea; sweating; troubled breathing; unexplained weight loss; vomiting)
    
myalgia ( difficulty in moving; joint pain; muscle aching, cramping pain or stiffness; swollen joints)

{01}Incidence rare
    
Rhabdomyolysis, with or without acute renal failure, secondary to myoglobinuria (dark-colored urine; fever; muscle cramps, pain, spasms, or stiffness; unusual tiredness or weakness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Chills
    
diarrhea
    
flu syndrome (chills; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
    
flushing (feeling of warmth; redness of the face, neck, arms and occasionally, upper chest)
    
edema (swelling )
    
headache
    
nausea
    
pruritus (itching skin)
    
rash
    
shortness of breath
    
sweating
    
syncope (feeling faint or fainting)
    
tachycardia (fast, pounding, or irregular heartbeat or pulse)
{01}
Incidence less frequent
    
dyspepsia (acid or sour stomach; belching; heartburn; indigestion; stomach discomfort, upset or pain)
    
vomiting
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Niacin
    
Cardiac arrhythmia (chest pain or discomfort; dizziness; fainting; fast, slow, or irregular heartbeat; lightheadedness; pounding or rapid pulse )
    
diarrhea
    
dizziness
    
dyspepsia (acid or sour stomach; belching; heartburn; indigestion; stomach discomfort upset or pain), flushing, severe (feeling of warmth redness of the face, neck, arms and occasionally, upper chest)
    
hypotension (blurred vision; confusion; dizziness; faintness; lightheadedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness), nausea and vomiting
syncope (fainting)
{01}
Lovastatin

Note: No specific symptoms of lovastatin overdose are currently available.

A few cases of lovastatin overdose have been reported with a maximum dose of 5 to 6 grams. No patients experienced any specific symptoms and all patients recovered without sequelae{01}.

Lethality occurred in mice after oral administration of greater than 15 gm per m2of body surface area{01}.


Treatment of overdose


Specific treatment:
Information on the overdose of niacin and lovastatin combination therapy is limited. Until further experience is obtained, no specific treatment of overdose is recommended. Treatment should be symptomatic and supportive{01}

No information is available on the potential for dialyzability of niacin or of lovastatin and its metabolites{01}



Monitoring:
Patient should be carefully observed and given supportive treatment{01}



Supportive Care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Niacin and Lovastatin (Systemic)..
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to niacin, lovastatin or any component of this medication.

Pregnancy—Contraindicated during pregnancy or in women planning to become pregnant in the near future.





Breast-feeding—Contraindicated in women who are breast-feeding
Pharmacogenetics—Niacin plasma concentrations are generally higher in women than in men, however this does not warrant dose adjustment





Dental—Treatment with niacin and lovastatin should be stopped a few days before dental surgery

Surgical
Patients undergoing elective major surgery, or have acute medical or surgical conditions, their treatment with niacin and lovastatin should be stopped a few days before thier surgery or when any major acute medical or surgical condition supervenes.
Other medications, especially alcohol-large quantities, antihypertensive agents, clarithromycin, clofibrate, coumarin anticoagulants, cyclosporine, erythromycin, fenofibrate, gemfibrozil, grapefruit juice (> 1 quart per day), HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, and niacin containing vitamins or supplements
Other medical problems, especially active peptic ulcer disease, acute hepatic disease, arterial bleeding, hepatic dysfunction, hypersensitivity to niacin or lovastatin, persistent elevations in serum transaminases, women who are pregnant and in lactating mothers

Laboratory value alterations especially catecholamine fluorometry, urine glucose tests, and creatine kinase.

Proper use of this medication
Patient monitoring especially lipid profile, liver function tests, glucose monitoring in diabetic patients, serum creatine kinase, phosphorous monitoring, platelet monitoring, and prothrombin time.

Not crushing or chewing tablets

Taking at bedtime with a snack. Not taking with grapefruit juice.

» Proper dosing, especially importance of not substituting sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses
Taking as soon as possible; not taking if almost time for next dose; do not double dose

Proper storage

Precautions while using this medication
Notifying physician immediately if pregnancy is suspected because of possible harm to the fetus

Notifying physician immediately if unexplained dark-colored urine, a fever, muscle cramps or spasms, muscle pain or stiffness, or feel very tired or weak, these symptoms may indicate rhabdomyolysis.


Side/adverse effects
Signs of potential side effects, especially abdominal pain, asthenia, flushing, generalized pain or back pain, hyperglycemia, infection, myalgia, and rhabdomyolysis.


General Dosing Information
Niacin and lovastatin, being a fixed-dose combination product is not indicated for initial therapy. Initial medical therapy is indicated with a single agent as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.{01}

Prior to starting niacin and lovastatin therapy, secondary causes for hypercholesterolemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other medication therapy, and alcoholism should be excluded and a lipid profile performed to measure total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).{01}

Niacin and lovastatin should be taken at bedtime with a low fat snack.

If niacin and lovastatin therapy has been discontinued for an extended length of time, re-initiate therapy by re-titrating the dose.{01}

Tablets should not be broken, crushed, or chewed, but should be swallowed whole.{01}

Diet/Nutrition
Before instituting therapy with niacin and lovastatin, an attempt should be made to control dyslipidemia with appropriate diet, exercise, and weight reduction in obese patients and to treat underlying medical problems. {01}

Do not administer niacin and lovastatin with grapefruit juice.{01}

Avoid alcohol or hot drinks around the time of administration of niacin and lovastatin to minimize flushing.{01}

For treatment of adverse effects
Skin flushing episodes were the most common adverse effect with the treatment of niacin and lovastatin which usually subsides after several weeks of consistent niacin use. Flushing may last several hours after dosing and varies in severity. Taking aspirin or another non-steroidal approximately 30 minutes prior to treatment may reduce the frequency or the severity of flushing. Also avoiding alcohol or hot drinks may minimize flushing. {01}

Flushing, pruritus and gastrointestinal distress are reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach.{01}


Oral Dosage Forms

NIACIN EXTENDED RELEASE AND LOVASTATIN TABLETS

Usual Adult Dose
Antihyperlipidemia{01}
Prior to niacin and lovastatin combination therapy, initial therapy consists of Niaspan at a starting dose of 500 mg a day at bedtime. Titrate the dose with increases of no more than 500 mg every four weeks, up to a maximum dose of 2000 mg a day. Patients already receiving a stable dose of Niaspan may be switched directly to a niacin-equivalent dose of niacin and lovastatin combination.{01}.

Equivalent doses of Niaspan should not be substituted for other modified-release (sustained-release or time-release) niacin preparation or immediate-release (crystalline) niacin preparation.{01}

Oral, initially 20 mg lovastatin component once a day. Increases in dose should not exceed 500 mg daily based on the Niaspan component every 4 weeks. Patients already receiving a stable dose of Niaspan and lovastatin may be switched directly to a niacin-equivalent dose of niacin and lovastatin.{01}

Note: If niacin and lovastatin combination therapy is discontinued for greater than 7 days, reinstituting of therapy should begin with the lowest dose of niacin and lovastatin.{01}



Usual adult prescribing limits
A daily dose of niacin and lovastatin greater than 2000 mg / 40 mg, respectively, is not recommended.{01}

Usual Pediatric Dose
Safety and efficacy have not been established. 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 patient with niacin and lovastatin is not recommended.{01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


500 mg of niacin and 20 mg of lovastatin (Rx) [Advicor (hydroxypropyl methylcellulose, povidone, stearic acid, polyethylene glycol, titanium, dioxide, polysorbate 80.)]{01}


750 mg of niacin and 20 mg of lovastatin (Rx) [Advicor (hydroxypropyl methylcellulose, povidone, stearic acid, polyethylene glycol, titanium, dioxide, polysorbate 80.)]{01}


1000 mg of niacin and 20 mg of lovastatin (Rx) [Advicor (hydroxypropyl methylcellulose, povidone, stearic acid, polyethylene glycol, titanium, dioxide, polysorbate 80.)]{01}

Canada—
Not commercially available

Packaging and storage:
Store at room temperature (20 to 25°C or 68 to 77°F){01}

Auxiliary labeling:
   • Avoid alcohol while on this medication.
   • Grapefruit and grapefruit juice should not be taken with this medication.
   • Take with food
   • Take at bedtime
   • Swallow whole. Do not crush or chew
   • Harmful if pregnant or breastfeeding
   • Ask before using non-prescription drugs
{01}


Developed: 09-03-02



References
  1. Product Information: Advicor™, niacin and lovastatin. Kos Pharmaceuticals, Inc., Miami, Florida, 33131 (PI revised 11/2001) reviewed 7/2002.
Hide
(web1)