Advicor: Indications, Dosage, Precautions, Adverse Effects
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Advicor - Product Information

Manufacture: Sepracor Pharmaceuticals, Inc.
Country: Canada
Condition: High Cholesterol, High Cholesterol, Familial Heterozygous, Hyperlipoproteinemia Type IIb, Elevated LDL VLDL, Hyperlipoproteinemia Type IIa, Elevated LDL, Hyperlipoproteinemia
Class: Antihyperlipidemic combinations
Form: Tablets
Ingredients: niacin, lovastatin, FD&C yellow No 615 (750/20 tablet only), hydroxypropyl methylcellulose, iron oxide yellow (500/20 and 1000/20 tablets only), iron oxide red (500/20, 1000/20 and 1000/40 tablets only), iron oxide black (1000/20 tablet only), macrogol, povidone, polyethylene glycol, polysorbate 80 (500/20, 750/20 and 1000/20 tablets only), stearic acid, and titanium dioxide

ADVICOR

extended-release niacin and lovastatin tablets

Summary Product Information

Route of
Administration
Dosage Form / Strength Clinically Relevant Nonmedicinal
Ingredients
Oral 500/20 mg, 750/20 mg,
1000/20 mg and 1000/40
mg Film-Coated Tablets
Hydroxypropyl methylcellulose, povidone,
stearic acid, polyethylene glycol, titanium
dioxide and polysorbate 80
For a complete listing see Dosage Forms,
Composition and Packaging section.

Indications and Clinical Use

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. Medical 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.

ADVICOR (extended-release niacin and lovastatin) is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidaemia (Frederickson Types IIa and IIb) in:

  • Patients treated with lovastatin who require further triglyceride (TG) lowering or high-density lipoprotein (HDL)-raising who may benefit from niacin added to their regimen;
  • Patients treated with extended-release niacin who require further LDL-lowering who may benefit from having lovastatin added to their regimen.

ADVICOR is not intended for initial therapy (see DOSAGE AND ADMINISTRATION). The dose of ADVICOR should be determined by the titration of individual components. The use of ADVICOR should be reserved for patients in whom treatment with lovastatin or NIASPAN (extended-release niacin) monotherapy has not been adequate to meet treatment goals.

Pediatrics

No studies in patients under 18 years of age have been conducted with ADVICOR.

Contraindications

  • Pregnant women and lactating mothers (see WARNINGS AND PRECAUTIONS, boxed Serious Warnings and Precautions).
  • Patients with active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS AND PRECAUTIONS).
  • Patients with active peptic ulcer, or active bleeding.
  • Patients who are hypersensitive to niacin, lovastatin or to any ingredient in the formulation or component of the container (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

Warnings and Precautions

Serious Warnings and Precautions

  • ADVICOR preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin or nicotinic acid. (see General section below).
  • 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 (see Hepatic/Biliary/Pancreatic section below).
  • ADVICOR should be used with caution in patients who consume substantial quantities of alcohol.
  • Active liver disease or unexplained transaminase elevations are contraindications to the use of ADVICOR.
  • Myopathy (see Skeletal Muscle section below).
  • Cholesterol and other products of cholesterol biosynthesis pathway are essential components of fetal development, including synthesis of steroids and cell membranes. Because of the ability of lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, ADVICOR may cause harm when administered to pregnant women.

ADVICOR should be administered to women of childbearing potential only when such patients practice a reliable form of contraception (see CONTRAINDICATIONS).

If the patient becomes pregnant, ADVICOR should be discontinued immediately and the patient should be informed of the potential hazard to the fetus.

Clinically significant warnings and precautions are listed below in alphabetical order.

General

Prior to initiating therapy with ADVICOR, secondary causes for elevation in plasma lipid levels should be excluded (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephritic syndrome, dysproteinemias, obstructive liver disease, and alcoholism) and a lipid profile performed to measure total cholesterol, LDL-C, HDL-C and TG. For patients with TG<4.52 mmol/L (< 400 mg/dL), LDL-C can be estimated using the following equation:

LDL-C (mmol) = total-C – [(0.37 x TG) + HDL-C]
LDL-C (mg/dL) = total-C – [(0.2 x TG) + HDL-C]

For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDLC concentrations should be measured directly, or by ultracentrifugation.

ADVICOR should not be substituted for equivalent doses of immediate-release (crystalline) niacin or nicotinic acid. 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. 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 immediaterelease (crystalline niacin) at equivalent doses (see DOSAGE AND ADMINISTRATION).

Before instituting therapy with a lipid-altering medication, an attempt should be made to control dyslipidaemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND CLINICAL USE).

While pretreatment with acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce flushing of the skin, some patients should not take these medications (e.g., patients who have peptic ulcer or active inflammatory disease of the gastrointestinal system or ASA hypersensitivity; refer to the Product Monograph for the NSAID product).

Niacin

Elevated uric acid levels have occurred with niacin therapy; therefore, in patients predisposed to gout, niacin therapy should be used with caution. Niacin is rapidly metabolized by the liver, and excreted through the kidneys. ADVICOR is contraindicated in patients with significant or unexplained hepatic dysfunction (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic) and should be used with caution in patients with renal dysfunction.

Lovastatin

Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS AND PRECAUTIONS, Hepatic and Skeletal Muscle, and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.

Cardiovascular

Data on the safety and efficacy of ADVICOR in patients with unstable angina or in the acute phase of myocardial infarction are not available. Therefore, caution should be used when ADVICOR is administered, particularly when such patients are also receiving vasodilator agents.

Carcinogenesis, Mutagenesis and Fertility Impairment

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

Endocrine and Metabolism

Niacin

Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout.

In placebo-controlled trials, extended-release niacin tablets have been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.

Periodic serum creatine phosphokinase (CK) and potassium determinations should be carried out.

Lovastatin

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

Gastrointestinal

Patients with a past history of jaundice or peptic ulcer should be observed closely during niacin therapy.

Hematologic

Extended-release niacin tablets have been associated with small, but statistically significant doserelated reductions in platelet count (mean of -11% with 2000 mg). In addition, extended-release niacin tablets have been associated with small but statistically significant increases in prothrombin time (PT) (mean of approximately +4% with 2000 mg); accordingly, patients undergoing surgery should be carefully evaluated. Caution should be observed when ADVICOR is administered concomitantly with anticoagulants; prothrombin time and platelet counts should be monitored closely in such patients.

It is recommended that in patients taking anticoagulants, PT be determined before starting ADVICOR and frequently enough during early therapy to ensure that no significant alteration of PT occurs. Once a stable PT has been documented, PT can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of ADVICOR is changed, the same procedure should be repeated.

In one long-term study of 106 patients treated with ADVICOR, elevations in prothrombin time (PT) >3 x ULN occurred in 2 patients (2%) during study drug treatment. In a long-term study of 814 patients treated with ADVICOR, 7 patients were noted to have platelet counts <100,000 during study drug treatment. Four of these patients were discontinued, and one patient with a platelet count <100,000 had prolonged bleeding after a tooth extraction. Prior studies have shown that NIASPAN can be associated with dose-related reductions in platelet counts (mean of -11% with 2000 mg) and increases of PT (mean of approximately +4% with 2000 mg). Accordingly, patients undergoing surgery should be carefully evaluated.

Hepatic/Biliary/Pancreatic

No clinical studies have been carried out in patients with impaired liver function.

Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during ADVICOR therapy. Frequent monitoring of liver function tests and blood glucose should be performed (see CONTRAINDICATIONS). ADVICOR should be used in patients with liver impairment only if the benefits outweigh the risks.

ADVICOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

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 levels.

In two double-blind controlled 28-week studies, the 48-week open-label extension of both trials, and one open-label 100-week trial, one percent of patients (10/1145 patients) with normal liver function treated with ADVICOR experienced reversible elevations in AST/ALT to more than 3 times the upper limit of normal (ULN). Three of 10 elevations occurred at doses outside the recommended dosing limit of 2000/40 mg. No patient receiving 1000/20 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. However, elevations in AST and ALT levels did appear to be dose related. Transaminase elevations were reversible upon discontinuation of ADVICOR.

Diabetic patients may experience a dose-related rise in fasting blood sugar (FBS). In clinical studies, which included 1028 patients exposed to ADVICOR (6 to 22% with diabetes type II at baseline), increases in FBS above normal occurred in 46-65% of patients during the study, and 1.4% of patients discontinued treatment. In patients treated with lovastatin or NIASPAN monotherapy, 24 to 41% and 43 to 58% of patients, respectively, had increases in FBS above normal.

Diabetic or potentially diabetic patients should be monitored closely during treatment with ADVICOR, and adjustment of diet and/or hypoglycemic therapy may be necessary.

Renal

No information is available on the safety of ADVICOR in patients with renal insufficiency. ADVICOR should be used with caution in patients with renal dysfunction.

Skeletal Muscle

Lovastatin

Lovastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is manifested as muscle pain or weakness associated with grossly elevated creatinine kinase (> 10 times ULN). Rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, has been reported rarely and can occur at any time.

Lovastatin is metabolised by the cytochrome P450 isoform 3A4. Drugs which share this metabolic pathway can raise the plasma level of lovastatin and may increase the risk of myopathy. These include cyclosporin, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, or grapefruit juice.

ADVICOR

Myopathy and/or rhabdomyolysis have been reported when lovastatin is used in combination with lipid-altering doses (≥1 g/day) of niacin. Physicians contemplating the use of ADVICOR, a combination of lovastatin and extended-release 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, 1 case of suspected myopathy and no cases of rhabdomyolysis were reported in 1,145 patients treated with ADVICOR at doses up to 2000/40 mg for periods up to 2 years, however, cases of myopathy and rhabdomyolysis have been identified in post-market use of ADVICOR.

Patients starting therapy with ADVICOR should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above 10 times ULN in a patient with unexplained muscle symptoms indicates myopathy. ADVICOR therapy should be discontinued if myopathy is diagnosed or suspected.

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 should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes. If ADVICOR therapy is discontinued for an extended period, reinstitution of therapy should include a titration period.

The risk of adverse muscle events with statins is dose related and the risk may be increased by concomitant use of statins with other lipid lowering drugs that can cause myopathy when given alone, including niacin. Accordingly, the higher doses of ADVICOR should be reserved for patients who require more aggressive lipid management. It is important that such patients be advised to report as soon as possible symptoms such as muscle ache or weakness. A baseline CK determination is recommended for patients who may require higher doses of ADVICOR.

Use of ADVICOR with other Drugs

The incidence and severity of myopathy may be increased by concomitant administration of ADVICOR with drugs that can cause myopathy when given alone, such as gemfibrozil and other fibrates. The use of ADVICOR in combination with fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. In patients taking concomitant cyclosporine or fibrates, the dose of ADVICOR should generally not exceed 1000/20 mg (see DOSAGE AND ADMINISTRATION), as the risk of myopathy may increase at higher doses. Interruption of ADVICOR therapy during a course of treatment with a systemic antifungal azole or a macrolide antibiotic should be considered.

Special Populations

Pregnant Women

ADVICOR is contraindicated in pregnancy. It should be administered to women of childbearing potential only if they practice a reliable method of contraception and have been informed of the potential hazard. Treatment should be immediately discontinued as soon as pregnancy is recognised (see CONTRAINDICATIONS).

Niacin

Animal reproduction studies have not been conducted with niacin or ADVICOR. It is also not known whether niacin at doses 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 becomes pregnant, the drug should be discontinued.

Lovastatin

Lovastatin is contraindicated in pregnancy. Lovastatin has been shown to produce fetal skeletal malformations in mice and rats.

Nursing Women

Use of ADVICOR in nursing mothers is contraindicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions).

Pediatrics (< 18 years of age)

Safety and effectiveness of ADVICOR therapy in pediatric patients have not been established. No studies in patients under 18 years of age have been conducted with ADVICOR.

Geriatrics (> 65 years of age)

No formal studies have been carried out in elderly patients. In controlled and open label studies, the safety and efficacy data in patients over 65 years of age treated with ADVICOR were comparable to data observed in younger patients.

Sex

Data indicate that in patients with primary hypercholesterolemia and dyslipidaemia treated with ADVICOR the changes in lipid concentrations are greater for women than for men.

Monitoring and Laboratory Tests

Liver tests should be performed on all patients during therapy with ADVICOR. Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at 6 month intervals). Special attention should be paid to patients who develop elevated serum transaminase levels. In these patients, measurements should be repeated promptly and 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.

Adverse Reactions

Adverse Drug Reaction Overview

The most frequently-reported events with ADVICOR (extended-release niacin/lovastatin) are flushing episodes (i.e, warmth, redness, itching and/or tingling), which generally become less common as treatment progresses.

The most frequent adverse events observed in double blind controlled clinical trials were: flushing, infection, headache, pain, diarrhea, nausea and pruritus.

The following potentially serious adverse reactions have been reported in controlled clinical trials: cholecystitis, cholelithiasis and kidney stones.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Clinical studies enrolled 1028 patients; 214 in two controlled trials of 24 weeks duration and 814 in a long term open label study at doses up to 2000/40 mg. Doses were titrated up every 4 weeks up to a maximum of 2000/40 mg.

Controlled Clinical Trials

In two controlled clinical trials, ADVICOR has been evaluated for safety in 214 patients treated for hypercholesterolemia, 65 at doses of 2000/40 mg. Discontinuation due to adverse events occurred in 19% (40/214) of the patients, 18/214 (8%) due to flushing.

The adverse events that occurred at an incidence of 2% or greater are given in the table below.

TABLE 1: Treatment-Emergent Adverse Events in Double Blind Controlled Trials, Irrespective of Causality, Occurring in Frequency of 2% or Greater in Patients Treated with ADVICOR
Adverse Event ADVICOR NIASPAN Lovastatin
Total Number of Patients2149294
Flushing71%65%18%
Body as a Whole49%54%45%
Asthenia5%7%5%
Flu Syndrome6%8%4%
Headache9%13%5%
Infection20%15%20%
Injury, Accidental3%4%4%
Pain8%9%10%
Pain, Abdominal4%1%6%
Pain, Back5%5%5%
Pain, Chest2%1%3%
Cardiovascular System18%14%10%
Hypertension2%2%2%
Digestive System24%28%17%
Diarrhea6%9%2%
Dyspepsia3%7%4%
Flatulence2%1%1%
Gastritis2%1%0
Nausea7%12%2%
Vomiting3%5%0
Hemic and Lymphatic System3%1%3%
Ecchymosis2%01%
Metabolic and Nutrit. System17%13%14%
CK Increased2%1%2%
Edema, Peripheral4%2%3%
Hyperglycemia4%7%6%
SGOT (AST) Increased3%01%
SGPT (ALT) Increased2%01%
Musculoskeletal System9%10%18%
Arthritis3%03%
Myalgia3%5%9%
Total Number of Patients2149294
Nervous System14%12%14%
Dizziness3%3%4%
Insomnia4%3%4%
Paresthesia2%2%1%
Respiratory System12%15%11%
Cough Increased4%3%1%
Rhinitis2%4%2%
Sinusitis4%1%2%
Skin and Appendages18%21%12%
Pruritus7%8%3%
Rash5%12%3%
Rash, Maculopapular2%00
Urticaria3%2%1%
Urogenital System9%8%12%
Infection, Urinary Tract3%2%2%

Less Common Clinical Trial Adverse Drug Reactions

The following adverse events have also been reported with niacin, lovastatin, and/or other HMGCoA reductase inhibitors, but not necessarily with ADVICOR, either during clinical studies or in routine patient management.

Body as a Whole: face edema; peripheral chest pain; abdominal pain; generalized edema; chills; malaise
Cardiovascular: atrial fibrillation; tachycardia; palpitations, and other cardiac arrhythmias; orthostasis; hypotension; syncope
Eye: toxic amblyopia; cystoid macular edema; ophthalmoplegia; eye irritation
Gastrointestinal: activation of peptic ulcers and peptic ulceration; dyspepsia; vomiting; anorexia; constipation; eructation; flatulence; pancreatitis; hepatitis; fatty change in liver; jaundice; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma
Metabolic: gout
Musculoskeletal: muscle cramps; myopathy; rhabdomyolysis; arthralgia; myasthenia
Nervous: dizziness; insomnia; dry mouth; paresthesia; anxiety; tremor; vertigo; memory loss; peripheral neuropathy; psychic disturbances; dysfunction of certain cranial nerves, leg cramps; nervousness
Skin: hyper-pigmentation; acanthosis nigricans; urticaria; alopecia; dry skin; sweating; and a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails)
Respiratory: dyspnea; rhinitis
Urogenital: gynecomastia; loss of libido; erectile dysfunction
Hypersensitivity: An apparent hypersensitivity syndrome has been reported rarely, which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Other: migraine

Abnormal Hematologic and Clinical Chemistry Findings

ADVICOR

Elevations in serum transaminases, creatinine kinase and fasting blood glucose, and a reduction in serum phosphorus have been observed.

Niacin

Extended-release niacin tablets have been associated with elevations in lactate dehydrogenase, uric acid, total bilirubin and amylase.

Extended-release niacin tablets have also been associated with reduction in platelet counts and prolongation of prothrombin time.

Lovastatin

Lovastatin has been associated with elevations in alkaline phosphatase, glutamyl transpeptidase and bilirubin, and thyroid function abnormalities (see WARNINGS AND PRECAUTIONS).

Open-label, Long-term Clinical Trial

In a 52-week, long-term, open-label study of 814 patients, 550 patients completed one-year of treatment and 454 patients continued into the 48-week extension phase of the trial. Of the 814 patients in the study, 610 received the 2000/40 mg dose and 376 patients remained on study medication for up to 104 weeks (85 - 88 wks at the 2000/40 mg dose). The mean treatment duration for all 814 patients was 66.2 weeks.

Discontinuations due to adverse events occurred in 25% (203/814 patients) during the first year of treatment and in 7% (32/454) during the second year. The most common adverse event that led to discontinuation was flushing (10% during the first year of treatment and 2% during the extension phase).

The adverse events that occurred at an incidence of 2% or greater, irrespective of causality, are given in the table below.

TABLE 2: Treatment-Emergent Adverse Events in Open-label, Long-Term Trial, Irrespective of Causality, Occurring in Frequency of 2% or Greater in Patients Treated in a Long Term Clinical Trial with ADVICOR
Adverse Event ADVICOR
Total Number of
Patients
814
Flushing65%
Body as a Whole65%
Allergic reaction4%
Asthenia7%
Fever3%
Flu Syndrome9%
Headache13%
Hernia2%
Infection28%
Infection, fungal3%
Injury, Accidental10%
Pain21%
Pain, Abdominal7%
Pain, Back8%
Pain, Chest5%
Pain, neck2%
Cardiovascular
System
73%
Angina pectoris2%
Cardiovascular
disease
3%
Hemorrhage2%
Hypertension4%
Occlusion, coronary2%
Palpitation2%
Vascular disorder2%
Digestive System39%
Abscess,
periodontal
2%
Anorexia2%
Colitis2%
Constipation5%
Diarrhea12%
Dyspepsia9%
Flatulence5%
Gastrointestinal
disorder
3%
Nausea12%
Vomiting7%
Total Number of
Patients
814
Hemic &
Lymphatic System
8%
Anemia2%
Ecchymosis3%
Metabolic &
Nutritional System
26%
Creatine PK
increased
5%
Diabetes, mellitus3%
Edema, peripheral6%
Glucose tolerance
decreased
3%
Hyperglycemia7%
Hypokalemia2%
Musculoskeletal
System
19%
Arthralgia2%
Arthritis3%
Bone disorder2%
Cramps, leg4%
Myalgia5%
Tendon disorder2%
Nervous System30%
Anxiety3%
Depression3%
Dizziness7%
Dry mouth3%
Hypertonia2%
Insomnia5%
Paresthesia5%

Post-Market Adverse Drug Reactions

In an open-label Phase IV study in over 4000 patients at doses of 1000/40 mg for 8 weeks, flushing was the most common adverse event leading to discontinuation of 6% of patients. Incidence of AST/ALT elevations > 3x ULN was 0.24%, increases in CK > 5x ULN occurred in 0.24% of patients and no cases of drug-induced myopathy were observed.

Anaphylactoid reaction, angioedema and thrombocytopenia have been observed during postmarketing use of ADVICOR. Rhabdomyolysis and/or myopathy have also been reported, albeit very rarely, during post-marketing use of ADVICOR. There were no differences in rates when compared with extended-release niacin or lovastatin used as monotherapy.

Cases of erectile dysfunction have been reported in association with the use of statins.

Interstitial lung disease: very rare cases of interstitial lung disease, especially with long term therapy. If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

The following adverse events have been reported with some statins: sleep disturbances, including insomnia and nightmares; mood related disorders including depression.

Drug Interactions

Overview

Extended-Release Niacin

Antihypertensive Therapy

Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.

Acetylsalicylic acid (ASA)

Concomitant administration of ASA may decrease the metabolic clearance of niacin (see WARNINGS AND PRECAUTIONS, General).

Bile-Acid Sequestrants

An interval of 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of ADVICOR. An in vitro study showed that about 98% of available niacin was bound to colestipol, and 10 to 30% was bound to cholestyramine.

Other

Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as nicotinamide may potentiate the adverse effects of ADVICOR.

Lovastatin

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

Coumarin Anticoagulants

Bleeding and/or increased prothrombin time (PT) have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin (see WARNINGS AND PRECAUTIONS, Hematologic).

Antipyrine

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.

Propranolol

In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.

Digoxin

In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

Oral Hypoglycemic Agents

In pharmacokinetic studies of lovastatin in hypercholesterolemic, non-insulin-dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.

Drug-Food Interactions

Concomitant consumption of alcohol or hot drinks may increase the side effects of flushing and pruritus and should be avoided around the time of ADVICOR ingestion.

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

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

Dosage and Administration

The dosage of ADVICOR (extended-release niacin/lovastatin) must be individualized. The fixed combination is not indicated for initial therapy. The dose of ADVICOR should be determined by titration of individual components (see Recommended Dose and Dose Adjustment).

Patients should be placed on a standard cholesterol-lowering diet at least equivalent to the NCEP Adult Treatment Panel III TLC diet before receiving ADVICOR and should continue on this diet during treatment with ADVICOR. If appropriate, a program of weight control and physical exercise should be implemented.

Dosing Considerations

  • Equivalent doses of ADVICOR may be substituted for equivalent doses of NIASPAN but should not be substituted for other modified-release (sustained release or time-release) niacin preparations or immediate-release (crystalline) niacin preparations (see WARNINGS AND PRECAUTIONS). Patients previously receiving niacin products other than NIASPAN should be started on NIASPAN with the recommended NIASPAN titration schedule, and the dose should subsequently be individualized based on patient response.
  • ADVICOR tablet strengths are not interchangeable.
  • Women may respond at lower ADVICOR doses than men.
  • Flushing of the skin may be reduced in frequency or severity by pretreatment with acetylsalicylic acid (see WARNINGS AND PRECAUTIONS, General).
  • Avoid administration on an empty stomach.
  • ADVICOR is contraindicated in patients with significant or unexplained hepatic dysfunction.
  • No information is available on the safety of ADVICOR in patients with renal insufficiency.
  • ADVICOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.

Recommended Dose and Dosage adjustment

ADVICOR should be taken during the evening hours, before or at bedtime, after a low-fat snack. Doses should be individualized according to patient response with the goal being to achieve recommended target lipid levels at the lowest possible dose.

ADVICOR can be substituted if the titrated doses of individual components corresponds to ADVICOR fixed dose combination as shown below in Table 3.

Table 3. Niaspan and Lovastatin Dosing Table
NIASPAN DOSE
(mg)
LOVASTATIN DOSE
(mg)
CORRESPONDING ADVICOR DOSE
(niacin extended release mg/lovastatin mg)
500 20 500/20
750 20 750/20
1000 20 1000/20
1000 40 500/20 (2 tablets) or 1000/40
1500 40 750/20 (2 tablets)
2000 40 1000/20 (2 tablets)

Note: A period of at least 4 weeks is recommended before increasing the dose during titration.

NIASPAN Monotherapy

The tablet strengths of NIASPAN are not interchangeable. Do not alternate between different strengths to provide the same daily dosage. The physician should specify the tablet strengths that the patient should use during titration and continue to use for maintenance therapy.

The recommended starting dose for NIASPAN is 500 mg to be taken at bedtime after a low-fat snack. To reduce the incidence and severity of adverse effects, the dose may be increased after 4 weeks by no more than 500 mg and by 500 mg every 4 weeks thereafter to a maximum of 2000 mg per day, depending on patient response. Patients already receiving a stable dose of NIASPAN may be switched directly to a niacin equivalent dose of ADVICOR (see Table 3).

Lovastatin Monotherapy

The recommended starting dose of lovastatin is 20 mg once daily given with the evening meal. If required, the dose of lovastatin may be increased to a maximum of 40 mg once daily after at least an interval of 4 weeks. Patients already receiving a stable dose of lovastatin, for whom adding NIASPAN is considered appropriate, may receive concomitant dosing with NIASPAN, and switch to ADVICOR once a stable dose of NIASPAN has been reached as recommended for NIASPAN monotherapy above. (see Table 3).

Doses of ADVICOR greater than 2000/40 mg daily are not recommended.

Dosage in Patients with Renal Insufficiency

Use of ADVICOR in patients with renal insufficiency has not been studied. No information is available regarding the safety of ADVICOR use in patients with renal insufficiency.

Dosage in Patients with Hepatic Insufficiency

Use of ADVICOR in patients with hepatic insufficiency has not been studied. ADVICOR is contraindicated in patients with significant or unexplained hepatic dysfunction (see CONTRAINDICATIONS).

Missed Dose

If a dose of this medication is missed, it is not necessary to make up the missed dose. Skip the missed dose and continue with the next scheduled dose. Do not double doses.

If ADVICOR therapy is discontinued for an extended period (>7 days), reinstitution of therapy should begin with the lowest dose of ADVICOR.

Overdosage

Supportive measures should be undertaken in the event of an overdose of ADVICOR. Monitor liver function and initiate appropriate therapy if required.

Action and Clinical Pharmacology

Mechanism of Action

Niacin

The mechanism by which niacin alters lipid profiles has not been well defined. It 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 and LDL, 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.

Pharmacodynamics

Epidemiologic, clinical and experimental studies have established that high LDL cholesterol (LDL-C), low High Density Lipoprotein cholesterol (HDL-C) and high plasma triglycerides (TG) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Increased levels of HDL-C are associated with decreased cardiovascular risk.

ADVICOR

ADVICOR reduces LDL-C, TC, TG, Lp(a), Apo B, TC:HDL and LDL:HDL, and increases HDL-C and Apo A-1 due to the individual actions of extended-release 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 TC, LDL-C, Apo B, Lp(a) and TG, and increases HDL-C. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. 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 particle containing only Apo A-I). Niacin treatment also decreases serum levels of Apo B, the major protein component of the VLDL and LDL fractions, and of lipoprotein a (Lp(a)), a variant form of LDL independently associated with coronary risk.

In addition, niacin preparations (including extended-release niacin) have been shown to cause favourable transformations in LDL particle size subclass distribution, converting the pattern B phenotype (characterised by a predominance of triglyceride-rich, small dense LDL) to pattern A (characterised by a predominance of large buoyant LDL) or the intermediate AB phenotype. Pattern B LDL phenotype is one manifestation of what has been termed the Atherogenic Lipoprotein Profile (ALP), a Mendelian dominant inherited condition which also includes low levels of HDL-C, raised triglyceride, and insulin resistance.

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 LDLC 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 slightly increase HDL-C, and modestly reduce VLDL-C and plasma TG.

Pharmacokinetics

Absorption

ADVICOR

In single-dose studies of ADVICOR, rate and extent of niacin and lovastatin absorption were bioequivalent under fed conditions to that from NIASPAN (extended-release niacin) and lovastatin given alone. After administration of two ADVICOR 1000/20 mg tablets, approximately 72% of the niacin dose was absorbed as measured by the recovery of niacin and its metabolites in the urine, with peak concentrations of nicotinuric acid in plasma averaging approximately 18 μg/ml and occurring about 5 hours after dosing.

The extent of niacin absorption from ADVICOR was increased by administration with food. The administration of two ADVICOR 1000/20 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.

Following the administration of a single dose of 1000 mg extended-release niacin and 40 mg lovastatin as the 1000/40 mg ADVICOR tablet formulation versus two 500/20 mg ADVICOR tablets the pharmacokinetic profiles of niacin and its metabolites are different. As a result, ADVICOR tablets of different strengths are not interchangeable.

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 lovastatin 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 lovastatin.

Distribution

Niacin

Niacin is less than 20% bound to serum proteins and distribute into milk. Studies using radiolabeled niacin in mice showed 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 dyslipidaemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of NAD. It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans.

Lovastatin

Lovastatin undergoes extensive first-pass extraction and metabolism by cytochrome P450 3A4 in the liver, its primary site of action. The major active metabolites present in human plasma are the beta-hydroxyacid of lovastatin (lovastatin acid), its 6'-hydroxy derivative, and two additional metabolites.

Excretion

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 lovastatin. 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 and Conditions

Pediatrics

No studies in patients under 18 years of age have been conducted with ADVICOR.

Geriatrics

In patients who received ADVICOR in double blind and open label studies, responses in LDL-C, HDL-C and TG were similar in younger patients and patients over 65 years of age and older. No overall differences were observed in selected chemistry values between the two groups, except for serum amylase which was higher in older patients.

Sex

Steady-state plasma concentrations of niacin and metabolites after administration of niacin are generally higher in women than in men. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both sexes. Data from the clinical trials suggest that women have a greater hypolipidaemic response than men at equivalent doses of NIASPAN and ADVICOR.

Hepatic Insufficiency

No studies have been performed in patients with hepatic insufficiency (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Renal Insufficiency

There are no data available on the use of ADVICOR in patients with impaired renal function (see WARNINGS AND PRECAUTIONS).

Storage and Stability

Temperature

Store at room temperature (15 to 30°C).

Other

Keep in a safe place out of the reach of children.

Dosage Forms, Composition and Packaging

ADVICOR is an unscored, capsule-shaped tablet containing 500, 750 or 1000 mg of niacin in an extended-release formulation and 20 or 40 mg of lovastatin in an immediate-release formulation. Tablets are colour-coated with the tablet strength code debossed on one side. ADVICOR 500/20 mg tablets are light yellow and debossed ‘502' on one side. ADVICOR 750/20 mg tablets are light orange and debossed ‘752’ on one side. ADVICOR 1000/20 mg tablets are dark pink/light purple and debossed ‘1002' on one side. ADVICOR 1000/40 mg tablets are reddish-brown/brown tablets and debossed ‘1004’ on one side. Tablets are supplied in bottles of 90 tablets. The 500/20 mg tablet strength is also supplied in a 3 tablet blister-pack.

ADVICOR contains the following non-medicinal ingredients: FD&C yellow No 615 (750/20 tablets only), hydroxypropyl methylcellulose, iron oxide yellow (500/20 and 1000/20 tablets only), iron oxide red (500/20, 1000/20 and 1000/40 tablets only), iron oxide black (1000/20 tablets only), macrogol, povidone, polyethylene glycol, polysorbate 80 (500/20, 750/20 and 1000/20 tablets only), stearic acid, and titanium dioxide.