Advicor

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).

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.

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

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.

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.

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).

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.

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

Interactions with herbal products have not been studied.

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

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

Concomitant administration of ASA may decrease the metabolic clearance of niacin (see Warnings and Precautions, General).

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

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).

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).

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.

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 dose.

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

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.

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.

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

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.

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 >3×ULN was 0.24%, increases in CK >5×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 post-marketing 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.

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.

toxic amblyopia; cystoid macular edema; ophthalmoplegia; eye irritation.

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.

migraine.

face edema; peripheral chest pain; abdominal pain; generalized edema; chills; malaise.

dyspnea; rhinitis.

gout.

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

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

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.

muscle cramps; myopathy; rhabdomyolysis; arthralgia; myasthenia.

gynecomastia; loss of libido; erectile dysfunction.

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.

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).

dizziness; insomnia; dry mouth; paresthesia; anxiety; tremor; vertigo; memory loss; peripheral neuropathy; psychic disturbances; dysfunction of certain cranial nerves, leg cramps; nervousness.

atrial fibrillation; tachycardia; palpitations, and other cardiac arrhythmias; orthostasis; hypotension; syncope.

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

Each reddish-brown/ brown, unscored, capsule-shaped tablet, debossed “1004” on one side, contains: 1000 mg niacin in an extended-release formulation and 40 mg lovastatin in an immediate-release formulation. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide red, macrogol, polyethylene glycol, povidone, stearic acid and titanium dioxide. Bottles of 90.

Each dark pink/light purple, unscored, capsule-shaped tablet, debossed “1002” on one side, contains: 1000 mg niacin in an extended-release formulation and 20 mg lovastatin in an immediate-release formulation. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide black, iron oxide red, iron oxide yellow, macrogol, polyethylene glycol, polysorbate 80, povidone, stearic acid and titanium dioxide. Bottles of 90.

Each light orange, unscored, capsule-shaped tablet, debossed “752” on one side, contains: 750 mg niacin in an extended-release formulation and 20 mg lovastatin in an immediate-release formulation. Nonmedicinal ingredients: FD&C yellow No 615, hydroxypropyl methylcellulose, macrogol, polyethylene glycol, polysorbate 80, povidone, stearic acid and titanium dioxide. Bottles of 90.

Each light yellow, unscored, capsule-shaped tablet, debossed “502” on one side, contains: 500 mg niacin in an extended-release formulation and 20 mg lovastatin in an immediate-release formulation. Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, macrogol, polyethylene glycol, polysorbate 80, povidone, stearic acid and titanium dioxide. Bottles of 90. Blister-packs of 3.

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.

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

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

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.

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.

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.

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.

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.

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.

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 1145 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.

Extended-release niacin tablets have been associated with small, but statistically significant dose-related 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×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.

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.

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×TG)+HDL-C]

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

For patients with TG levels >4.52 mmol/L (>400 mg/dL), this equation is less accurate and LDL-C 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 immediate release (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).

Liver tests should be performed on all patients during therapy with ADVICOR. Serum transaminase levels, including AST and ALT, 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.

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.

Use of ADVICOR in nursing mothers is contraindicated (see Contraindications and Warnings and Precautions, Serious Warnings and Precautions).

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.

No studies have been performed in patients with hepatic insufficiency (see Contraindications and Warnings and Precautions, Hepatic/Biliary/Pancreatic).

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.

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.

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.

There are no data available on the use of ADVICOR in patients with impaired renal function (see Warnings and Precautions).

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.

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.

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.

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