Advicor Side Effects

Please note - some side effects for Advicor may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Advicor - for the Consumer

Advicor

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Advicor:

Back pain; chills; constipation; diarrhea; fainting; flu syndrome; flushing (itching, redness, tingling, warmth); gas; headache; increased heartbeat; indigestion; infection (fever, sore throat); itching; muscle aches; nausea; pain; pounding in the chest; rash; shortness of breath; stomach upset; sweating; swelling; vomiting; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry, or bloody stools; change in amount of urine; change in taste; chest pain; dark urine; dizziness; increased thirst; joint pain; muscle pain, tenderness, or weakness (especially if associated with fever and a general feeling of discomfort); numbness or persistent tingling of the skin; stomach pain; swelling of the hands, legs, or feet; unusual tiredness/fatigue; vomit that looks like coffee grounds; yellowing eyes or skin.

Advicor Side Effects - for the Professional

Advicor

Overview

In controlled clinical studies, 40/214 (19%) of patients randomized to Advicor discontinued therapy prior to study completion. Of the 214 patients enrolled 18 (8%) discontinued due to flushing. In the same controlled studies, 9/94 (10%) of patients randomized to lovastatin and 19/92 (21%) of patients randomized to NIASPAN also discontinued treatment prior to study completion secondary to adverse events. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events, and occurred in 53% to 83% of patients treated with Advicor. Spontaneous reports with NIASPAN and clinical studies with Advicor suggest that flushing may also be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, chills, and/or edema.

Adverse Reactions Information

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

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

In addition to flushing, other adverse events occurring in 5% or greater of patients treated with Advicor are shown in Table 8 below.

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.

Clinical Laboratory Abnormalities

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

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

Side Effects by Body System

Musculoskeletal

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

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

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

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

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

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

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

Dermatologic

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

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

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

Endocrine

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

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

Gastrointestinal

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

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

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

Cardiovascular

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

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

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

Genitourinary

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

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

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

Hematologic

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

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

Hypersensitivity

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

Hepatic

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

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

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

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

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

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

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

Immunologic

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

Metabolic

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

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

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

Nervous system

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

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

Ocular

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

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

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

Psychiatric

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

Renal

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

Other

Other side effects associated with the administration of lovastatin-niacin have included headache, back pain, and migraine. Fatigue has been reported in postmarketing experience with lovastatin.

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