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The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are coadministered with drugs that inhibit the cytochrome P-450 enzyme system. Atorvastatin is metabolized by cytochrome P-450 isoform 3A4 and as such may interact with agents that inhibit this enzyme. (See Warnings and Precautions, Muscle Effects, and Drug Interactions.)

Effects on skeletal muscle such as myalgia, myopathy and very rarely, rhabdomyolysis have been reported in patients treated with LIPITOR.

Very rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria, have been reported with LIPITOR and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. LIPITOR therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

LIPITOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: personal or family history of hereditary muscular disorders; previous history of muscle toxicity with another HMG-CoA reductase inhibitor; concomitant use of a fibrate, or niacin; hypothyroidism; alcohol abuse; excessive physical exercise; age >70 years; renal impairment; hepatic impairment; diabetes with hepatic fatty change; surgery and trauma; frailty; situations where an increase in plasma levels of active ingredient may occur.

LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (such as sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals or nefazodone. As there is no experience to date with the use of LIPITOR given concurrently with these drugs, with the exception of pharmacokinetic studies conducted in healthy subjects with erythromycin and clarithromycin, the benefits and risks of such combined therapy should be carefully considered.

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

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

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

In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy.

Higher drug dosages (80 mg/day) required for some patients with severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of atorvastatin. Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see Warnings and Precautions, Pharmacokinetic Interactions, Muscle Effects; Drug Interactions; Dosage and Administration).

In clinical trials, persistent increases in serum transaminases greater than three times the upper limit of normal occurred in <1% of patients who received LIPITOR. When the dosage of LIPITOR was reduced, or when drug treatment was interrupted or discontinued, serum transaminase levels returned to pretreatment levels. The increases were generally not associated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a reduced dose of LIPITOR without clinical sequelae.

Liver function tests should be performed before the initiation of treatment, and periodically thereafter. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients measurements should be repeated promptly and then performed more frequently.

If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to greater than 3 times the upper limit of normal and are persistent, the dosage should be reduced or the drug discontinued.

LIPITOR, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of LIPITOR; if such a condition should develop during therapy, the drug should be discontinued.

Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.

Plasma concentrations and LDL-C lowering efficacy of LIPITOR was shown to be similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see Warnings and Precautions, Muscle Effects; Drug Interactions). Refer also to Dosage and Administration.

An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included 1 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. Although to date hypersensitivity syndrome has not been described as such, LIPITOR should be discontinued if hypersensitivity is suspected.

LIPITOR is contraindicated during pregnancy (see Contraindications).

There are no data on the use of LIPITOR during pregnancy. LIPITOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking LIPITOR, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking LIPITOR should not breast-feed (see Contraindications).

Safety and effectiveness of LIPITOR in patients 10-17 years of age (N=140) with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had a safety and tolerability profile generally similar to that of placebo. Doses greater than 20 mg have not been studied in this patient population.

LIPITOR had no effect on growth or sexual maturation in boys and in girls. The effects on menstrual cycle were not assessed (see Adverse Reactions, Pediatrics Patients; and Dosage and Administration for Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)).

Adolescent females should be counselled on appropriate contraceptive methods while on LIPITOR therapy (see Contraindications and Warnings and Precautions, Pregnant Women). LIPITOR has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.

Doses of LIPITOR up to 80 mg/day for 1 year have been evaluated in 8 pediatric patients with homozygous familial hypercholesterolemia.

Treatment experience in adults 70 years or older (N=221) with doses of LIPITOR up to 80 mg/day has demonstrated that the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age. Pharmacokinetic evaluation of atorvastatin in subjects over the age of 65 years indicates an increased AUC. As a precautionary measure, the lowest dose should be administered initially.

LIPITOR is generally well-tolerated. Adverse reactions have usually been mild and transient. In controlled clinical studies (placebo-controlled and active-controlled comparative studies with other lipid lowering agents) involving 2502 patients, <2% of patients were discontinued due to adverse experiences attributable to LIPITOR. Of these 2502 patients, 1721 were treated for at least 6 months and 1253 for 1 year or more.

Adverse experiences occurring at an incidence ≥1% in patients participating in placebo-controlled clinical studies of LIPITOR and reported to be possibly, probably or definitely drug related