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General: Before instituting therapy with atorvastatin calcium, an attempt should be made to control elevated serum lipoprotein levels with appropriate diet, exercise and weight reduction in overweight patients, and to treat other underlying medical problems (see Indications). Patients should be advised to inform subsequent physicians of the prior use of atorvastatin or any other lipid-lowering agents.
Pharmacokinetic Interactions: The use of HMG-CoA reductase inhibitors has been associated with severe myopathy including rhabdomyolysis which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P-450 (CYP450) enzyme system. Atorvastatin is metabolized by CYP450 isoform 3A4 (CYP3A4) and as such may interact with agents that inhibit this enzyme (see Muscle effects as follows and Interactions).
Muscle Effects: Effects on skeletal muscle eg, myalgia, myopathy and rarely, rhabdomyolysis have been reported in patients treated with atorvastatin.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobulinuria have been reported with atorvastatin 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 >10 x ULN, 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. Atorvastatin therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.
Pre-Disposing Factors for Myopathy/Rhabdomyolysis: Atorvastatin, 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 >65 years, renal and hepatic impairment, diabetes with hepatic fatty change, surgery and trauma, frailty and situations where an increase in plasma levels of atorvastatin calcium may occur.
The risk of myopathy and rhabdomyolysis during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of drugs that interfere with metabolism of atorvastatin via CYP3A4 eg, cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals or nefazodone. Concomitant use of strong inhibitors of CYP3A4 with atorvastatin should be used with caution. If such use must be instituted, lower starting and maintenance doses of atorvastatin should be considered and patients should be monitored closely for musculoskeletal effects (see Pharmacology: Pharmacokinetics under Actions, Pharmacokinetic Interactions as previously mentioned and Interactions).
In cases where co-administration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg. Temporary suspension of atorvastatin during fusidic acid therapy is recommended (see Interactions).
Although patients with renal impairment are known to be predisposed to the development of rhabdomyolysis with administration of HMG-CoA reductase inhibitors (also known as statins), those with a history of renal impairment may also be predisposed to the development of rhabdomyolysis. Such patients merit close monitoring for skeletal muscle effects.
Atorvastatin 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 (eg, sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Atorvastatin therapy should be discontinued if markedly elevated creatine phosphokinase (CPK) levels occur or myopathy is diagnosed or suspected.
Cardiovascular: Hemorrhagic Stroke in Patients with Recent Stroke or Transient Ischemic Attack (TIA): A post hoc analysis of a clinical study in 4,731 patients without CHD who had a stroke or TIA with in the preceding 6 months revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80 mg group compared to placebo. Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke. The potential risk of hemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients with recent (1-6 months) stroke or TIA.
Effect on Ubiquinone (CoQ10) Levels: 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.
Endocrine and Metabolism: Endocrine Function: 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 (eg, ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.
Effect on Lipoprotein (a): In some patients, the beneficial effect of lowered total-C 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 CHD. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy.
Patients with Severe Hypercholesterolemia: 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 with digoxin or CYP3A4 inhibitors (see Dosage & Administration, Pharmacokinetic Interactions and Muscle Effects as previously mentioned and Interactions).
Hepatic/Biliary/Pancreatic: Hepatic Effects: In clinical trials, persistent increases in serum transaminases >3 x ULN occurred in <1% of patients who received atorvastatin. When the dosage of atorvastatin 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 atorvastatin 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 >3 x ULN and are persistent, the dosage should be reduced or the drug should be discontinued.
Atorvastatin, 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 atorvastatin; if such a condition should develop during therapy, the drug should be discontinued.
Ophthalmologic: Effect on the Lens: Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.
Renal: Renal Insufficiency: Plasma concentrations and LDL-C lowering efficacy of atorvastatin 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 atorvastatin should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [CrCl <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see Muscle Effects as previously mentioned and Interactions). Refer also to Dosage & Administration.
Sensitivity/Resistance: Hypersensitivity: An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included ≥1 of the following features: Anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibodies (ANA), increase erythrocyte sedimentation rate (ESR), 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, atorvastatin should be discontinued if hypersensitivity is suspected.
Use in lactation: 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 atorvastatin should not breastfeed.
Use in children: Safety and effectiveness of atorvastatin in patients 10-17 years (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 atorvastatin had a safety and tolerability profile generally similar to that of placebo. Doses >20 mg have not been studied in this patient population.
Safety and effectiveness of atorvastatin in pediatric patients has not been determined in the prevention of myocardial infarction.
Atorvastatin had no effect on growth or sexual maturation in boys and in girls. The effects on menstrual cycle were not assessed (see Pharmacology: Pharmacodynamics under Actions, Dosage & Administration and Adverse Reactions).
Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy (see Contraindications). Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients <10 years.
Doses of atorvastatin up to 80 mg/day for 1 year have been evaluated in 8 pediatric patients with homozygous familial hypercholesterolemia (see Pharmacology: Pharmacodynamics under Actions).
Use in the elderly: Treatment experience in adults ≥70 years (N=221) with doses of atorvastatin 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. Pharmacokinetic evaluation of atorvastatin in subjects >65 years indicates an increased AUC. As a precautionary measure, the lowest dose should be administered initially (see Pharmacology: Pharmacokinetics under Actions).
Elderly patients may be more susceptible to myopathy (see Muscle Effects: Predisposing Factors for Myopathy/Rhabdomyolysis as previously mentioned).
