Indications And Usage

Atorvastatin is indicated for the treatment of several types of dyslipidemias, including primary hyperlipidemia and mixed dyslipidemia in adults, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications.

Dyslipidemia describes an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis.

Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles.

Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors and in patients with type 2 diabetes without coronary heart disease but multiple risk factors.

Atorvastatin may be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease.

Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.

Administration

Hyperlipidemia and Mixed Dyslipidemia:

The recommended starting dose of Atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of Atorvastatin should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of Atorvastatin, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to17 Years of Age):

The recommended starting dose of Atorvastatin is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.

Homozygous Familial Hypercholesterolemia:

The dosage of Atorvastatin in patients with HoFH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Concomitant Lipid-Lowering Therapy:

Atorvastatin may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution.

Dosage in Patients with Renal Impairment:

Renal disease does not affect the plasma concentrations nor LDL-C reduction of Atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary

Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors:

In patients taking cyclosporine or the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir or letermovir when co-administered with cyclosporine, therapy with Atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of Atorvastatin. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir or letermovir therapy with Atorvastatin should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atorvastatin is used. In patients taking the HIV protease inhibitor nelfinavir therapy with Atorvastatin should be limited to 40 mg. When co-prescribing atorvastatin with other protease inhibitors, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atorvastatin is used

Contraindications

Hypersensitivity to atorvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases.

Concurrent therapy with cyclosporine or glecaprevir/pibrentasvir

Precautions

Diabetes mellitus: Increases in HbA_1c and fasting blood glucose have been reported.

• Hepatotoxicity: Persistent elevations in serum transaminases have been reported; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Postmarketing reports of fatal and nonfatal hepatic failure have been reported and are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly. If an alternate etiology is not identified, do not restart atorvastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated and if signs/symptoms of liver injury occur. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

Myopathy/rhabdomyolysis: Rhabdomyolysis with acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of strong CYP3A4 inhibitors; if concurrent use is warranted, consider lower starting and maintenance doses of atorvastatin. Use caution in patients with inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase inhibitors use has also been reported. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.

Disease-related concerns:

• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease; use is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases.
• Renal impairment: Use with caution in patients with renal impairment; these patients are predisposed to myopathy.
• Stroke: Patients with recent stroke or TIA receiving long-term therapy with high-dose (ie, 80 mg/day) atorvastatin may be at increased risk for hemorrhagic stroke (SPARCL Investigators .A subsequent post-hoc analysis demonstrated that patients with lacunar or hemorrhagic stroke may be at higher risk of hemorrhagic stroke; however, this finding was determined to be hypothesis generating. The overall benefit of treatment with atorvastatin (ie, reduced risk of stroke and cardiovascular events) in this population seems to outweigh the increased risk of hemorrhagic stroke if one truly exists

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in patients with advanced age, these patients are predisposed to myopathy.

Other warnings/precautions:

• Appropriate use: Secondary causes of hyperlipidemia should be ruled out prior to therap

Adverse Reactions

>10%

Gastrointestinal: Diarrhea (7% to 14%)

Neuromuscular & skeletal: Arthralgia (9% to 12%)

Respiratory: Nasopharyngitis (13%)

1% to 10%:

Cardiovascular: Hemorrhagic stroke (2%)

Central nervous system: Insomnia (5%), malaise (<2%), nightmares (<2%)

Dermatologic: Urticaria (<2%)

Endocrine & metabolic: Diabetes mellitus (6%), hyperglycemia (<2%)

Gastrointestinal: Nausea (7%), dyspepsia (6%), abdominal distress (<2%), cholestasis (<2%), eructation (<2%), flatulence (<2%)

Genitourinary: Urinary tract infection (7% to 8%), urine abnormality (white blood cells positive in urine: <2%)

Hepatic: Increased serum transaminases (≤2%), abnormal hepatic function tests (<2%), hepatitis (<2%), increased serum alkaline phosphatase (<2%)

Neuromuscular & skeletal: Limb pain (9%), myalgia (4% to 8%), musculoskeletal pain (5%), muscle spasm (4% to 5%), increased creatine phosphokinase (<2%), joint swelling (<2%), muscle fatigue (<2%), neck pain (<2%)

Ophthalmic: Blurred vision (<2%)

Otic: Tinnitus (<2%)

Respiratory: Pharyngolaryngeal pain (3% to 4%), epistaxis (<2%)

Miscellaneous: Fever (<2%)

Frequency not defined: Central nervous system: Myasthenia

<1%

postmarketing, and/or case reports: Abdominal pain, alopecia, amnesia (reversible), anaphylaxis, anemia, angioedema, anorexia, back pain, bullous rash, chest pain, cognitive dysfunction (reversible), confusion (reversible), cystitis, depression, dizziness, dysgeusia, elevated glycosylated hemoglobin (HbA_1c), erythema multiforme, fatigue, gynecomastia, hepatic failure, hypoesthesia, increased serum glucose, interstitial pulmonary disease, jaundice, memory impairment (reversible), myopathy, myositis, pancreatitis, paresthesia, peripheral edema, peripheral neuropathy, pruritus, rhabdomyolysis, rupture of tendon, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, vomiting, weight gain

Pregnancy and lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned

Renal and liver Impairment

Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease; use is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases.

• Renal impairment: Use with caution in patients with renal impairment; these patients are predisposed to myopathy.

Laboratory Tests

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Grundy 2019]; ACC/AHA [Stone 2014]):

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Lipid profile (fasting or nonfasting) before initiating treatment. Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.

Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (AST and ALT); measure AST, ALT, total bilirubin, and alkaline phosphatase if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.

CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).

Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.

If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.