Atorvastatin

Pronunciation

(a TORE va sta tin)

U.S. Brand Names

Lipitor®

Generic Available

Canadian Brand Names

Lipitor®

Use

Primary prevention of CVD in high-risk patients

Used with dietary therapy for the following:

Hyperlipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with primary hypercholesterolemia (elevations of 1 or more components are present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias)

Treatment of homozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH): In adolescent patients (10-17 years of age, females >1 year postmenarche) with HeFH having LDL-C 190 mg/dL or LDL 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with 2 or more CVD risk factors in the adolescent patient

Pregnancy Risk Factor

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to atorvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy; breast-feeding

Warnings/Precautions

Secondary causes of hyperlipidemia should be ruled out prior to therapy. Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses

1 g/day) or during concurrent use with potent CYP3A4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors such as indinavir, nelfinavir, or ritonavir). Weigh the risk versus benefit when combining any of these drugs with atorvastatin. Discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis. Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Safety and efficacy have not been established in patients <10 years or in premenarcheal girls.

Adverse Reactions

>10%: Central nervous system: Headache (3% to 17%)

2% to 10%:

Cardiovascular: Chest pain, peripheral edema

Central nervous system: Insomnia, dizziness

Dermatologic: Rash (1% to 4%)

Gastrointestinal: Abdominal pain (up to 4%), constipation (up to 3%), diarrhea (up to 4%), dyspepsia (1% to 3%), flatulence (1% to 3%), nausea

Genitourinary: Urinary tract infection

Hepatic: Transaminases increased (2% to 3% with 80 mg/day dosing)

Neuromuscular & skeletal: Arthralgia (up to 5%), arthritis, back pain (up to 4%), myalgia (up to 6%), weakness (up to 4%)

Respiratory: Sinusitis (up to 6%), pharyngitis (up to 3%), bronchitis, rhinitis

Miscellaneous: Infection (3% to 10%), flu-like syndrome (up to 3%), allergic reaction (up to 3%)

<2% (Limited to important or life-threatening): Abnormal dreams, acne, alopecia, amblyopia, anemia, angina, anorexia, appetite increased, arrhythmia, biliary pain, bursitis, cheilitis, cholestatic jaundice, colitis, cystitis, deafness, depression, dry skin, dry eyes, duodenal ulcer, dysphagia, dyspnea, dysuria, ecchymosis, eczema, edema, emotional lability, enteritis, epididymitis, epistaxis, eructation, esophagitis, eye hemorrhage, facial edema, facial paralysis, fever, fibrocystic breast disease, gastritis, gastroenteritis, gingival hemorrhage, glaucoma, glossitis, gout, hematuria, hepatitis, hypesthesia, hyperglycemia, hyperkinesia, hypertension, hypertonia, hypoglycemia, impotence, incoordination, kidney calculus, leg cramps, libido decreased, lymphadenopathy, malaise, melena, metrorrhagia, migraine, mouth ulcer, myasthenia, myopathy, myositis, neck rigidity, nephritis, nocturia, palpitation, pancreatitis, paresthesia, parosmia, peripheral neuropathy, petechiae, pharyngitis, phlebitis, photosensitivity, pneumonia, postural hypotension, pruritus, rectal hemorrhage, rhinitis, seborrhea, skin ulcer, somnolence, stomatitis, syncope, taste loss, taste perversion, tendinous contracture, tenesmus, thrombocytopenia, tinnitus, torticollis, transaminases increased (dose related), urticaria, vaginal hemorrhage, vasodilation, vomiting, weight gain, xerostomia

Postmarketing reports: Anaphylaxis, angioneurotic edema, bullous rash, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, rhabdomyolysis

Additional class-related events or case reports (not necessarily reported with atorvastatin therapy): Alkaline phosphatase increased, alopecia, anaphylaxis, angioedema, anorexia, anxiety, arthritis, cataracts, chills, cholestatic jaundice, cirrhosis, CPK increased (>10x normal), depression, dermatomyositis, dryness of skin/mucous membranes, dyspnea, eosinophilia, erectile dysfunction, erythema multiforme, ESR increased, extraocular muscle movement impaired, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, GGT increased, gynecomastia, hemolytic anemia, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity reaction, impotence, leukopenia, libido decreased, malaise, memory loss, myopathy, nail changes, nodules, ophthalmoplegia, pancreatitis, paresthesia, peripheral nerve palsy, peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, psychic disturbance, purpura, rash, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, skin discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome, taste alteration, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased, tremor, urticaria, vasculitis, vertigo, vomiting

Overdosage/Toxicology

Treatment is supportive.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

Antacids: Plasma concentrations may be decreased when given with magnesium-aluminum hydroxide containing antacids (reported with atorvastatin and pravastatin). Clinical efficacy is not altered, no dosage adjustment is necessary

Cholestyramine and colestipol (bile acid sequestrants): Reduce absorption of several HMG-CoA reductase inhibitors; separate administration times by at least 4 hours. Cholesterol-lowering effects are additive.

Clofibrate and fenofibrate may increase the risk of myopathy and rhabdomyolysis.

CYP3A4 inhibitors: May increase the levels/effects of atorvastatin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Digoxin: Plasma concentrations of digoxin may be increased by ~20%; monitor.

Grapefruit juice: May inhibit metabolism of atorvastatin via CYP3A4; more likely to occur with lovastatin or simvastatin; avoid high dietary intake of grapefruit juice

Niacin may increase the risk of myopathy and rhabdomyolysis.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid excessive ethanol consumption (due to potential hepatic effects).

Food: Atorvastatin serum concentrations may be increased by grapefruit juice; avoid concurrent intake of large quantities (>1 quart/day).

Herb/Nutraceutical: St John's wort may decrease atorvastatin levels.

Mechanism of Action

Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism

Pharmacodynamics/Kinetics

Onset of action: Initial changes: 3-5 days; Maximal reduction in plasma cholesterol and triglycerides: 2 weeks

Absorption: Rapid

Protein binding: 98%

Metabolism: Hepatic; forms active ortho- and parahydroxylated derivates and an inactive beta-oxidation product

Half-life elimination: Parent drug: 14 hours

Time to peak, serum: 1-2 hours

Excretion: Bile; urine (2% as unchanged drug)

Dosage

Oral: Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 2-4 weeks

Children 10-17 years (females >1 year postmenarche): HeFH: 10 mg once daily (maximum: 20 mg/day)

Adults:

Hyperlipidemias: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; range: 10-80 mg once daily

Primary prevention of CVD: 10 mg once daily

Dosing adjustment in renal impairment: No dosage adjustment is necessary.

Dosing adjustment in hepatic impairment: Do not use in active liver disease.

Administration

May be administered with food if desired; may take without regard to time of day

Monitoring Parameters

Lipid levels after 2-4 weeks; LFTs, CPK

It is recommended that liver function tests (LFTs) be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter

Dietary Considerations

May take with food if desired; may take without regard to time of day. Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. May take without regard to food. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You will need laboratory evaluation during therapy. May cause headache (consult prescriber for approved analgesic); diarrhea (buttermilk, boiled milk, or yogurt may help); euphoria, giddiness, or confusion (use caution when driving or engaging in tasks that require alertness until response to medication is known). Report unresolved diarrhea, unusual muscle cramping or weakness, changes in mood or memory, yellowing of skin or eyes, easy bruising or bleeding, or unusual fatigue. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during therapy. Consult prescriber for instructions on appropriate contraceptive measures. This drug can cause severe fetal defects. Do not donate blood while taking this medication and for same period of time after discontinuing. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations

Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years), gender (occurs in women more frequently than men), small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery) , and drug interactions (use with caution or avoid).

Cardiovascular Considerations

HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (

2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (ie, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html (last accessed July 3, 2003). LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.

Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (Sever PS, 2003), patients with HTN and at least 3 other risk factors were randomized to 10 mg daily of atorvastatin or placebo. These patients had a total nonfasting cholesterol below 250 mg/dL before treatment. LDL-C levels were 132 mg/dL before treatment and fell to an average of 90 mg/dL in the atorvastatin-treated group. There was a significant reduction in stroke, cardiovascular events and coronary events in the atorvastatin-treated group as compared to the placebo group. There was no difference in mortality between the groups.

Secondary prevention trials indicate that "statin" therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations. PROVE IT is a randomized, double-blind trial evaluating hospitalized patients with acute coronary syndrome to determine the effects of intense LDL-C lowering therapy. Four thousand patients with an LDL-C levels of 106 mg/dL were randomized to pravastatin 40 mg daily or atorvastatin 80 mg daily. After 2 years, the combined cardiovascular endpoint (death, MI, unstable angina requiring hospitalization, revascularization and stroke) was ~26% in the pravastatin patients (median LDL-C 95 mg/dL) and ~22% in the atorvastatin treated patients (median LDL-C 62 mg/dL).

HMG-CoA reductase inhibitors decrease levels of high-sensitivity C-reactive protein (hs-CRP). They also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus S, 2002).

Myopathy: Currently marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, perioperative periods (higher risk when continued during hospitalization for major surgery), drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Rare reports of euphoria

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Tablet: 10 mg, 20 mg, 40 mg, 80 mg

References

de Denus S and Spinler SA, "Early Statin Therapy for Acute Coronary Syndromes," Ann Pharmacother , 2002, 36(11):1749-58.

Cannon CP, Braunwald E, McCabe CH, et al, "Intensive Versus Moderate Lipid Lowering With Statins After Acute Coronary Syndromes. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators," N Engl J Med , 2004, 350(15):1495-504.

"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)," JAMA , 2001, 285(19):2486-97.

Fonarow GC, French WJ, Parsons LS, et al, "Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction: Data From the National Registry of Myocardial Infarction 3," Circulation , 2001, 103(1):38-44.

Grundy SM, Cleeman JI, Merz CN, et al, "Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines," J Am Coll Cardiol , 2004, 44(3):720-32.

Koren MJ, Smith DG, Hunninghake DB, et al, "The Cost of Reaching National Cholesterol Education Program (NCEP) Goals in Hypercholesterolaemic Patients. A Comparison of Atorvastatin, Simvastatin, Lovastatin and Fluvastatin," Pharmacoeconomics , 1998, 14(1):59-70.

"MRC/BHF Heart Protection Study of Cholesterol Lowering With Simvastatin in 20,536 High-Risk Individuals: A Randomised Placebo-Controlled Trial. Heart Protection Study Collaborative Group," Lancet , 2002, 360(9326):7-22.

Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al, "ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins," Stroke , 2002, 33(9):2337-41. Available at: http://www.acc.org/clinical/alerts/statins_june02.htm. Accessed June 18, 2003.

Pearson TA, Mensah GA, Alexander RW, et al, "Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association," Circulation , 2003, 107(3):499-511.

Phillips BG, Yim JM, Brown EJ Jr, et al, "Pharmacologic Profile of Survivors of Acute Myocardial Infarction at United States Academic Hospitals," Am Heart J , 1996, 131(5):872-8.

Pitt B, Waters D, Brown WV, et al, "Aggressive Lipid-Lowering Therapy Compared With Angioplasty in Stable Coronary Artery Disease. Atorvastatin Versus Revascularization Treatment Investigators," N Engl J Med , 1999, 341(2):70-6.

Sever PS, Dahlof B, Poulter NR, et al, "Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial," Lancet , 2003, 361(9364):1149-58.

Shepherd J, Cobbe SM, Ford I, et al, "Prevention of Coronary Heart Disease With Pravastatin in Men With Hypercholesterolemia. West of Scotland Coronary Prevention Study Group," N Engl J Med , 1995, 333(20):1301-7.

International Brand Names

Ampliar® (AR); Atarva® (AR); Ateroclar® (AR); Atoris® (PL, SI); Atorlip® (CO); Atorsyn® (CO); Ator® (TR); Atorva® (IN); Atorvastan® (AR); Atorvastatina MK® (CO); Atorvastatin® (NO); Atovarol® (CO); Axo® (CO); Cardyl® (ES); Citalor® (BR); Edy® (CO); Farmalip® (CO); Glustar® (CO); Liparex® (AR); Lipibec® (AR); Lipicare® (CO); Lipifen® (AR); Lipitor® (AR, AU, BE, BR, CA, CL, CO, CY, EG, FI, GB, ID, IE, IL, IT, JO, KW, LB, MX, NL, NO, NZ, SE, SG, TH, TR, ZA); Lipocambi® (AR); Lipotropic® (CL); Liprimar® (RU); Lowlipen® (CO); Normalip® (AR); Prevencor® (ES); Sortis® (AT, CH, CZ, DE, HR, HU, PL, RO, SI, YU); Sortis Orifarm® (DK); Tahor® (FR); Torivas® (AR); Torvast® (IT); Totalip® (IT); Tulip® (HR, PL, SI); Xarator® (IT); Zarasterol "Paranova"® (DK); Zarator® (AR, CL, DK, ES, PT)

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