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Dosage and Administration

General

• Patients should be placed on a standard lipid-lowering diet before initiation of atorvastatin therapy and should remain on this diet during treatment with the drug.

Monitoring during Antilipemic Therapy

• Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

Administration

Oral Administration

Administer orally at any time of day without regard to meals.

Dosage

Available as atorvastatin calcium; dosage expressed in terms of atorvastatin. Also available in fixed combination with amlodipine besylate (Caduet^®).

Pediatric Patients

Dyslipidemias

Oral

Children ≥10 years of age: Initially, 10 mg once daily.

Adjust dosage at intervals ≥4 weeks until the desired effect on lipoprotein concentrations is observed or a daily dosage of 20 mg is reached.

Adults

Dyslipidemias and Prevention of Cardiovascular Events

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

Initially, 10 or 20 mg once daily; patients who require a large reduction in LDL-cholesterol concentration (>45%) may receive 40 mg once daily. Determine serum lipoprotein concentrations within 2–4 weeks after initiating and/or titrating therapy and adjust dosage accordingly. Usual maintenance dosage is 10–80 mg once daily.

Atorvastatin/amlodipine fixed combination (Caduet^®): Use as a substitute for individually titrated drugs; to provide additional therapy for patients currently receiving one component of the preparation; or to initiate treatment in patients with dyslipidemias who have hypertension and/or CAD.

Homozygous Familial Hypercholesterolemia

Oral

10–80 mg once daily.

Prescribing Limits

Pediatric Patients

Oral

Children ≥10 years of age: Maximum 20 mg daily.

Special Populations

Dosage in Renal Impairment

Dosage modification not required.

Cautions

Contraindications

• Active liver disease or unexplained, persistent elevations of serum aminotransferases.
• Pregnancy or lactation. Administer to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
• Known hypersensitivity to atorvastatin or any ingredient in the formulation.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis could cause fetal harm. Congenital anomalies following intrauterine exposure to statins reported rarely.

Administer 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 the drug, discontinue therapy and apprise the patient of the potential hazard to the fetus.

Hepatic Effects

Associated with increases in serum aminotransferase (AST, ALT) concentrations.

Possible pancreatitis, hepatitis, cholestatic jaundice, and biliary pain. Fatty change in liver, increased serum alkaline phosphatase concentrations, increased serum γ-glutamyl transpeptidase concentrations, increased bilirubin concentrations, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma have been reported with other statins.

Perform liver function tests before and at 12 weeks after initiation of therapy or any increase in dosage and periodically (e.g., semiannually) thereafter.

Patients who develop increased serum AST/ALT concentrations or manifestations of liver disease should receive frequent liver function tests thereafter until the abnormalities return to normal. If increases in AST or ALT concentrations of >3 times the upper limit of normal (ULN) persist, reduce dosage or discontinue therapy.

The National Lipid Association (NLA) statin safety assessment task force recommends that clinicians be alert to signs and symptoms of hepatotoxicity (e.g., jaundice, malaise, fatigue, lethargy, hepatomegaly, increased indirect bilirubin concentrations, elevated PT). If substantial hepatotoxicity is suspected, discontinue therapy, determine etiology, and refer patient to a gastroenterologist or hepatologist if indicated.

Musculoskeletal Effects

Myopathy (manifested as muscle pain, tenderness, or weakness and CK (CPK) concentration increases >10 times the ULN) have been reported.

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10 times the ULN] in serum CK concentrations and increases in S_cr [usually accompanied by brown urine and urinary myoglobinuria]) with acute renal failure secondary to myoglobinuria have been reported.

Risk of myopathy increased in patients receiving higher doses of statins; in patients with multisystem disease (e.g., renal or hepatic impairment); in patients with concurrent serious infections or hypothyroidism; in patients (particularly women) of advanced age (especially >80 years of age); in patients with small body frame and frailty; and in patients undergoing surgery (i.e., during perioperative periods). Risk also may be increased by concomitant administration of cyclosporine, niacin, fibric acid derivatives, macrolide antibiotics (e.g., erythromycin), certain azole antifungals, alcohol, and large quantities (>1 quart daily) of grapefruit juice. (See Interactions.)

Measure baseline serum CK concentrations prior to initiation of therapy, particularly in patients at high risk of developing musculoskeletal toxicity (e.g., geriatric patients, black men, patients receiving concomitant therapy with myotoxic drugs).

Obtain serum CK concentrations and compare with baseline concentrations in patients presenting with musculoskeletal symptoms suggestive of myopathy; because hypothyroidism may be a predisposing factor, TSH concentrations also should be obtained in such patients.

Discontinue if serum CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.

Monitor patients weekly if myalgia (muscle pain, tenderness) is present with either no CK elevation or a moderate elevation (3–10 times the ULN) until manifestations improve; discontinue if manifestations worsen.

Dosage reduction or temporary discontinuance may be prudent in patients with muscle discomfort and/or weakness in the presence of progressive elevation of CK concentrations on serial measurements.

Temporarily withhold or discontinue therapy in any patient experiencing an acute or serious condition suggestive of a myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures). Initiate IV hydration therapy (in a hospital setting) in patients experiencing rhabdomyolysis as needed.

General Precautions

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.

Renal Effects

NLA recommends performing renal function tests prior to initiating statin therapy; routine monitoring of S_cr and proteinuria is not necessary. If S_cr is elevated in the absence of rhabdomyolysis, may continue therapy but dosage adjustment may be necessary per labeling recommendations. If unexpected proteinuria develops, determine etiology; may continue therapy but dosage adjustment may be necessary per labeling recommendations.

Peripheral Neuropathy

If manifestations of peripheral neuropathy occur, NLA recommends evaluating patient to rule out secondary causes (e.g., diabetes mellitus, renal impairment, alcohol abuse, vitamin B₁₂ deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome [AIDS], Lyme disease, heavy metal intoxication). If a secondary cause is not identified, discontinue statin therapy for 3–6 months.

If neurologic manifestations improve over this period, a presumptive diagnosis of statin-induced peripheral neuropathy may be made; however, consider reinitiating therapy with a different statin and dosage.

If neurologic manifestations do not improve during period of discontinuance, reinitiate statin therapy, taking into consideration the risks and benefits of such therapy.

CNS Effects

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in animals.

If manifestations of impaired cognition occur, NLA recommends evaluating patient to rule out secondary causes. If a secondary cause is not identified, discontinue statin therapy for 1–3 months. If no improvement, reinitiate statin therapy, taking into consideration the risks and benefits of such therapy.

Ocular Effects

Optic nerve degeneration observed in animals with other statins.

Use of Fixed Combination

When used in fixed combination with amlodipine, consider the cautions, precautions, and contraindications associated with the concomitant agent.

Specific Populations

Pregnancy

Category X. (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Lactation

Distributed into milk in animals; may distribute into milk in humans. Use not recommended.

Pediatric Use

Safety and efficacy not established in prepubertal children or in children <10 years of age. Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.

Safety and efficacy of the fixed combination containing atorvastatin and amlodipine not established in pediatric patients.

Geriatric Use

Mean reductions in LDL-cholesterol concentrations were slightly higher in patients ≥65 years of age compared to younger adults. However, no clinically relevant differences in laboratory abnormalities or rates of discontinuance were reported. Caution in patients (particularly women) of advanced age (especially >80 years of age) and in those with small body frame and frailty.

Safety and efficacy of the fixed combination containing atorvastatin and amlodipine not established in geriatric patients.

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.

Contraindicated in patients with active liver disease or unexplained, persistent increases in liver function test results.

Renal Impairment

Dosage modification is not necessary in patients with renal impairment.

Not studied in patients with end-stage renal disease; hemodialysis not expected to substantially enhance clearance of drug.

Common Adverse Effects

GI disturbances (e.g., constipation, flatulence, dyspepsia, abdominal pain, diarrhea), headache, infection, sinusitis, myalgia, arthralgia, accidental injury, back pain, flu syndrome, asthenia, allergic reaction (e.g., rash), pharyngitis.