General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Atorvastatin may be administered at any time of day. Nighttime administration, as is recommended with some other agents, is not necessary.
-May be administered without regard to meals.
Atorvastatin is generally well-tolerated. Less than 2% of patients discontinue therapy due to adverse events. In a 26-week controlled study in 140 pediatric patients aged 10-17 years treated with 10-20 mg of atorvastatin, the safety and tolerability profile was generally similar to that of placebo.
White blood cells in the urine have been seen in patients receiving atorvastatin.
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins, such as atorvastatin. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 cases per 100,000 patient-years) were diagnosed with ALS.
In a limited controlled study by the manufacturer (n = 187, age 10 to 17 years), infection occurred more often in patients receiving atorvastatin compared to those receiving placebo (19.3% vs. 14.9%). As reported in the product labeling, the most frequent infectious or respiratory adverse reactions occurring in adult patients treated with atorvastatin during placebo-controlled trials are urinary tract infection (5.7% vs. 5.6%), naso-pharyngitis (8.3% vs. 8.2%), and pharyngolaryngeal pain (2.3% vs. 2.1%). Fever has also been reported in adult patients receiving atorvastatin in placebo-controlled trials. Interstitial lung disease has been reported with atorvastatin in postmarketing experience.
In a limited controlled study by the manufacturer in pediatric patients (n = 187, age 10-17 years), headache occurred more often in patients receiving atorvastatin compared to those receiving placebo (9.3% vs. 6.4%). The most frequent central nervous system (CNS) adverse reaction reported by adult patients treated with atorvastatin during placebo-controlled trials was insomnia (3% vs. 2.9%). Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, postmarketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Other CNS adverse reactions reported during clinical trials with atorvastatin include nightmares and malaise. Depression and dizziness have been reported in the postmarketing use of atorvastatin.
HMG-CoA reductase inhibitors have been associated with toxicity to skeletal muscles. Rhabdomyolysis with acute renal failure (unspecified) secondary to myoglobinuria has been reported with atorvastatin and other HMG-CoA reductase inhibitors. The most frequent musculoskeletal adverse reactions occurring in adult patients during placebo-controlled trials are muscle spasms (3.6% vs. 3%), musculoskeletal pain (3.8% vs. 3.6%), pain in the extremity (6% vs. 5.9%), myalgia (3.5% vs. 3.1%), and arthralgia (6.9% vs. 6.5%). Tendon rupture and myositis have been reported with postmarketing use of atorvastatin. Occasionally, atorvastatin may cause myopathy. Consider myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values greater than 10 times upper limit of normal (ULN), in any patient with diffuse myalgias, unexplained muscle tenderness or weakness, and/or marked elevation of CPK. Statin-induced myopathy is generally dose-related. The risk of developing myopathy is increased when HMG-CoA reductase inhibitors are used in combination with certain interacting drugs. During clinical trials, CPK elevations have been reported to occur in 0.1 to 0.3% of patients; pediatric-specific incidences are not known. Any evidence of myalgia, muscle weakness (myasthenia), or elevated CPK values may indicate myopathy or rhabdomyolysis risks, particularly if symptoms include fever, lethargy/drowsiness, and/or fatigue. In general, rhabdomyolysis is a rare complication of HMG-CoA reductase inhibitor therapy. Rhabdomyolysis may occur anytime during drug treatment and the risk may be increased by a number of confounding factors including age, concomitant drug therapy, renal dysfunction, and concomitant disease states. Many cases result in hospitalization and a need for dialysis for treatment. Vigilant clinical monitoring during prescribing can help limit serious adverse events. Discontinue atorvastatin immediately in any patient who develops myopathy or severe elevations in CPK.
Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor therapy. Hepatitis, fatty changes of the liver, cholestasis with jaundice, pancreatitis, and rarely, cirrhosis, fulminant hepatic necrosis, hepatic failure, and hepatoma have been reported during therapy with HMG-CoA reductase inhibitors. Atorvastatin therapy has been associated with elevated hepatic enzymes. This condition generally resolves upon withdrawal of the drug. Perform liver function tests (LFTs) prior to initiation of therapy with atorvastatin and then repeat as clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin. During clinical trials, 0.7% of adult patients developed persistent increased transaminase levels while receiving atorvastatin. The incidence of these elevations was dose-related with persistent elevations occurring in 0.2%, 0.2%, 0.6%, and 2.3% of patients receiving 10, 20, 40, and 80 mg, respectively. One patient in clinical trials with atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has rarely been reported with HMG-CoA reductase inhibitors, such as atorvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.
Tinnitus, blurred vision, and epistaxis have been reported during clinical trials with atorvastatin (incidence not reported).
Urticaria has been reported in adult patients receiving atorvastatin in placebo-controlled trials. Dermatological and hypersensitivity events reported rarely during postmarketing experience with atorvastatin, regardless of causality, include: anaphylaxis, angioedema, bullous rash, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A variety of general skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails) have been reported during HMG-CoA reductase inhibitor therapy. An apparent hypersensitivity syndrome has been reported rarely with HMG-CoA reductase inhibitors which has included one or more of the following features or anaphylactoid reactions: anaphylaxis, angioedema, lupus-like symptoms, polymyalgia rheumatica, dermatomyositis, 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, and Stevens-Johnson syndrome.
An association between HMG-CoA reductase inhibitors (statins), including atorvastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 adult patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8-7.6); similar results have been found in other population based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically > 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect.
Diabetes mellitus and hyperglycemia have been reported with the use of atorvastatin. The risk in pediatric patients is not clear. In the SPARCL trial, diabetes was reported in 6.1% of adult patients in the atorvastatin group compared to 3.8% in the placebo. A meta-analysis of 13 statin trials with 91,140 adult participants showed a 9% increase in the likelihood of the development of diabetes (OR 1.09; 95% CI 1.02-1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70-82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal women is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38-1.59). No difference in the risk for diabetes between statins was detected in either analysis. The increased risk of diabetes should be considered when initiating simvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
A higher incidence of hemorrhagic stroke was seen in adult patients receiving atorvastatin 80 mg/day PO compared to placebo (2.3% vs. 1.4%) in a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. The clinical implications of these findings for pediatric patients is not known. SPARCL consisted of 4731 subjects without CHD who had a stroke or transient ischemic attack (TIA) within the previous 6 months who were administered atorvastatin 80 mg/day PO or placebo. The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). However, the incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (1.6%) compared to the placebo group (0.7%). The risk of hemorrhagic stroke was increased in those having hemorrhagic stroke as the qualifying study entry event, males, and those with increasing age. Additionally, patients having stage 2 hypertension (defined by JNC-7) at the last study visit prior to a hemorrhagic stroke were also at increased risk. There was no relationship between the risk of hemorrhagic stroke and baseline or recent LDL level in atorvastatin-treated patients.
The most frequent gastrointestinal adverse reactions occurring in adult patients treated with atorvastatin during placebo-controlled trials were dyspepsia (4.7% vs. 4.3%), diarrhea (6.8% vs. 6.3%), and nausea (4% vs. 3.5%). Abdominal pain, eructation, and flatulence have also been reported in adult patients receiving atorvastatin in placebo-controlled trials.
Gynecomastia has been reported with statins. Statins interfere with cholesterol synthesis and lower circulating cholesterol concentrations and theoretically may blunt gonadal steroid hormone production. In a limited controlled study by the manufacturer in pediatric patients (n = 187, age 10-17 years), there was no detectable effect of atorvastatin on growth or sexual maturation in boys or on menstrual cycle length in postmenarchal girls. Monitor patients carefully for any potential adverse effects on endocrine function and use caution if other drugs that affect endogenous steroid hormones are used concomitantly.
HMG-CoA reductase inhibitors (statins), such as atorvastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with vitamin Co-Enzyme Q-10 may limit potential adverse reactions.
Atorvastatin is contraindicated in patients with active hepatic disease (including cholestasis, hepatic encephalopathy, hepatitis, or jaundice) or unexplained persistent elevations in serum aminotransferase concentrations. Use atorvastatin with caution in patients with a history of liver disease. Atorvastatin should also be used with caution in patients who consume substantial quantities of alcohol (e.g., alcoholism); discuss the additional risks of alcohol use with patients approaching the age when alcohol consumption may occur. HMG-CoA reductase inhibitors have been associated with liver injury, which in rare cases, has been fatal. The incidence of elevated hepatic transaminases is dose-related. Assess liver enzymes prior to initiation of atorvastatin therapy and repeat as clinically indicated. Previous recommendations included a specific schedule for monitoring liver enzymes; however, after extensive data review, the FDA has concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. Instruct patients and caregivers to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, discontinue therapy. If an alternate etiology is not found, do not restart atorvastatin.
Discontinue atorvastatin immediately in any patient who develops myopathy, marked elevations in CPK, or rhabdomyolysis. Consider myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values greater than 10 times upper limit of normal (ULN), in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Females, patients with renal impairment, and those with uncontrolled hypothyroidism appear to be predisposed to developing myopathy. Temporary withdrawal of atorvastatin is recommended in patients with acute or serious conditions that can cause decreased renal perfusion because renal failure is possible if atorvastatin-induced myopathy and rhabdomyolysis occurs. Predisposing conditions for renal failure secondary to rhabdomyolysis include hypotension, sepsis or severe acute infection, severe/uncontrolled endocrine disease, acute electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of developing myopathy also appears to be increased when HMG-CoA reductase inhibitors are used in combination with selected drugs (e.g., fibrates and others). Use atorvastatin with caution in organ transplant and other patients receiving immunosuppressant therapy such as cyclosporine because of an increased risk of rhabdomyolysis and renal failure; lower initial and maximum doses of atorvastatin are recommended. Renal disease has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions; dosage adjustments are not needed in patients with renal impairment.
A higher incidence of hemorrhagic stroke was seen in adult patients receiving atorvastatin 80 mg/day PO compared to placebo ( 2.3% vs. 1.4%) in a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. The implications of this finding for pediatric patients is not known. The risk of hemorrhagic stroke was increased in those having hemorrhagic stroke as the qualifying study entry event, males, and those with increasing age. Additionally, patients having stage 2 hypertension (defined by JNC-7) at the last study visit prior to a hemorrhagic stroke were also at increased risk. There was no relationship between the risk of hemorrhagic stroke and baseline or recent LDL level in atorvastatin-treated patients. SPARCL consisted of 4731 subjects without CHD who had a stroke or transient ischemic attack (TIA) within the previous 6 months who were administered atorvastatin 80 mg/day PO or placebo. The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). However, the incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (1.6%) compared to the placebo group (0.7%).
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as atorvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed. Prior to starting the patient on another HMG-CoA reductase inhibitor, the risks of therapy should be carefully considered. Any patient started on an alternate HMG-CoA reductase inhibitor should be monitored for signs and symptoms of IMNM.
HMG-CoA reductase inhibitors are known to have various endocrine effects that may be clinically significant in selected patients. Increased hemoglobin A1c, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. If atorvastatin is initiated in a patient with diabetes mellitus, increased monitoring of blood glucose control may be warranted. In addition, because cholesterol synthesis is altered, atorvastatin may theoretically blunt adrenal and/or gonadal steroid production. However, clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentrations or impair adrenal reserve, and in a limited controlled study by the manufacturer in pediatric patients (n = 187, age 10-17 years), there was no detectable effect on growth or sexual maturation in boys or on menstrual cycle length in postmenarchal girls.
Safe use of atorvastatin in neonates, infants, children under 10 years of age or in pre-pubertal females has not been established. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children in not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8-10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.
Use atorvastatin with caution in females who could become pregnant. Counsel adolescents about the necessity of the prevention of pregnancy and about using effective contraception during treatment. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes; therefore, reduction of cholesterol synthesis by atorvastatin may cause fetal harm if administered during pregnancy. Atorvastatin is pregnancy category X.
Description: Atorvastatin is a selective, competitive HMG-CoA reductase inhibitor. Atorvastatin is effective in reducing total and LDL-cholesterol as well as plasma triglycerides and apolipoprotein B. At the maximum recommended dosage, it is one of the most potent HMG Co-A reductase inhibitors currently available in terms of LDL-lowering capacity. At doses of 5-20 mg once daily, atorvastatin reduces mean LDL concentrations in pediatric patients by approximately 40%. Atorvastatin is indicated in adult patients to prevent fatal and nonfatal cardiovascular events based on the favorable findings of several studies that demonstrated reduced all-cause mortality, coronary deaths, and rates of stroke, myocardial infarction, and revascularization. Although evidence of beneficial long term effects on cardiovascular outcomes and mortality in pediatric patients is not available, statins are recommended as first-line pharmacologic therapy for hyperlipidemia in pediatric patients based on evidence of short-term safety and efficacy. Atorvastatin is FDA-approved in pediatric patients as young as 10 years of age with heterozygous familial hypercholesterolemia.
General dosing information
-Atorvastatin is FDA-approved for the treatment of heterozygous familial high cholesterol and is recommended for hyperlipidemia when either: 1) the LDL-C remains greater than or equal to 190 mg/dL, or 2) the LDL-C remains greater than or equal to 160 mg/dL and there is an increased risk for cardiovascular disease (e.g., positive family history of premature cardiovascular disease or two or more other risk factors are present).
-Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of hypercholesterolemia, hyperlipoproteinemia, and/or hypertriglyceridemia, as an adjunct to dietary control, for the purpose of reducing the risk of cardiovascular events (e.g., myocardial infarction prophylaxis, stroke prophylaxis):
Children 6 to 9 years*: 5 mg PO once daily increased to 10 mg PO once daily after 4 weeks if the goal LDL of less than 130 mg/dL was not reached was used in a small, short-term study of pediatric patients with heterozygous familial hypercholesterolemia. Patients were dosed based on Tanner Stage, with Tanner Stage 1 patients (n = 15, age 6 to 14 years) receiving an initial dose of 5 mg/day PO and Tanner Stage 2 patients (n = 24, age 9 to 17 years) receiving an initial dose of 10 mg/day PO. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 34%, 40.7%, and 6%, respectively, in the Tanner Stage 1 patients after 8 weeks of treatment. Similar reductions were seen in the Tanner Stage 2 patients, with the exception of triglycerides, which decreased by 21%. Although pharmacologic therapy is not generally recommended for patients less than 10 years of age or Tanner Stage 1, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease).
Children and Adolescents 10 years and older (females should be at least 1 year post-menarche): 10 mg PO once daily initially. The dosage may be increased to 20 mg/day PO after 4 weeks or longer if necessary to attain the target LDL and lipid goals. In a randomized, placebo controlled trial of pediatric patients with familial hypercholesterolemia or severe hyperlipidemia (n = 187), mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 32%, 40%, and 12%, respectively, after 26 weeks of treatment with atorvastatin.
For graft coronary artery disease prevention after heart transplantation*:
Children and Adolescents: 0.2 mg/kg/day PO rounded to the nearest 2.5 mg resulted in a lower incidence of graft coronary artery disease (GCAD) compared to no early (before 9 weeks post-transplant) HMG-coenzyme A reductase inhibitor therapy. Atorvastatin initiated before the ninth week post-transplant (n = 33, mean age 12.3 +/- 3.7 years) was compared to a control group who did not receive the drug before the ninth week (n = 32, mean age 10.4 +/- 6.1 years). Patients in the control group started atorvastatin at an average of 95 weeks post-transplant. Significantly fewer patients in the early atorvastatin group developed graft coronary artery disease compared to the control group (2 vs. 12, p < 0.005). Freedom from graft coronary artery disease at 1, 3, and 5 years was significantly higher in those patients receiving early atorvastatin treatment (97%, 93%, and 93%, respectively) compared to the control group (72%, 65%, and 60%, respectively). In addition, patients in the early atorvastatin group had fewer episodes of treated rejection in the first year post-transplant compared to the control group (0.2 +/- 0.4 episodes vs. 1 +/- 1.1 episodes, respectively [p = < 0.05]).
Maximum Dosage Limits:
Safety and efficacy have not been established.
Safety and efficacy have not been established.
6-9 years: Safety and efficacy have not been established; however, doses up to 10 mg/day PO have been included in some study protocols.
>= 10 years: 20 mg/day PO.
20 mg/day PO.
Patients with Hepatic Impairment Dosing
Contraindicated in patients with active liver disease or with unexplained or persistent hepatic transaminase elevations.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Monograph content under development
Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Atorvastatin ultimately reduces the levels of circulating total cholesterol, LDL-cholesterol, and serum triglycerides. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. As with other HMG-CoA reductase inhibitors, atorvastatin exhibits no effects on antipyrine hepatic metabolism.
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
Pharmacokinetics: Atorvastatin is administered orally. It is >= 98% bound to plasma proteins. A blood/plasma ratio of 0.25 indicates poor drug penetration into red blood cells. Atorvastatin undergoes extensive metabolism to active ortho- and parahydroxylated metabolites, which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Elimination of atorvastatin and its metabolites occurs primarily in bile after hepatic and/or extrahepatic metabolism. It does not appear that the drug undergoes enterohepatic recirculation. Less than 2% of an oral dose is recovered in the urine. The mean plasma elimination half-life of atorvastatin in adults is approximately 14 hours; however, the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours because of the active metabolites.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), OATP1B1, OATP1B3, BCRP
Atorvastatin is a substrate of CYP3A4 hepatic metabolism. Atorvastatin is also a substrate of P-gp and an inhibitor of P-gp. Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Atorvastatin has the potential for significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and potential toxicity (i.e., myopathy, rhabdomyolysis). Inducers of CYP3A4 can reduce atorvastatin plasma concentrations.
After oral administration, atorvastatin is rapidly absorbed with peak plasma concentrations occurring within 1 to 2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability is approximately 14%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Presystemic clearance and/or hepatic first-pass metabolism accounts for the low systemic bioavailability. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively; however, LDL-cholesterol reduction is similar whether the drug is given with or without food. Similarly, atorvastatin plasma concentrations are lower after evening dosing compared to morning dosing, but LDL-cholesterol reduction is the same regardless of the time of day the drug is administered.
Children and Adolescents
Based on the results of a population pharmacokinetic study (n = 39), the oral clearance of atorvastatin in pediatric patients 6 to 17 years of age is similar to that reported in adult patients. The estimated oral clearance in Tanner Stage 1 (approximately 35 kg) and Tanner Stage 2 (approximately 50 kg) patients was 533 L/hour and 543 L/hour, respectively, compared to an estimated clearance of 699 L/hour in adults. Weight was the primary factor affecting the variability of atorvastatin pharmacokinetics in pediatric patients.
Cmax and AUC are both 4-fold greater in patients with Child-Pugh Class A hepatic disease. Cmax and AUC are increased by approximately 16-fold and 11-fold, respectively, in patients with Child-Pugh Class B hepatic disease. In patients with chronic alcoholic hepatic disease, atorvastatin plasma concentrations are increased.
Renal disease does not affect atorvastatin plasma concentrations or LDL cholesterol reductions; no dosage adjustments are needed. Hemodialysis does not enhance the clearance of atorvastatin or its metabolites.