LIPITOR (Brand for ATORVASTATIN CALCIUM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Atorvastatin may be administered at any time of day. Nighttime administration, as is recommended with some other agents, is not necessary.
-Missed dose: Instruct patients to take a missed dose as soon as possible. If a dose is missed by more than 12 hours, skip the missed dose and resume with the next scheduled dose.
Oral Solid Formulations
Tablets:
-Atorvastatin tablets may be taken with or without food.

Oral Liquid Formulations
Oral Suspension:
-Measure atorvastatin suspension doses using a calibrated oral syringe or other oral dosing device scored using metric units of measurement (i.e., mL).
-Administer atorvastatin suspension orally once daily at any time of day on an empty stomach (1 hour before or 2 hours after a meal).
-Storage: Discard any unused suspension after 60 days of first opening the bottle.

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 to 17 years treated with 10 to 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, infectious or respiratory adverse reactions occurring in adult patients treated with atorvastatin during placebo-controlled trials are urinary tract infection (4.1% to 8% vs. 5.6%), naso-pharyngitis (4.2% to 12.9% vs. 8.2%), pharyngolaryngeal pain (0.7% to 3.9% vs. 2.1%), and fever. 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 to 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 (1.1% to 5.3% 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, dizziness, and fatigue have been reported in the postmarketing use of atorvastatin.

Atorvastatin can cause myopathy (muscle pain, muscle tenderness, or muscle weakness (myasthenia) associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin. Discontinue atorvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher atorvastatin dosage. Monitor all patients with renal impairment for increased risk of myopathy. During clinical trials, myalgia occurred in 3.5% (2.7 to 8.4%) of patients taking atorvastatin vs. 3.1% of patients receiving placebo. Other frequent musculoskeletal adverse reactions occurring in adult patients during placebo-controlled trials were muscle spasms (2.4 to 5.1% vs. 3%), musculoskeletal pain (2.3% to 5.2% vs. 3.6%), pain in the extremity (3.1% to 9.3% vs. 5.9%), arthralgia (4.3% to 11.7% vs. 6.5%), muscle fatigue, neck pain, and joint swelling. Rhabdomyolysis, myositis, and tendon rupture have been reported with postmarketing use.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as atorvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.

Increases in hepatic transaminases have been reported with atorvastatin. In most cases, these changes appeared soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. Consider assessing liver function tests (LFTs) prior to initiation of atorvastatin and then repeat as clinically indicated thereafter. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly discontinue therapy. During clinical trials, 0.7% of patients developed persistent elevated hepatic enzymes while receiving atorvastatin. The incidence of transaminase 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. Hepatitis and cholestasis have been reported in adult individuals receiving atorvastatin in placebo-controlled trials. Pancreatitis and hepatic failure (fatal and non-fatal) have been reported with use of atorvastatin in postmarketing reports

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 during postmarketing experience with atorvastatin include: anaphylaxis (anaphylactoid reactions), angioneurotic edema, bullous rash, dermatographism, dermatomyositis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), erythema multiforme, lichen planus-like eruption, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The following adverse skin effects have been reported with HMG-CoA reductase inhibitors, including atorvastatin: acute generalized exanthematous pustulosis (AGEP), alopecia, angioedema, bullous dermatosis, cheilitis, chronic actinic dermatitis, cutaneous lupus erythematosus (lupus-like symptoms), DRESS, eczema, eosinophilic fasciitis, erythema multiforme, erythematous rash, ichthyosis, lichen planus-like eruption (e.g., lichenoid drug eruptions, lichen planus pemphigoides), photosensitivity/phototoxicity, pityriasis lichenoides chronica, pityriasis rubra pilaris, porphyria cutanea tarda, purpuric lesions (purpura), skin ulcers, and toxic epidermal necrolysis.

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 to 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 greater than 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. Peripheral neuropathy was reported with postmarketing use of atorvastatin.

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 to 1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70 to 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 to 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 (3.2% to 6% vs. 4.3%), diarrhea (5.2% to 14.1% vs. 6.3%), and nausea (3.7% to 7.1% 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 to 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.

Exacerbation and induction of myasthenia gravis, including ocular myasthenia, has been reported during treatment with statins, including atorvastatin. Reports of recurrence have been noted when the same or a different statin was administered. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

Atorvastatin is contraindicated in patients with acute hepatic failure or decompensated cirrhosis. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of hepatic disease. Increases in hepatic transaminases have been reported with atorvastatin. In most cases, increases in hepatic transaminases occurred soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. Persistent increases of more than three times the upper limit of normal in hepatic transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. Consider assessing liver enzyme tests prior to initiation of atorvastatin and repeat as clinically indicated thereafter. Elevated hepatic transaminases have been reported in patients receiving HMG-CoA reductase inhibitors; these abnormalities were not associated with cholestasis and did not appear to be associated with treatment duration. After extensive data review, the FDA 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. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, discontinue atorvastatin.

Atorvastatin can cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin. Discontinue atorvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher atorvastatin dosage. Monitor all patients with renal impairment for increased risk of myopathy. Atorvastatin levels may be increased when coadministered with medications that inhibit cytochrome P450 enzyme 3A4 and/or transporters (breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3], and p-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Consumption of large quantities of grapefruit juice (greater than 1.2 L/day) is not recommended. Inform patients of the risk of myopathy and rhabdomyolysis when initiating or increasing the dosage of atorvastatin. Instruct patients to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as atorvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.
Use atorvastatin with caution in patients with a recent hemorrhagic stroke. Consider the risk versus benefit of atorvastatin 80 mg/day in patients with recent hemorrhagic stroke. In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg/day vs. placebo was administered in 4,731 adult subjects without coronary heart disease who had a stroke or transient ischemic attack (TIA) within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI 1.09 to 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (1.6%) as compared to the placebo group (0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group. The implications of this finding for pediatric patients is not known.

Increased hemoglobin A1C, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Optimization of lifestyle measures, including regular exercise, maintaining a healthy body weight and making healthy food choices are recommended. If atorvastatin is initiated in a patient with diabetes mellitus, increased monitoring of blood glucose control may be warranted. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes mellitus should be considered when initiating atorvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established. Although an analysis of participants from the JUPITER trial found an increased incidence of developing diabetes in patients allocated to rosuvastatin compared to placebo (270 reports of diabetes vs. 216 in the placebo group; HR 1.25, 95% CI 1.05 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with 1 or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or A1C more than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, CI 0.21 to 1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

Safety and efficacy of atorvastatin have not been established in infants and children younger than 10 years of age. 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 is 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 to 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 persons with myasthenia gravis. Closely monitor for myasthenia gravis exacerbation and encourage reporting of any muscle-related symptoms. Exacerbation of myasthenia gravis, including ocular myasthenia gravis, has been reported during treatment with statins, including atorvastatin. Reports of recurrence have been noted when the same or a different statin was administered. The onset of symptom exacerbation following initiation of statin therapy has ranged from 1 week to 4 months. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents.

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 to 20 mg 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):
Oral dosage:
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 range is 10 to 20 mg PO once daily. The daily dose may be given at any time during the day. After atorvastatin initiation, assess LDL-C levels as early as 4 weeks or when clinically appropriate and adjust dosage as necessary. 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*:
Oral dosage:
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 less than 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 or less]).

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established.
6 to 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 to 12 years: 20 mg/day PO.
-Adolescents
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.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme necessary for the intracellular synthesis of cholesterol. 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% or more bound to plasma proteins. Atorvastatin has a blood/plasma ratio of 0.25, which indicates poor drug penetration into red blood cells. Atorvastatin undergoes extensive metabolism to various beta-oxidation products and active ortho- and parahydroxylated metabolites. The active ortho- and parahydroxylated metabolites 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 contribution of 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.


-Route-Specific Pharmacokinetics
Oral Route
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. Atorvastatin plasma concentrations are lower, by approximately 30% for both Cmax and AUC, following evening administration compared to morning dosing; however, LDL-cholesterol reduction is the same regardless of the time of day the drug is administered.
-Oral suspension: Administration of atorvastatin suspension with a high fat meal resulted in a 30% decrease in atorvastatin AUC and a 63% decrease in Cmax compared to administration without food. The decrease in atorvastatin exposure can be clinically significant; therefore atorvastatin suspension should be taken on an empty stomach (1 hour before or 2 hours after a meal).
-Oral tablets: Administration of atorvastatin tablets with 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.


-Special Populations
Pediatrics
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.

Hepatic Impairment
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 Impairment
Renal disease does not affect atorvastatin plasma concentrations or LDL cholesterol reductions; no dosage adjustments are needed. Since atorvastatin is highly bound to plasma proteins, hemodialysis does not enhance the clearance of atorvastatin or its metabolites.