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  • CLASSES

    HMG-CoA Reductase Inhibitors/Statins

    DEA CLASS

    Rx

    DESCRIPTION

    Potent HMG-CoA reductase inhibitor 
    Used to treat hypercholesterolemia and hypertriglyceridemia, to prevent cardiovascular events in patients at risk for CHD or with clinical evidence of CHD, and for homozygous familial hypercholesterolemia; reduces LDL cholesterol, apoprotein B, and triglycerides; increases HDL
    Has a long half-life and high hepatic selectivity

    COMMON BRAND NAMES

    Lipitor

    HOW SUPPLIED

    Atorvastatin/Atorvastatin Calcium/Lipitor Oral Tab: 10mg, 20mg, 40mg, 80mg

    DOSAGE & INDICATIONS

    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
    Adults

    Initially, 10 to 20 mg PO once daily. May start at 40 mg PO once daily in patients requiring greater than 45% LDL-reduction. The dosage range is 10 to 80 mg PO once daily (mean LDL reduction range: 43% to 60% LDL). The daily dose may be given at any time during the day and without regard to meals. After dosage initiation or titration, lipid concentrations should be analyzed within 2 to 4 weeks. Adjust dosage to attain the target LDL and lipid goals based on the NCEP guidelines. In general, geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors.

    Adults taking clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, or fosamprenavir alone or in combination with ritonavir

    Initially, 10 to 20 mg PO once daily. Do not exceed 20 mg PO once daily due to the increased risk for myopathy and rhabdomyolysis. The daily dose may be given at any time during the day and without regard to meals. After dosage initiation or titration, lipid concentrations should be analyzed within 2 to 4 weeks. Adjust dosage to attain the target LDL and lipid goals based on the NCEP guidelines. In general, geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors.

    Adults taking boceprevir or nelfinavir

    Initially, 10 to 20 mg PO once daily. Do not exceed 40 mg PO once daily due to the increased risk for myopathy and rhabdomyolysis. The daily dose may be given at any time during the day and without regard to meals. After dosage initiation or titration, lipid concentrations should be analyzed within 2 to 4 weeks. Adjust dosage to attain the target LDL and lipid goals based on the NCEP guidelines. In general, geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors.

    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.

    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).

    For slowing the progression of atherosclerosis† (e.g., carotid, coronary, femoral).
    Oral dosage
    Adults

    80 mg PO once daily has been shown to reduce the progression of atherosclerosis in clinical trials.
    NOTE: Patients taking select medications require downward dose adjustments, and maximum recommended dosages should not be exceeded.

    For cerebral vasospasm prophylaxis† after aneurysmal subarachnoid hemorrhage.
    Oral dosage
    Adults

    Dosage not established. 40 mg PO once daily for 21 days has been used.

    For the treatment of chronic heart failure†.
    Oral dosage
    Adults

    Dosage not established. 10 to 40 mg PO daily for 6 to 12 months has been studied. Limited data suggest atorvastatin may improve inflammatory markers and left ventricular ejection fraction, especially in patients with dilated cardiomyopathy. However, clinical practice guidelines for the treatment of heart failure in adults recommend statins only in patients with a recent or remote history of myocardial infarction or acute coronary syndrome to prevent symptomatic heart failure and cardiovascular events.

    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 < 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]).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO.

    Geriatric

    80 mg/day PO.

    Adolescents

    20 mg/day PO.

    Children

    10 to 12 years: 20 mg/day PO.
    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.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin.

    Renal Impairment

    Renal impairment has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions. No dosage adjustments are needed.
     
    Intermittent hemodialysis
    Hemodialysis does not enhance the clearance of atorvastatin or its metabolites ; no dosage adjustment is needed.

    ADMINISTRATION

     
    NOTE: Patients receiving atorvastatin therapy should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.

    Oral Administration

    Administer orally at about the same time each day, at any time of day. Atorvastatin may be administered orally without regard to meals. Avoid grapefruit juice to avoid potential increases in drug serum concentrations.

    STORAGE

    Lipitor:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Atorvastatin is contraindicated in patients with atorvastatin hypersensitivity or hypersensitive to any components of the product selected.

    Alcoholism, cholestasis, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Atorvastatin is contraindicated in patients with active hepatic disease (including cholestasis, hepatic encephalopathy, hepatitis, and jaundice) or unexplained persistent elevations in serum aminotransferase concentrations. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of liver disease. 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. Assess liver enzymes prior to initiation of atorvastatin therapy and repeat as clinically indicated. 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, therapy should be interrupted. If an alternate etiology is not found, do not restart atorvastatin.

    Electrolyte imbalance, endocrine disease, females, hypotension, hypothyroidism, infection, myopathy, organ transplant, renal failure, renal impairment, rhabdomyolysis, seizure disorder, sepsis, surgery, trauma

    Myopathy is a potential serious side effect of HMC-CoA reductase inhibitors; rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other drugs in this class. Atorvastatin therapy should be discontinued if myopathy is diagnosed or suspected or if a patient who develops marked elevations in CPK or rhabdomyolysis. Myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values more than 10 times upper limit of normal (ULN), should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin may be contraindicated or temporarily withheld in conditions that can cause decreased renal perfusion since renal failure is possible if atorvastatin-induced myopathy and rhabdomyolysis occurs. Predisposing risk factors for myopathy and/or rhabdomyolysis include renal dysfunction, females, hypotension, sepsis or severe acute infection, severe/uncontrolled endocrine disease such as uncontrolled hypothyroidism, acute electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of developing myopathy is also increased when HMG-CoA reductase inhibitors are used in combination with selected drugs (e.g., fibrates and others). Atorvastatin should be used 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 for such patients. Renal disease has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions; dosage adjustments are not needed in patients with renal impairment.

    Diabetes mellitus

    If atorvastatin is initiated in a patient with diabetes mellitus, increased monitoring of blood glucose control may be warranted. Increased hemoglobin A1C, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. 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.

    Contraception requirements, pregnancy

    Atorvastatin therapy is contraindicated for use during pregnancy. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. Because atorvastatin decreases cholesterol synthesis, the drug may cause fetal harm. If a patient becomes pregnant while taking this drug, atorvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. In a prospective review of about 100 pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. However, atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Atorvastatin should be administered to females of childbearing age, including adolescents that are post-menarche, only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of atorvastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with atorvastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately.

    Breast-feeding

    Atorvastatin is contraindicated for use in women who are breast-feeding. It is likely that atorvastatin is excreted to some degree in human milk. In animal studies, nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Cholesterol and other products of cholesterol biosynthesis are essential components for infant development; atorvastatin may also have other adverse effects on the nursing infant. If the drug is absolutely necessary to the mother, nursing should be discontinued. Otherwise, since atherosclerosis and its complications are a chronic health issue, discontinuation of atorvastatin for some time in order to allow for nursing of an infant would be expected to have little effect on the long-term outcomes associated with hypercholesterolemia. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and efficacy of atorvastatin in infants or children less than 10 years of age or in pre-pubertal females have 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 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.

    Geriatric

    Since advanced age (65 years or more) is a predisposing risk factor for myopathy, atorvastatin should be prescribed with caution in the geriatric patient. During clinical trials, no overall differences in safety or effectiveness were observed and other reported clinical experience has not identified differences in clinical responses between elderly and younger adult patients. In general, geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors. Plasma concentrations of atorvastatin are higher (about 40% for Cmax and 30% for AUC) in healthy elderly subjects than in young adults. In addition, the LDL-cholesterol reduction at a given atorvastatin dosage is somewhat greater than that seen in younger adult patient populations. However, rates of drug discontinuation due to adverse events or rates of clinically significant laboratory abnormalities are similar in both elderly and younger adult groups. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications.

    Stroke

    Use atorvastatin with caution in patients with a recent stroke or transient ischemic attack (TIA). 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 subjects without coronary heart disease who had a stroke or 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.

    ADVERSE REACTIONS

    Severe

    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    hepatic failure / Delayed / 0-1.0
    rhabdomyolysis / Delayed / Incidence not known
    renal tubular obstruction / Delayed / Incidence not known
    myoglobinuria / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    tendon rupture / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    diabetes mellitus / Delayed / 6.1-6.1
    amnesia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    memory impairment / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0.7-0.7
    depression / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    bullous rash / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    myalgia / Early / 2.7-8.4
    arthralgia / Delayed / 6.9-6.9
    diarrhea / Early / 6.8-6.8
    insomnia / Early / 1.1-5.3
    dyspepsia / Early / 4.7-4.7
    nausea / Early / 4.0-4.0
    musculoskeletal pain / Early / 3.8-3.8
    abdominal pain / Early / 0-3.8
    flatulence / Early / 1.1-2.8
    dizziness / Early / 0-2.0
    malaise / Early / 0-2.0
    nightmares / Early / 0-2.0
    urticaria / Rapid / 0-2.0
    drowsiness / Early / Incidence not known
    weakness / Early / Incidence not known
    fatigue / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    eructation / Early / Incidence not known
    chills / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    infection / Delayed / Incidence not known
    fever / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Acetaminophen; Butalbital; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Aliskiren: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Aliskiren; Amlodipine: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Aliskiren; Valsartan: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
    Alogliptin; Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Aluminum Hydroxide: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Amiodarone: (Moderate) Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with atorvastatin. Amiodarone may inhibit hepatic CYP3A4 isoenzymes, and therefore has the potential to increase serum concentrations of atorvastatin.
    Amobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin.
    Antacids: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if atorvastatin and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in atorvastatin-related adverse effects for several days after administration. Atorvastatin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of atorvastatin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Atazanavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increase atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid concurrent administration of atorvastatin with cobicistat. Taking these drugs together increases the plasma concentrations of atorvastatin. If these drugs must be used concurrently, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy). Do not exceed an atorvastatin dose of 20 mg per day. (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increase atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) HMG-CoA reductase inhibitors have been administered safely with niacin (nicotinic acid) in some patients; however the risk of potential myopathy should be considered. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in lipid-altering doses (i.e., >=1 g/day) and HMG-CoA reductase inhibitors (Statins) concurrently. The serious risk of myopathy or rhabdomyolysis should be carefully weighed against the potential risks. Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Azithromycin: (Moderate) Monitor for evidence of rhabdomyolysis if atorvastatin is coadministered with azithromycin. A clinically significant pharmacokinetic interaction was not observed when atorvastatin was administered with azithromycin in a drug interaction study. However, a case series in the World Health Organization Adverse Drug Reaction (WHO-ADR) database was suggestive of a possible drug interaction resulting in rhabdomyolysis between statins, incuding atorvastatin, and azithromycin.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Black Cohosh, Cimicifuga racemosa: (Moderate) Use black cohosh with caution in combination with atorvastatin. In one case report, a patient taking atorvastatin (Lipitor) developed significantly elevated liver function tests (LFTs) after starting black cohosh 100 mg PO four times daily. Liver enzymes returned to normal when black cohosh was discontinued. It is unclear whether the elevated liver enzymes were due to the black cohosh product or an interaction between atorvastatin and black cohosh. The black cohosh dose is above that usually recommended for dietary supplementation, and cases of hepatotoxicity have been reported with black cohosh alone.
    Boceprevir: (Major) Use the lowest effective dose of atorvastatin and do not exceed a total daily dose of 40 mg when coadministered with boceprevir. The AUC and Cmax of atorvastatin were increased by 2.3-fold and 2.66-fold, respectively in a drug interaction study with boceprevir.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
    Bosentan: (Moderate) Bosentan induces CYP3A4 and is expected to reduce plasma concentrations of atorvastatin. The possibility of reduced anti-lipemic efficacy should be considered. Monitor cholesterol levels after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
    Brigatinib: (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with brigatinib is necessary. Atorvastatin is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of atorvastatin may decrease.
    Butabarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Cabozantinib: (Moderate) Monitor for an increase in atorvastatin-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of atorvastatin may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Calcium Carbonate: (Moderate) Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered. (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Calcium Carbonate; Risedronate: (Moderate) Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered.
    Calcium; Vitamin D: (Moderate) Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered.
    Carbamazepine: (Moderate) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, such as atorvastatin.
    Carvedilol: (Moderate) Concomitant use of carvedilol and atorvastatin may result in increased atorvastatin concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and atorvastatin is a P-gp substrate. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Ceritinib: (Moderate) Monitor for atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and atorvastatin is metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of atorvastatin by 3.3-fold and 20%, respectively, while coadministration with a moderate CYP3A4 inhibitor increased the atorvastatin AUC and Cmax by 33% and 38%, respectively. The strength of inhibition of CYP3A4 by ceritinib is unknown.
    Cimetidine: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administion of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Ciprofloxacin: (Major) The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with ciprofloxacin, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and ciprofloxacin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Clarithromycin: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin.
    Clopidogrel: (Minor) Atorvastatin has been reported to attenuate the antiplatelet activity of clopidogrel potentially by inhibiting CYP3A4 metabolism to its active metabolite; however, conflicting data exists. Patients should be monitored for therapeutic effectiveness when clopidogrel is administered with atorvastatin.
    Cobicistat: (Major) Avoid concurrent administration of atorvastatin with cobicistat. Taking these drugs together increases the plasma concentrations of atorvastatin. If these drugs must be used concurrently, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy). Do not exceed an atorvastatin dose of 20 mg per day.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent administration of atorvastatin with cobicistat. Taking these drugs together increases the plasma concentrations of atorvastatin. If these drugs must be used concurrently, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy). Do not exceed an atorvastatin dose of 20 mg per day.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent administration of atorvastatin with cobicistat. Taking these drugs together increases the plasma concentrations of atorvastatin. If these drugs must be used concurrently, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy). Do not exceed an atorvastatin dose of 20 mg per day.
    Colchicine: (Moderate) Case reports exist describing the development of myotoxicity (i.e., muscle pain and weakness, rhabdomyolysis) with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (Statins). Statins involved in the reported cases include simvastatin, atorvastatin, fluvastatin, lovastatin, and pravastatin. The pharmacokinetic and/or pharmacodynamic mechanism of this interaction is not clear; however, both colchicine and statins are associated with the development of myotoxicity and concurrent use may increase the risk of myotoxicity. Patients receiving these agents concurrently should be monitored for myotoxicity.
    Colestipol: (Moderate) Coadministration of atorvastatin with colestipol resulted in approximately 25% lower plasma concentrations of atorvastatin. However, LDL-cholesterol reduction was greater when atorvastatin and colestipol were administered together than when either drug was given alone.
    Conivaptan: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and atorvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with atorvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as atorvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as atorvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Conjugated Estrogens; Bazedoxifene: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged.
    Crizotinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Cyclosporine: (Major) Avoid the coadministration of atorvastatin and cyclosporine because the risk of developing myopathy increases when these two drugs are given together. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higer atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone.
    Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Dalfopristin; Quinupristin: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
    Danazol: (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
    Daptomycin: (Moderate) Daptomycin has been associated with elevated CPK in clinical trials. HMG-CoA reductase inhibitors are known to cause myopathy. Since data regarding co-administration of daptomycin with HMG-CoA reductase inhibitors are limited, temporary suspension of HMG-CoA reductase inhibitor therapy should be considered in patients receiving daptomycin.
    Darunavir: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with darunavir boosted with either ritonavir or cobicisat. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy or rhabdomyolysis increases when atorvastatin is used concomitantly with darunavir plus ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.4-fold with the concomitant administration of darunavir plus ritonavir. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and darunavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Darunavir; Cobicistat: (Major) Avoid concurrent administration of atorvastatin with cobicistat. Taking these drugs together increases the plasma concentrations of atorvastatin. If these drugs must be used concurrently, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy). Do not exceed an atorvastatin dose of 20 mg per day. (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with darunavir boosted with either ritonavir or cobicisat. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy or rhabdomyolysis increases when atorvastatin is used concomitantly with darunavir plus ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.4-fold with the concomitant administration of darunavir plus ritonavir. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and darunavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Delavirdine: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Coadminister delavirdine and atorvastatin cautiously; use the lowest possible dose of atorvastatin. Delavirdine is a potent inhibitor of CYP3A4. Atorvastatin is a substrate of CYP3A4. If these drugs are coadministered, carefully monitor the patient. If treatment with an HMG-CoA reductase inhibitor is necessary, pravastatin should also be considered, since it is not significantly metabolized by CYP3A4 or CYP2C9 isoenzymes.
    Digoxin: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
    Diltiazem: (Major) According to the manufacturer of diltiazem, clinicians should consider use of a non-CYP3A4-metabolized statin (e.g., pitavastatin, pravastatin, rosuvastatin) in combination with diltiazem. Coadministration of atorvastatin 40 mg with diltiazem 240 mg was associated with a higher plasma concentration of atorvastatin. Increased concentrations of atorvastatin are associated with an increased risk of myopathy and rhabdomyolysis. Diltiazem is a CYP3A4 inhibitor; coadministration with atorvastatin (CYP3A4 substrate) may result in increased concentrations of atorvastatin.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin.
    Drospirenone; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Efavirenz: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution.
    Elbasvir; Grazoprevir: (Moderate) Studies have shown plasma concentrations of atorvastatin are increased when administered concurrently with elbasvir; grazoprevir. If these drugs are use together, the daily dose of atorvastatin should not exceed 20 mg. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
    Eliglustat: (Moderate) Coadministration of atorvastatin and eliglustat may result in increased plasma concentrations of atorvastatin. Monitor patients closely for atorvastatin-related adverse effects including myalgia, myopathy, myasthenia, and/or rhabdomyolysis; if appropriate, consider reducing the atorvastatin dosage and titrating to clinical effect. Atorvastatin is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as atorvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered.
    Enzalutamide: (Major) Monitor for decreased efficacy of atorvastatin if coadministration with enzalutamide is necessary. Atorvastatin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80%.
    Erlotinib: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Erythromycin: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with erythromycin, a CYP3A4 inhibitor. In healthy individuals, the plasma concentration of atorvastatin was increased 40% with coadministration of atorvastatin and erythromycin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and erythromycin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Erythromycin; Sulfisoxazole: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with erythromycin, a CYP3A4 inhibitor. In healthy individuals, the plasma concentration of atorvastatin was increased 40% with coadministration of atorvastatin and erythromycin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and erythromycin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipds are noted.
    Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Desogestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Etonogestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norelgestromin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norethindrone: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norgestimate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Ethinyl Estradiol; Norgestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Etravirine: (Moderate) Concomitant use of etravirine and atorvastatin decreases atorvastatin serum concentrations and increases concentrations of the metabolite, 2-OH-atorvastatin. Atorvastatin may be a substrate of the CYP3A4 isoenzyme and etravirine induces the CYP3A4 isoenzyme. According to the manufacturer of etravirine, atorvastatin can be given without any dose adjustments, although its dose may need to be altered based on clinical response. The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors.
    Fenofibrate: (Major) Use caution when coadministering atorvastatin and fenofibrate. Using lower starting and maintenance doses of atorvastatin should be considered. The risk of myopathy increases when HMG-CoA reductase inhibitors are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Fenofibric Acid: (Major) Use caution when coadministering atorvastatin and fenofibric acid. Using lower starting and maintenance doses of atorvastatin should be considered. The risk of myopathy increases when HMG-CoA reductase inhibitors are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Fluconazole: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with fluconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and fluconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Fosamprenavir: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with fosamprenavir alone or in combination with ritonavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabomyolysis increases when atorvastatin is used concomitantly with fosamprenavir or fosamprenavir plus ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 2.3-2.53-fold with the concomitant administration of fosamprenavir and fosamprenavir in combination with ritonavir. In addition, the AUC of fosamprenavir (without ritonavir) was reduced by 27% when coadministered with atorvastain; however, the addition of atorvastatin did not alter the fosamprenavir AUC when fosamprenaivr was boosted with ritonavir. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and fosamprenavir or fosamprenavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Gemfibrozil: (Major) Avoid the concomitant administration of atorvastatin and gemfibrozil. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with atorvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1/3; glecaprevir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin. (Major) Coadministration of pibrentasvir with atorvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin.
    Glimepiride; Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Grapefruit juice: (Major) Grapefruit juice should be avoided in patients taking atorvastatin to avoid the potential for drug accumulation and toxicity (i.e., myopathy and rhabdomyolysis). Grapefruit juice contains a compound that inhibits the CYP3A4 isozyme in the gut wall. In one pharmacokinetic study, coadministration of 240 ml grapefruit juice once daily with a single 40 mg dose of atorvastatin resulted in a 37% increase in the AUC and a 16% increase in Cmax of atorvastatin. Excessive consumption of grapefruit juice (i.e., >= 750 ml to 1.2 L/day) has been reported to result in an up to 2.5-fold increase in AUC and/or a 71% increase in Cmax of atorvastatin.
    Hydantoins: (Moderate) Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
    Idelalisib: (Severe) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with atorvastatin, a CYP3A substrate, as atorvastatin toxicities, such as myopathy, may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Consider an alternative to atorvastatin. A single dose of 10 mg of rosuvastatin was administered alone and after idelalsib150 mg for 12 doses in healthy subjects and no changes in exposure to rosuvastatin were observed.
    Imatinib: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Indinavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with indinavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with CYP3A4 inhibitors such as indinavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and protease inhibitor therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Insulin Degludec; Liraglutide: (Minor) Liraglutide did not change the AUC of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of atorvastatin was decreased by 38% and the median Tmax of atorvastatin was delayed from 1 hour to 3 hours. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If atorvastatin and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered atorvastatin effect.
    Insulin Glargine; Lixisenatide: (Minor) Atorvastatin Cmax and Tmax were decreased approximately 31% and 3.25 hours, respectively, but atorvastatin AUC was not affected when lixisenatide 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days. When atorvastatin was administered in the evening and lixisenatide in the morning, no increase for Tmax was observed, but the atorvastatin AUC and Cmax were increased by 27% and 66%, respectively. The mechanism of this potential interaction has not been described (although it may be due to delayed gastric emptying) and the potential for clinical significance is unknown. Monitor lipid panel for interaction.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with atorvastatin may result in elevated atorvastatin concentrations and increase the risk for adverse reactions, such as myopathy. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of hepatic isoenzyme CYP3A4 as well as the drug transporter P-glycoprotein (P-gp); atorvastatin is a substrate of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Itraconazole: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with itraconazole. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when higher doses of atorvastatin are used concomitantly with itraconazole. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5-3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively). The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and atorvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as atorvastatin, can increase atorvastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Atorvastatin is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in atorvastatin concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketoconazole: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with ketoconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and ketoconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. In addition, because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established.
    Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
    Letermovir: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Liraglutide: (Minor) Liraglutide did not change the AUC of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of atorvastatin was decreased by 38% and the median Tmax of atorvastatin was delayed from 1 hour to 3 hours. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If atorvastatin and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered atorvastatin effect.
    Lixisenatide: (Minor) Atorvastatin Cmax and Tmax were decreased approximately 31% and 3.25 hours, respectively, but atorvastatin AUC was not affected when lixisenatide 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days. When atorvastatin was administered in the evening and lixisenatide in the morning, no increase for Tmax was observed, but the atorvastatin AUC and Cmax were increased by 27% and 66%, respectively. The mechanism of this potential interaction has not been described (although it may be due to delayed gastric emptying) and the potential for clinical significance is unknown. Monitor lipid panel for interaction.
    Lomitapide: (Major) Concomitant use of lomitapide and atorvastatin may result in increased lomitapide concentrations. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Atorvastatin is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to lopinavir; ritonavir inhibition of CYP3A4 metabolism of atorvastatin. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); lopinavir is an OATP1B1 inhibitor.
    Lovastatin; Niacin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and atorvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as atorvastatin, can increase atorvastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Magnesium Hydroxide: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Mephobarbital: (Moderate) Monitor for potential reduced cholesterol lowering efficacy when barbiturates are coadministered with atorvastatin. Barbiturates are significant hepatic CYP3A4 inducers; atorvastatin is a CYP3A4 substrate.
    Mestranol; Norethindrone: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. Area-under-the-curve values for norethindrone and ethinyl estradiol were increased by approximately 30% and 20%, respectively, when atorvastatin was given concurrently. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
    Metformin; Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Methohexital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Mifepristone, RU-486: (Moderate) Coadministration of mifepristone may lead to an increase in serum levels of atorvastatin. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Mifepristone inhibits CYP3A4; atorvastatin is a CYP3A4 substrate. Monitor closely for "statin" related side effects, such as myopathy. The dose of atorvastatin, when administered with a strong CYP3A4 inhibitor, should not exceed 40 mg/day.
    Mitotane: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin.
    Nefazodone: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone.
    Nelfinavir: (Major) Do not exceed 40 mg atorvastatin daily in adults when coadministered with nelfinavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with nelfinavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased by 74% with the concomitant administration of nelfinavir. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and nelfinavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Nevirapine: (Minor) Nevirapine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Niacin, Niacinamide: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Niacin; Simvastatin: (Moderate) The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with antilipemic doses of niacin (i.e., 1 g per day or more). Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Nicardipine: (Moderate) Monitor for evidence of myopathy if nicardipine is coadministered with atorvastatin. Nicardipine is an inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
    Nilotinib: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with atorvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated atorvastatin systemic concentrations. Atorvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme.
    Omeprazole; Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Oritavancin: (Moderate) Atorvastatin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of atorvastatin may be reduced if these drugs are administered concurrently.
    Oxcarbazepine: (Moderate) Monitor for potential reduced cholesterol-lowering efficacy when oxcarbazepine is coadministered with atorvastatin. Oxcarbazepine, which is a CYP3A4 inducer, may decrease the efficacy of atorvastatin, a CYP3A4 substrate.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and atorvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of atorvastatin. Use caution when administering these drugs concomitantly.
    Pentobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Phenobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
    Posaconazole: (Severe) The concurrent use of posaconazole and atorvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If treatment with posaconazole is unavoidable, a brief suspension of atorvastatin therapy can be considered. Coadministration of these drugs may result in elevated atorvastatin plasma concentrations, causing an increased risk for adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for atorvastatin metabolism.
    Primidone: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Quinine: (Moderate) Patients receiving concomitant atorvastatin and quinine should be monitored closely for muscle pain or weakness. Lower starting doses of atorvastatin should be considered while patients are receiving quinine. Atorvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of atorvastatin leading to an increased potential of rhabdomyolysis.
    Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Ranolazine: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
    Red Yeast Rice: (Severe) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with atorvastatin, a CYP3A4 substrate, is necessary, as the systemic exposure of atorvastatin may be increased resulting in an increase in atorvastatin-related adverse reactions.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib, a moderate CYP3A4 inhibitor, with atorvastatin, a CYP3A4 substrate, is necessary, as the systemic exposure of atorvastatin may be increased resulting in an increase in atorvastatin-related adverse reactions.
    Rifabutin: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Rifapentine: (Minor) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of atorvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors (Statins). To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
    Ritonavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and atorvastatin may result in increases in rivaroxaban exposure and may increase bleeding risk. Atorvastatin is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and atorvastatin as coadministration may result in increased systemic exposure of atorvastatin. Atorvastatin is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of atorvastatin.
    Saquinavir: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with saquinavir in combination with ritonavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with saquinavir plus ritonavir. Patients should be monitoried for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.9-fold with the concomitant administration of saquinavir in combination with ritonavir in a pharmacokinetic study; however, the dose of saquinavir plus ritonavir used in the study was lower than doses used in clinical practice. The increase in atorvastatin AUC due to coadministration with clinically appropriate doses of saquinavir plus ritonavir are likely to be even higher. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and saquinavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Sarilumab: (Moderate) In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 45% decrease in simvastatin exposure was noted 1 week after a single sarilumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using sarilumab with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as atorvastatin.
    Secobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
    Siltuximab: (Minor) Caution is warranted in patients with co-administered CYP3A4 substrates, such as atorvastatin, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Simeprevir: (Moderate) Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations. If these drugs are given together, use the lowest effective atorvastatin dose; do not exceed 40 mg daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Sofosbuvir; Velpatasvir: (Major) Montior patient closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gP) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Montior patient closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gP) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4. (Moderate) Caution is advised when administering voxilaprevir with atorvastatin. Taking these drugs together may increase atorvastatin plasma concentrations; thereby increasing the risk for adverse events, such as myopathy or rhabdomyolysis. Initiate atorvastatin at the lowest approved dose. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Atorvastatin is a substrate of P-glycoprotein (P-gp) and Organic Anion Transporting Polypeptides 1B1 (OATP1B1). Voxilaprevir is an inhibitor of both P-gp and OATP1B1.
    Spironolactone: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Coadministration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including atorvastatin.
    Streptogramins: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
    Tacrolimus: (Moderate) The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors may be increased when used with tacrolimus.
    Telaprevir: (Major) The concurrent use of atorvastatin and telaprevir should be avoided because of the potential for serious adverse reactions, including myopathy and rhabdomyolysis. Telaprevir is an inhibitor of CYP3A4, which is responsible for atorvastatin metabolism; coadministration results in significant increases in the pharmacokineitic parameters (AUC and Cmax) of atorvastatin.
    Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) The concurrent use of telithromycin with atorvastatin is not recommended. Therapy with atorvastatin should be suspended while taking telithromycin; there are no known adverse effects with short-term discontinuation of statins. Rhabdomyolysis has been reported during concurrent use of atorvastatin and telithromycin. Telithromycin is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Increased exposure to atorvastatin increases the risk of myopathy and rhabdomyolysis.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and atorvastatin is necessary, as the systemic exposure of atorvastatin may be decreased resulting in reduced efficacy. Monitor patients for suboptimal efficacy of atorvastatin. Atorvastatin is a CYP3A4 substrate; telotristat ethyl is a CYP3A4 inducer.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with atorvastatin is necessary, and monitor for an increase in atorvastatin-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor, while atorvastatin is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to atorvastatin is likely to increase.
    Teriflunomide: (Moderate) Concurrent use of teriflunomide, an inhibitor of the hepatic uptake organic anion transporting polypeptide OATP1B1, with some HMG-CoA reductase inhibitors (Statins), including atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin may increase the AUC of the statin. Administration of cyclosporine, another OATP1B1 inhibitor, increased the plasma AUC of pravastatin 9.9-fold. Additive hepatotoxicity may occur. Caution should also be exercised when using combination dosage forms, such as amlodipine; atorvastatin, ezetimibe; simvastatin, lovastatin; niacin, niacin; simvastatin, and simvastatin; sitagliptin. Monitor patients for signs of myopathy or hepatotoxicity.
    Thiopental: (Minor) Significant CYP3A4 inducers, such as thiopental, may decrease the efficacy of HMG-CoA reductase inhibitors, such as atorvastatin, which are CYP3A4 substrates. Monitor for potential reduced cholesterol-lowering efficacy when thiopental is coadministered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
    Tipranavir: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with tipranavir and ritonavir. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 9.4-fold with the concomitant administration of tipranavir in combination with ritonavir.
    Tocilizumab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as atorvastatin.
    Trandolapril; Verapamil: (Major) Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concenrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Atorvastatin is a substrate of PGP and CYP3A4 and an inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Major) Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Voriconazole: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with voriconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and voriconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Warfarin: (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and atorvastatin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Atorvastatin is contraindicated for use in women who are breast-feeding. It is likely that atorvastatin is excreted to some degree in human milk. In animal studies, nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Cholesterol and other products of cholesterol biosynthesis are essential components for infant development; atorvastatin may also have other adverse effects on the nursing infant. If the drug is absolutely necessary to the mother, nursing should be discontinued. Otherwise, since atherosclerosis and its complications are a chronic health issue, discontinuation of atorvastatin for some time in order to allow for nursing of an infant would be expected to have little effect on the long-term outcomes associated with hypercholesterolemia. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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 para-hydroxylated metabolites which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear to undergo enterohepatic recirculation. Less than 2% of an oral dose is recovered in the urine. The mean plasma elimination half-life 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), and OATP1B1
    Atorvastatin is a substrate of CYP3A4 hepatic metabolism. Atorvastatin is also a substrate of P-gp and OATP1B1 transporters and an inhibitor of P-gp. 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.

    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. 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 following evening doses compared with morning dosing and LDL-cholesterol reduction is the same regardless of the time of day the drug is administered.