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    HMG-CoA Reductase Inhibitors/Statins and Other Lipid Modifying Agent Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antilipemic combination of a potent cholesterol absorption inhibitor (ezetimibe) and HMG-CoA reductase inhibitor (atorvastatin); results in synergistic cholesterol-lowering effects
    Used for primary or mixed hyperlipidemia and as an adjunct in patients with homozygous familial hypercholesterolemia
    No incremental benefit on cardiovascular morbidity and mortality has been demonstrated with ezetimibe; atorvastatin over atorvastatin alone

    COMMON BRAND NAMES

    Liptruzet

    HOW SUPPLIED

    Liptruzet Oral Tab: 10-10mg, 10-20mg, 10-40mg, 10-80mg

    DOSAGE & INDICATIONS

    For use as an adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia or mixed hyperlipoproteinemia AND for reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments.
    Oral dosage
    Adults

    Usual starting dose is ezetimibe 10 mg/atorvastatin 10 mg or ezetimibe 10 mg/atorvastatin 20 mg PO once daily at any time of day with or without food. May initiate at ezetimibe 10 mg/atorvastatin 40 mg PO once daily for patients requiring a larger reduction in LDL-C (greater than 55%). The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe 10 mg/atorvastatin 40 mg/day or ezetimibe 10 mg/atorvastatin 80 mg/day PO. After initiation or titration of doses, lipid levels may be analyzed after 2 or more weeks. Adjust dosage, as needed to achieve the target LDL and lipid goals based on the NCEP guidelines. The usual dosage range is ezetimibe 10 mg/atorvastatin 10 mg to ezetimibe 10 mg/atorvastatin 80 mg/day PO.

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

    Do not exceed ezetimibe 10 mg/atorvastatin 20 mg PO once daily due to the increased risk for myopathy and rhabdomyolysis.

    Adults taking boceprevir or nelfinavir

    Do not exceed ezetimibe 10 mg/atorvastatin 40 mg PO once daily due to the increased risk for myopathy and rhabdomyolysis.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO ezetimibe and 80 mg/day PO atorvastatin for most patients.

    Geriatric

    10 mg/day PO ezetimibe and 80 mg/day PO atorvastatin for most patients.

    Adolescents

    Safety and efficacy have not been established.

    Children

    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

    Atorvastatin; ezetimibe is contraindicated in patients with active hepatic disease or unexplained transaminase elevations.

    Renal Impairment

    No dosage adjustment is needed.

    ADMINISTRATION

    Oral Administration

    Administer atorvastatin; ezetimibe as a single daily dose at any time of the day, with or without food.
    Tablets should be swallowed whole. Tablets should not be crushed, dissolved, or chewed.
    Dosing should occur either >= 2 hours before or >= 4 hours after administration of an interacting bile acid sequestrant.

    STORAGE

    Liptruzet:
    - Do not use more than 30 days after opening
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place
    - Store unused product in foil pouch

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the atorvastatin and ezetimibe together. Consult individual drug monographs for more detailed information.
     
    Atorvastatin is contraindicated in patients with atorvastatin hypersensitivity or hypersensitive ezetimibe or to any components of the product selected.

    Alcoholism, hepatic disease

    Atorvastatin; ezetimibe is contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum aminotransferase concentrations. Atorvastatin; ezetimibe should be used with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of liver disease. Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic 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; ezetimibe 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; ezetimibe.

    Electrolyte imbalance, endocrine disease, females, hypotension, hypothyroidism, infection, myopathy, renal impairment, rhabdomyolysis, seizure disorder, 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; ezetimibe 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; ezetimibe 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.

    Contraception requirements, pregnancy

    Atorvastatin; ezetimibe is contraindicated for use during pregnancy and in women who may become pregnant. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. 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; ezetimibe should be administered to females of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Contraception requirements are advised; females 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; ezetimibe is contraindicated for use during breast-feeding. Atorvastatin may pass into human milk. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway; other adverse effects to the nursing infant are possible. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. 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 thus 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. 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.

    Stroke

    Use atorvastatin; ezetimibe 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.

    Diabetes mellitus

    If atorvastatin; ezetimibe 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 greater 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.

    Geriatric

    Since advanced age (65 years or more) is a predisposing risk factor for myopathy, atorvastatin; ezetimibe 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. 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.

    Children, infants

    The safety and efficacy of atorvastatin; ezetimibe in infants or children less than 18 years of age or in pre-pubertal females have not been established. Other HMG CoA reductase inhibitors, used as monotherapy, have been approved for use in selected pediatric patients. childBecause 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.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    diabetes mellitus / Delayed / 6.1-6.1
    elevated hepatic enzymes / Delayed / 0.7-5.0
    confusion / Early / 0-1.0
    amnesia / Delayed / 0-1.0
    memory impairment / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    myopathy / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    pharyngitis / Delayed / 8.3-8.3
    diarrhea / Early / 4.1-6.8
    dyspepsia / Early / 4.7-4.7
    musculoskeletal pain / Early / 4.0-4.0
    insomnia / Early / 3.0-3.0
    arthralgia / Delayed / 3.0-3.0
    nausea / Early / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    fatigue / Early / 2.4-2.4
    dizziness / Early / 2.0-2.0
    weakness / Early / 2.0-2.0
    cough / Delayed / 2.0-2.0
    sinusitis / Delayed / 2.0-2.0
    influenza / Delayed / 2.0-2.0
    asthenia / Delayed / 0-1.0
    flushing / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    malaise / Early / 0-1.0
    photosensitivity / Delayed / 0-1.0
    chills / Rapid / 0-1.0
    fever / Early / 0-1.0
    purpura / Delayed / 0-1.0
    paresthesias / Delayed / Incidence not known
    headache / Early / Incidence not known
    myalgia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: 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: 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: 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.
    Afatinib: If the concomitant use of atorvastatin and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of atorvastatin. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and atorvastatin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Aliskiren: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Amiodarone: 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: 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: 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. Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Amoxicillin; Clarithromycin; Omeprazole: 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. Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Antacids: Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered. Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Aprepitant, Fosaprepitant: 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: 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: 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; Omeprazole: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Atazanavir: Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. 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. 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: The plasma concentrations of atorvastatin may increase when administered with cobicistat. Use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events. Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. 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. 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: 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: 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. 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: Both atorvastatin and azithromycin are P-glycoprotein (P-gp) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: 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: 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: Close clinical monitoring is advised when coadministering atorvastatin with boceprevir due to an increased potential for atorvastatin-related adverse events. During coadministration, the lowest effective atorvastatin dose is recommended, and a maximum dose of 40 mg daily should not be exceeded. If dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways. Atorvastatin is a substrate of the drug efflux transporter P-glycoprotein (P-gp) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated atorvastatin plasma concentrations.
    Bortezomib: 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: 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: 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: 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: 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: Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered. Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Calcium Carbonate; Magnesium Hydroxide: Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered. Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered. Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Calcium Carbonate; Risedronate: Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered. Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Calcium; Vitamin D: Concomitant administration of atorvastatin with antacids (Maalox TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered. Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Carbamazepine: Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, such as atorvastatin.
    Carvedilol: 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: Ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp); atorvastatin is a P-gp inhibitor. Increased concentrations of ceritinib are possible if it is coadministered with atorvastatin; exercise caution.
    Cholestyramine: The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants, such as cholestyramine. The incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively.
    Cimetidine: 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: 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: 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: 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: The plasma concentrations of atorvastatin may increase when administered with cobicistat. Use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: The plasma concentrations of atorvastatin may increase when administered with cobicistat. Use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: The plasma concentrations of atorvastatin may increase when administered with cobicistat. Use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events. Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as atorvastatin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: If concurrent use of cobimetinib and atorvastatin is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and atorvastatin is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Colchicine: 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.
    Colesevelam: The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colesevelam with ezetimibe; however, this potential interaction has not been studied.
    Colestipol: 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. The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol with ezetimibe; however, this potential interaction has not been studied.
    Conivaptan: 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: 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: Use caution if coadministration of atorvastatin with crizotinib is necessary, due to the risk of increased atorvastati exposure and-related adverse reactions; there is also a small chance of increased crizotinib exposure. Monitor patients for statin-related toxicity, including myopathy or rhabdomyolysis. Atorvastatin is a CYP3A4 and P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor, as well as a P-gp inhibitor at clinically relevant concentrations. Coadministration with crizotinib increased the AUC of a sensitive CYP3A4 substrate by 3.7-fold. Additionally, crizotinib is a P-gp substrate in vitro and atorvastatin is a weak P-gp inhibitor. When multiple doses of atorvastatin and another P-gp substrate were coadministered, steady-state concentrations of the P-gp substrate increased by approximately 20%.
    Cyclosporine: 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. Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
    Dabigatran: Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with atorvastatin, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like atorvastatin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with atorvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: 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: Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
    Danazol: 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: 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: Do not exceed 20 mg atorvastatin daily in adults when coadministered with darunavir 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 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: Do not exceed 20 mg atorvastatin daily in adults when coadministered with darunavir 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 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. The plasma concentrations of atorvastatin may increase when administered with cobicistat. Use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: 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: 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: 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: 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.
    Doxorubicin: Atorvastatin is a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of atorvastatin and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronedarone: 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: 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: 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.
    Edoxaban: Coadministration of edoxaban and atorvastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and atorvastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of atorvastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: 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: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as atorvastatin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. 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: 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: 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: 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. Use caution and monitor for adverse reactions if eltrombopag and ezetimibe are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as ezetimibe, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as atorvastatin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as atorvastatin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Erlotinib: 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: 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: 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: 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.
    Esomeprazole: Atorvastatin is a HMG-CoA reductase inhibitor (statin) recognized as a substrate and inhibitor of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin with esomeprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Esomeprazole; Naproxen: Atorvastatin is a HMG-CoA reductase inhibitor (statin) recognized as a substrate and inhibitor of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin with esomeprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Ethinyl Estradiol: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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.
    Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with atorvastatin. Atorvastatin is an inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: 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.
    Everolimus: Immunosuppressants such as everolimus, especially when used along with cyclosporine, can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine. Deterioration of renal function increases the risk for myopathy and rhabomyolysis with lipid-lowering therapy such as the HMG-CoA reductase inhibitors (statins). Carefully monitor for renal function deterioration and symptoms of myopathy. Because of the interaction of statins with cyclosporine, clinical trials of everolimus and cyclosporine in kidney transplant patients strongly discouraged patients from receiving either simvastatin or lovastatin. Population pharmacokinetic analyses detected no influence of simvastatin, a CYP3A4 substrate, on the clearance of everolimus. Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin, or everolimus to a clinically relevant extent; however, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Creatine phosphokinase (CPK) levels should be assessed in patients reporting symptoms of muscle toxicity, and the statin should be discontinued if markedly elevated CPK levels occur or myopathy or myositis is suspected or diagnosed.
    Fenofibrate: 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. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    Fenofibric Acid: 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. Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Fluconazole: 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: 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: 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. The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Glimepiride; Pioglitazone: 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: 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: 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: 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: 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, STI-571: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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.
    Lansoprazole: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Lansoprazole; Naproxen: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Lanthanum Carbonate: Oral compounds known to interact with antacids, like HMG-CoA reductase inhibitors, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Ledipasvir; Sofosbuvir: Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Both ledipasvir and atorvastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Liraglutide: 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: 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: 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.
    Loperamide: The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with atorvastatin, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with atorvastatin, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: 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. 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: 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: 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: 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: Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Maraviroc: Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and atorvastatin as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); atorvastatin is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mephobarbital: 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: 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: 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: 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: 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: 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: Nefazodone may reduce the metabolism of atorvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with either lovastatin or simvastatin. 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: 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: Nevirapine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Niacin, Niacinamide: 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: 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: 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: Concomitant use of nilotinib, a CYP3A4 inhibitor and a substrate and inhibitor of P-glycoprotein (P-gp) and atorvastatin, a CYP3A4 and P-gp substrate, may result in increased atorvastatin levels. A atorvastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy.
    Nintedanib: Atorvastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of atorvastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Olaparib: Use caution if coadministration of olaparib with atorvastatin is necessary, due to an increased risk of atorvastatin- and olaparib-related adverse reactions. Atorvastatin is a P-glycoprotein (P-gp) substrate / inhibitor, as well as a substrate of OATP1B1. Olaparib is also an in vitro P-gp substrate / inhibitor, and an inhibitor of OATP1B1. Atorvastatin increased steady-state plasma concentrations of digoxin, another P-gp substrate, by approximately 20%. The clinical relevance is unknown.
    Ombitasvir; Paritaprevir; Ritonavir: 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. In addition, atorvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates.
    Ombitasvir; Paritaprevir; Ritonavir: 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.
    Omeprazole: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Omeprazole; Sodium Bicarbonate: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction. Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered. Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Oritavancin: 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.
    Osimertinib: Use caution if coadministration of osimertinib and atorvastatin is necessary, due to the risk of increased exposure to osimertinib. Atorvastatin is a P-glycoprotein (P-gp) inhibitor and osimertinib is a P-gp substrate in vitro. When multiple doses of atorvastatin and digoxin, another P-gp substrate, were co-administered, steady-state plasma digoxin concentrations increased by approximately 20%. Coadministration may increase osimertinib-related adverse reactions.
    Oxcarbazepine: 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.
    Pantoprazole: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Pazopanib: 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: 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: 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: 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: 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. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for atorvastatin metabolism. Further, both drugs are substrates of the drug efflux protein P-glycoprotein; concurrent administration may increase the absorption or decrease the clearance of the other drug. Coadministration of these drugs may result in elevated atorvastatin plasma concentrations, causing an increased risk for adverse events.
    Primidone: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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.
    Rifaximin: Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and atorvastatin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: 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: 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: 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: 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: 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: 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: 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: 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: Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered. Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Sofosbuvir; Velpatasvir: 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.
    Spironolactone: 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: 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: Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
    Tacrolimus: The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors may be increased when used with tacrolimus.
    Telaprevir: 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: 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: 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: Use caution if coadministration of telotristat ethyl and atorvastatin is necessary, as the systemic exposure of atorvastatin may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of atorvastatin as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of atorvastatin if necessary. Atorvastatin is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and atorvastatin is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: Use caution if coadministration of temsirolimus with atorvastatin is necessary, and monitor for an increase in temsirolimus- and atorvastatin-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro, while atorvastatin is also a P-gp substrate/inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both atorvastatin and temsirolimus (and active metabolite, sirolimus) is likely to increase.
    Tenofovir, PMPA: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as atorvastatin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Teriflunomide: 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: 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.
    Ticagrelor: Coadministration of ticagrelor and atorvastatin may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and atorvastatin is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tigecycline: Coadministration of P-glycoprotein (P-gp) inhibitors, such as atorvastatin, may increase tigecycline serum concentrations. Based on an in vitro study, tigecycline is a P-gp substrate; however, the potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.
    Tipranavir: 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: 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.
    Topotecan: Avoid the concomitant use of atorvastatin, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of atorvastatin and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to combination products containing atorvastatin, including amlodipine; atorvastatin and atorvastatin; ezetimibe. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Trandolapril; Verapamil: Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Vandetanib: Use vandetanib and atorvastatin together with caution; atorvastatin levels may increase resulting in increased adverse events. Atorvastatin is a P-glycoprotein (P-gp) substrate; vandetanib increased the AUC and Cmax values of a sensitive P-gp substrate by 23% and 29%.
    Vemurafenib: 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.
    Venetoclax: Avoid the concomitant use of venetoclax and atorvastatin. Venetoclax is a substrate of P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; atorvastatin is a substrate and an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering atorvastatin at least 6 hours before venetoclax. If atorvastatin is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: Verapamil may increase the serum concentrations of atorvastatin. Verapamil is a CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate.
    Vincristine Liposomal: Atorvastatin inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: Atorvastatin inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: Caution is warranted when atorvastatin is administered with vinorelbine as there is a potential for elevated vinorelbine concentrations; this may also apply to combination products that contain atorvastatin, such as amlodipine; atorvastatin and atorvastatin; ezetimibe. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression. Vinorelbine is a substrate of P-glycoprotein (P-gp) and atorvastatin is an inhibitor of P-gp.
    Voriconazole: 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: Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. 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: 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; ezetimibe is contraindicated for use during pregnancy and in women who may become pregnant. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. 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; ezetimibe should be administered to females of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Contraception requirements are advised; females 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.

    MECHANISM OF ACTION

    Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Atorvastatin and ezetimibe exhibit synergistic mechanisms that reduce elevated serum total-C, LDL-C, Apo B, TG, and non-HDL-C concentrations and increase serum HDL-C concentrations through inhibition of cholesterol absorption and synthesis. The effects of combined therapy with ezetimibe and HMG-CoA reductase inhibitors ('statins') result in greater LDL reductions and therapeutic benefit than either ezetimibe or statin monotherapy.
     
    Atorvastatin: 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 up-regulation 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.
    Ezetimibe: Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents. Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Ezetimibe localizes and appears to act at the brush border of the small intestine. It inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2 week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo. In humans, the effects of ezetimibe to reduce triglycerides (TG) (8%) or to lower HDL-cholesterol (1%) are less prominent than the LDL-lowering effects; ezetimibe therapy usually increases HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content. In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.

    PHARMACOKINETICS

    Atorvastatin; ezetimibe is administered orally. Atorvastatin; ezetimibe is bioequivalent and has been shown to be clinically equivalent in LDL-C response to corresponding coadministered doses of atorvastatin and ezetimibe.
    Atorvastatin: Atorvastatin is administered orally. Atorvastatin is >= 98% bound to plasma proteins. A blood/plasma ratio of 0.25 indicates poor drug penetration into red blood cells. Animal data reveal that atorvastatin is likely to be secreted in human milk. Atorvastatin undergoes extensive metabolism to active ortho- and parahydroxylated metabolites which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Based on in vitro studies, hepatic cytochrome p450 enzyme CYP3A4 may also contribute to the metabolism of atorvastatin. In animals, the ortho-hydroxy metabolite is further metabolized by glucuronidation. Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear that the drug undergoes enterohepatic recirculation. Less than 2% of an oral dose is recovered in the urine. The mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, however, the half-life of HMG-CoA reductase inhibitory activity is 20—30 hours because of the active metabolites.
    Ezetimibe: Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10—20% and 80—90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. After oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10 day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.

    Oral Route

    Atorvastatin: Following oral administration, atorvastatin is rapidly absorbed with peak plasma concentrations occurring within 1—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%. Pre-systemic 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.
    Ezetimibe: The absolute bioavailability of ezetimibe is not known. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, co-administration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%.