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  • CLASSES

    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 (simvastatin); results in synergistic cholesterol-lowering effects; 10—80 mg of simvastatin with ezetimibe achieves LDL reductions of approximately > 51%
    Used for primary hypercholesterolemia or mixed hyperlipidemia; also effective for homozygous familial hypercholesterolemia
    Myopathy, including rhabdomyolysis, is greater in patients receiving 80 mg/day of simvastatin compared to lower doses or other statin therapies; therefore, 10/80 mg dose is restricted to patients who have taken 10/80 mg/day chronically (e.g. >= 12 months) without evidence of myopathy

    COMMON BRAND NAMES

    Vytorin

    HOW SUPPLIED

    Ezetimibe, Simvastatin/Vytorin 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 (e.g., LDL apheresis) or if such treatments are unavailable.
    Oral dosage
    Adults

    Usual starting dose is ezetimibe 10 mg/simvastatin 10 mg or ezetimibe 10 mg/simvastatin 20 mg PO once daily in the evening. May initiate at ezetimibe 10 mg/simvastatin 40 mg PO once daily in the evening 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/simvastatin 40 mg once daily in the evening. After initiation or titration of doses, lipid levels may be analyzed after 2 or more weeks. The usual dosage range for Vytorin is ezetimibe 10 mg/simvastatin 10 mg to Vytorin ezetimibe 10 mg/simvastatin 40 mg PO, given once daily in the evening. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. NOTE: The ezetimibe 10 mg/simvastatin 80 mg dose should only be used in patients who have taken ezetimibe 10 mg/simvastatin 80 mg chronically (e.g. 12 months or longer) without evidence of myopathy. Patients who are taking ezetimibe 10 mg/simvastatin 40 mg and are unable to reach their target LDL-C goal should be switched to an alternative agent and not be titrated to ezetimibe 10 mg/simvastatin 80 mg. Also, Chinese patients taking lipid-modifying doses of niacin-containing products should receive doses lower than 80 mg/day.[29596]

    Children 10 years or older and Adolescents (males and postmenarchal females only)

    Usual starting dose is ezetimibe 10 mg/simvastatin 10 mg or ezetimibe 10 mg/simvastatin 20 mg PO once daily in the evening (Max: ezetimibe 10 mg/simvastatin 40 mg). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 males and 106 postmenarchal females aged 10 to 17 years were randomized to receive either ezetimibe 10 mg/simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin alone (10 mg, 20 mg, or 40 mg) for 6 weeks, then ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg monotherapy for the next 27 weeks. After this time, patients received open-label ezetimibe coadministered with simvastatin (10 mg, 20 mg, or 40 mg) for 20 more weeks. Total cholesterol, LDL, Apo B, Non-HDL cholesterol, and triglycerides were all reduced more in the ezetimibe plus simvastatin group compared to the simvastatin monotherapy group. There was no effect on growth or sexual maturation in the males or females and no effect on menstrual cycle length in the females in this study. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO ezetimibe and 40 mg/day PO simvastatin for most patients; 80 mg/day PO simvastatin for patients already taking 80 mg/day chronically without evidence of myopathy.

    Geriatric

    10 mg/day PO ezetimibe and 40 mg/day PO simvastatin for most patients; 80 mg/day PO simvastatin for patients already taking 80 mg/day chronically without evidence of myopathy.

    Adolescents

    10 mg/day PO ezetimibe and 40 mg/day PO simvastatin.

    Children

    >= 10 years: 10 mg/day PO ezetimibe and 40 mg/day PO simvastatin.
    < 10 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Ezetimibe; simvastatin is contraindicated in patients with active hepatic disease or unexplained persistent elevations in hepatic transaminases.

    Renal Impairment

    CrCl >= 60 mL/min: No dosage adjustment necessary.
    CrCl < 60 mL/min and chronic kidney disease: 10 mg/day PO ezetimibe and 20 mg/day PO simvastatin; higher doses should be used with caution and close monitoring.

    ADMINISTRATION

    Oral Administration

    Administer ezetimibe; simvastatin as a single daily dose in the evening, with or without food.
    Dosing should occur either >= 2 hours before or >= 4 hours after administration of an interacting bile acid sequestrant.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the ezetimibe and simvastatin together. Consult individual drug monographs for more detailed information.

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

    Ezetimibe; simvastatin is contraindicated in patients with active hepatic disease including cholestasis, hepatic encephalopathy, hepatitis, jaundice or unexplained persistent elevations in serum aminotransferase concentrations. In addition, patients should minimize alcohol intake while receiving ezetimibe; simvastatin therapy, and ezetimibe; simvastatin should be avoided in patients with alcoholism. Assess liver enzymes prior to initiation of ezetimibe; simvastatin 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. Instruct patients to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice) during ezetimibe; simvastatin therapy. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ezetimibe; simvastatin, therapy should be interrupted. If an alternate etiology is not found, do not restart ezetimibe; simvastatin.

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

    Discontinue ezetimibe; simvastatin immediately in any patient who develops myopathy, elevations in CPK, or signs of rhabdomyolysis. The risk of myopathy, including rhabdomyolysis, is greater in patients receiving 80 mg/day of simvastatin compared to lower doses or other statin therapies. Therefore, the 10/80 mg dose of ezetimibe; simvastatin is restricted to patients who have taken 10/80 mg/day chronically (e.g. 12 months or greater) without evidence of myopathy. The risk is highest during the first year of treatment, and patients 65 years or older, females, and those with uncontrolled hypothyroidism appear to be predisposed to developing myopathy. Ezetimibe; simvastatin is contraindicated in organ transplant patients receiving immunosuppressant therapy such as cyclosporine because of an increased risk of rhabdomyolysis and renal failure. The risk of developing myopathy is increased when ezetimibe; simvastatin is used in combination with CYP3A4 inhibitors or drugs that have an independent risk of myopathy. The manufacturer suggests a lower maximum dosage of ezetimibe; simvastatin when used with some drugs known to increase the risk of myopathy. If a patient who is stabilized on the 10/80 mg/day dose needs to be initiated on an interacting drug that is contraindicated or is associated with a lower maximum simvastatin dose, then that patient should be switched to an alternative statin with less potential for the drug interaction. Chinese patients taking lipid-modifying doses of niacin-containing products (1 g/day or greater of niacin) should not receive the 80 mg dose of simvastatin due to an increased risk for myopathy. Simvastatin may be contraindicated in conditions that can cause decreased renal perfusion since renal failure is possible if simvastatin-induced rhabdomyolysis occurs. Predisposing conditions include renal disease or renal insufficiency, hypotension, acute infection, endocrine disease, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. Although in the SHARP trial there was no significant difference in the incidence of adverse events between ezetimibe 10/20 mg/day PO and placebo in patients with moderate-to-severe renal impairment, higher doses of ezetimibe; simvastatin should be approached with caution and close clinical monitoring because renal impairment is a risk factor for statin-associated myopathy.

    Geriatric

    Some geriatric patients may be more sensitive to the effects of the usual adult dosage of simvastatin; dosage should be individualized to achieve serum lipoprotein goals. A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in patients aged 70—78 compared with patients aged 18—30 years. However, long-term therapy with 20—80 mg/day PO has been used safely in elderly patients in clinical trials, with no differences in safety compared to younger patients. In the 4S trial and the Heart Protection Study, 23% and 52% of the patients, respectively, were elderly. The were no differences in the cardiovascular or stroke protection benefits of simvastatin between older and younger patients in these clinical outcome trials.

    Immune-mediated necrotizing myopathy

    Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as atorvastatin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.    Prior to starting the patient on another HMG-CoA reductase inhibitor, the risks of therapy should be carefully considered. Any patient started on an alternate HMG-CoA reductase inhibitor should be monitored for signs and symptoms of IMNM.

    Breast-feeding

    Ezetimibe; simvastatin is contraindicated for use in breast-feeding women. 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, and there may be other adverse effects to the nursing infant. The importance of continued ezetimibe; simvastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or to discontinue therapy.[29596] If pharmacotherapy is necessary for 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.[30812] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Pregnancy

    Ezetimibe; simvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. If the patient becomes pregnant while taking this ezetimibe; simvastatin, discontinue therapy immediately and inform the patient of the potential hazard to the fetus.[29596] 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.[24910] 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. Ezetimibe; Simvastatin should only be administered to females of child-bearing potential, including adolescents at least 1-year post-menarche, when such patients are highly unlikely to conceive and have been informed of the potential hazards.[29596]

    Children, infants, neonates

    The safety and efficacy of ezetimibe; simvastatin combinations have not been established in neonates, infants, children < 10 years, or in pre-pubertal females. Counsel adolescent females regarding appropriate methods of contraception while on therapy. The long-term efficacy of therapy in childhood to reduce morbidity and mortality later in adulthood has not been established. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children in not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8—10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.

    Asian patients

    Chinese patients taking lipid-modifying doses of niacin-containing products (niacin 1 g/day or greater) should not receive ezetimibe; simvastatin due to increased risk for myopathy. In a double-blind, randomized cardiovascular outcomes trial, there was an increased incidence of myopathy in Chinese patients compared with non-Chinese patients taking ezetimibe; simvastatin 10/40 mg or simvastatin 40 mg/day coadministered with extended-release niacin 2 g/day. Chinese patients may be at increased risk for myopathy; coadministration of lipid-modifying dose niacin (1 g/day or greater) with ezetimibe; simvastatin or simvastatin should be avoided in this patient population. It is unknown if this increased risk of myopathy observed in Chinese patients applies to other Asian patients.[29596]

    Diabetes mellitus

    If ezetimibe; simvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose 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 simvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established. 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—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 one or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI >= 30 kg/m2, or HbA1c > 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—0.79, p = 0.0001),nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, 0.39—1.06, p = 0.08) and total mortality (0.83, 0.64—1.07, p = 0.15), and a 28% increase in diabetes (1.28, 1.07—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—0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, 0.21—1.03, p = 0.05) and total mortality (HR 0.78, 0.59—1.03, p = 0.08), and no increase in diabetes (HR 0.99, 0.45—2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

    Contraception requirements

    Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while receiving ezetimibe; simvastatin therapy.[29596]

    Myasthenia gravis

    Exacerbation and induction of myasthenia gravis have been reported during treatment with statins, including simvastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

    ADVERSE REACTIONS

    Severe

    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    atrial fibrillation / Early / Incidence not known
    cholecystitis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    myasthenia gravis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0.7-3.6
    cataracts / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    depression / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    headache / Early / 5.8-5.8
    infection / Delayed / 3.6-3.6
    diarrhea / Early / 2.8-2.8
    influenza / Delayed / 2.3-2.3
    musculoskeletal pain / Early / 2.3-2.3
    rash / Early / 0.6-0.6
    pruritus / Rapid / 0.5-0.5
    myalgia / Early / 3.6
    vertigo / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    flatulence / Early / Incidence not known
    fatigue / Early / Incidence not known
    back pain / Delayed / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    malaise / Early / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    dizziness / Early / Incidence not known
    insomnia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amiodarone: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
    Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Atorvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Benazepril: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Celecoxib: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Olmesartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Valsartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
    Amprenavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Antacids: (Minor) 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: (Moderate) Use caution if simvastatin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simvastatin-related adverse effects, including myopathy and rhabdomyolysis, for several days after administration of a multi-day aprepitant regimen. Simvastatin 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 simvastatin. 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; Citric Acid; Sodium Bicarbonate: (Minor) 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.
    Atazanavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Atazanavir; Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Barbiturates: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
    Bempedoic Acid: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
    Bempedoic Acid; Ezetimibe: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
    Berotralstat: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Simvastatin is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor.
    Boceprevir: (Contraindicated) The concurrent use of simvastatin and boceprevir is contraindicated due to the potential for serious/life-threatening reactions. Boceprevir is a potent inhibitor of CYP3A4, which is responsible simvastatin metabolism. Coadministration may result in large increases in simvastatin serum concentrations, which could cause adverse events such as myopathy and rhabdomyolysis.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
    Bosentan: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
    Calcium Carbonate: (Minor) 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; Famotidine; Magnesium Hydroxide: (Minor) 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: (Minor) 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: (Minor) 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; Simethicone: (Minor) 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.
    Cannabidiol: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with cannabidiol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; cannabidiol is a P-gp inhibitor.
    Carbamazepine: (Minor) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, including simvastatin.
    Ceritinib: (Contraindicated) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlorzoxazone: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
    Cholestyramine: (Moderate) 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: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration 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: (Moderate) Monitor for evidence of myopathy, including rhabdomyolysis, during coadministration of ciprofloxacin and simvastatin. There are case reports of rhabdomyolysis in patients stabilized on a simvastatin regimen after the addition of ciprofloxacin. Ciprofloxacin may increase simvastatin exposure. Simvastatin is a substrate for CYP3A4; ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
    Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
    Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    Colesevelam: (Moderate) 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: (Moderate) 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: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Crizotinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Contraindicated) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. (Major) 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: (Moderate) Consider a statin other than lovastatin or simvastatin if HMG-CoA reductase inhibition is necessary for a patient receiving dabigatran. Increased serum concentrations of dabigatran are possible when coadministered with lovastatin. If use together is medically necessary, patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. A mechanism for this interaction may be the inhibition of P-gp by simvastatin; dabigatran is a P-gp substrate. In one clinical trial, patients receiving dabigatran with lovastatin or simvastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Danazol: (Contraindicated) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
    Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
    Darolutamide: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
    Darunavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Darunavir; Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
    Delavirdine: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Concomitant use of delavirdine and the CYP3A4 substrate simvastatin is not recommended. 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: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
    Diltiazem: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism by diltiazem.
    Dronedarone: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
    Duvelisib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with duvelisib is necessary. Coadministration may increase the exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4 and duvelisib is a moderate CYP3A4 inhibitor.
    Efavirenz: (Moderate) Efavirenz has 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 simvastatin with caution.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz has 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 simvastatin with caution.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has 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 simvastatin with caution.
    Elbasvir; Grazoprevir: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for simvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of simvastatin. Simvastatin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3. (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Eltrombopag: (Moderate) 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. (Moderate) Use caution and monitor for adverse reactions if eltrombopag and simvastatin are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as simvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
    Enasidenib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
    Encorafenib: (Moderate) Coadministration of encorafenib with simvastatin may result in increased toxicity or decreased efficacy of simvastatin. Simvastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Erythromycin: (Contraindicated) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Erythromycin; Sulfisoxazole: (Contraindicated) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
    Etravirine: (Moderate) The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors. Concomitant use of etravirine and simvastatin (CYP3A4 substrate) may result in lower plasma concentrations of the HMG-CoA reductase inhibitor; dose adjustments for may be necessary.
    Everolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
    Fedratinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
    Fenofibrate: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. 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. (Moderate) Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    Fenofibric Acid: (Moderate) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure is increased with higher doses of simvastatin. 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. (Moderate) 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.
    Flibanserin: (Moderate) In a cross-over study in 12 healthy men and women, the effect of flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily was evaluated. Flibanserin increased the AUC of simvastatin, a substrate of CYP3A4, by 1.3-fold and the Cmax by 1.2-fold. The AUC and Cmax of simvastatin acid were increased by 1.5-fold and 1.4-fold, respectively.
    Fluconazole: (Major) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with CYP3A4 inhibitors including systemic fluconazole. There are no known adverse effects with short-term discontinuation of simvastatin; discontinuation of simvastatin may be advisable when concurrent short-term therapy with systemic fluconazole is needed.
    Fluvoxamine: (Moderate) Coadministration of fluvoxamine (CYP3A4 inhibitor) and simvastatin (CYP3A4 substrate) would be expected to result in an increase in simvastatin serum concentrations. Elevation of simvastatin serum concentrations can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Monitor patients receiving concomitant simvastatin and fluvoxamine closely for muscle pain or weakness.
    Fosamprenavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Fostamatinib: (Moderate) Monitor for simvastatin toxicities that may require simvastatin dose reduction if given concurrently with fostamatinib. Coadministration of fostamatinib with simvastatin increased the AUC by 64% and Cmax by 113%. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; simvastatin is a sensitive substrate for CYP3A4.
    Fostemsavir: (Moderate) Use the lowest possible starting dose for simvastatin when administered concurrently with fostemsavir and monitor for signs of simvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together may increase the systemic exposure of simvastatin. Simvastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
    Gemfibrozil: (Contraindicated) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1. (Major) 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.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of OATP1B1/3; glecaprevir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin. (Major) Coadministration of pibrentasvir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of the drug transporters OATP1B1/3; pibrentasvir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin.
    Grapefruit juice: (Major) Large quantities of grapefruit juice are contraindicated during simvastatin therapy due to the increased risk of myopathy. Grapefruit juice contains compounds that inhibits the CYP3A4 isozyme in the gut wall. Coadministration with grapefruit juice increases the peak serum concentrations and the AUC of lovastatin and may have a similar effect on the serum concentrations of simvastatin. Grapefruit juice should be avoided or minimized in patients taking simvastatin to avoid the potential for myopathy and rhabdomyolysis.
    Hydantoins: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as simvastatin, leading to reduced efficacy of simvastatin.
    Idelalisib: (Contraindicated) Coadministration of idelalisib, a strong CYP3A inhibitor, with simvastatin, a CYP3A substrate, is contraindicated as simvastatin toxicities, including the risk for myopathy, may be significantly increased. Consider an alternative to simvastatin.
    Imatinib: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
    Indinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Isavuconazonium: (Moderate) Closely monitor for evidence of myopathy, including rhabdomyolysis if simvastatin and isavuconazonium are coadministered. Concomitant use of isavuconazonium with simvastatin may result in increased serum concentrations of simvastatin. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of CYP3A4.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Itraconazole: (Contraindicated) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of simvastatin during coadministration of ivosidenib; a simvastatin dose adjustment may be necessary. Simvastatin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased simvastatin concentrations.
    Ketoconazole: (Contraindicated) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
    Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
    Lefamulin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oral lefamulin is necessary. Simvastatin is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
    Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
    Letermovir: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
    Levamlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Lomitapide: (Major) Reduce the simvastatin dose by 50% when starting lomitapide due to an increased risk for myopathy, including rhabdomyolysis. In patients taking lomitapide, do not exceed a simvastatin dose of 20 mg/day in general, or 40 mg/day in patients who have previously tolerated simvastatin 80 mg/day for at least 1 year without evidence of muscle toxicity. For patients chronically receiving simvastatin 80 mg/day who need to be started on lomitapide, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of lomitapide and simvastatin against the potential risks. Lomitapide increases the simvastatin exposure by approximately 2-fold.
    Lonafarnib: (Contraindicated) Coadministration of simvastatin and lonafarnib is contraindicated due to the risk of elevated plasma concentrations of simvastatin leading to myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and a P-gp substrate; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
    Lopinavir; Ritonavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Lovastatin; Niacin: (Major) There is no clear indication for routine use of niacin in combination with simvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with simvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue simvastatin immediately if myopathy is diagnosed or suspected. Coadministration is not recommended in Chinese patients, as the risk of myopathy is greater in this population. It is unknown if this risk applies to other Asian patients.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Maralixibat: (Minor) Maralixibat may reduce the oral absorption of HMG-CoA reductase inhibitors, also known as statins, which may reduce their efficacy. This risk is greatest with maralixibat doses greater than 4.75 mg. Monitor statin therapy and adjust the dose as needed based on clinical response. Maralixibat is a OATP2B1 inhibitor and statins are OATP2B1 substrates.
    Metformin; Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia.
    Mifepristone: (Contraindicated) When mifepristone is used in the treatment of Cushing's syndrome, coadministration is contraindicated based on studies demonstrating significant simvastatin exposure increases which may lead to an increased risk of myopathy and rhabdomyolysis. Consider interruption of simvastatin therapy during use of mifepristone for pregnancy termination. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Mifepristone is a strong CYP3A4 inhibitor; simvastatin is a sensitive CYP3A4 substrate. Coadministration of mifepristone and simvastatin increased simvastatin and simvastatin acid exposure by 10.4-fold and 15.7-fold, respectively, in drug interaction studies.
    Mitotane: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
    Nefazodone: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
    Nelfinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Neratinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nevirapine: (Minor) Nevirapine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
    Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with simvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with simvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue simvastatin immediately if myopathy is diagnosed or suspected. Coadministration is not recommended in Chinese patients, as the risk of myopathy is greater in this population. It is unknown if this risk applies to other Asian patients.
    Niacin; Simvastatin: (Major) There is no clear indication for routine use of niacin in combination with simvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with simvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue simvastatin immediately if myopathy is diagnosed or suspected. Coadministration is not recommended in Chinese patients, as the risk of myopathy is greater in this population. It is unknown if this risk applies to other Asian patients.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to simvastatin. Simvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Omeprazole; Amoxicillin; Rifabutin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Omeprazole; Sodium Bicarbonate: (Minor) 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.
    Oxcarbazepine: (Minor) Oxcarbazepine which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are coadministered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and simvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of simvastatin. Use caution when administering these drugs concomitantly.
    Perindopril; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with simvastatin. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Posaconazole: (Contraindicated) The concurrent use of posaconazole and simvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If therapy with posaconazole is unavoidable, simvastatin therapy must be suspended during the course of posaconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Probenecid; Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
    Propranolol: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
    Protease inhibitors: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Quinine: (Moderate) Patients receiving concomitant simvastatin and quinine should be monitored closely for muscle pain or weakness. Simvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of simvastatin leading to an increased potential of rhabdomyolysis. Lower starting doses of simvastatin should be considered while patients are receiving quinine. Discontinue simvastatin if marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values greater than 10 times the upper limit of normal) is diagnosed or suspected.
    Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Ranolazine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
    Red Yeast Rice: (Contraindicated) 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.
    Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia.
    Ribociclib: (Contraindicated) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Contraindicated) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
    Rifabutin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ritonavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Saquinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Sarilumab: (Moderate) Utilize caution with concomitant use of sarilumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. A 45% decrease in simvastatin exposure was noted 1 week after a single sarilumab dose. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
    Siltuximab: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Simeprevir: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sirolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
    Sodium Bicarbonate: (Minor) 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: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3. (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of voxilaprevir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate OATP1B1; voxilaprevir is an inhibitor of OATP1B1.
    Sotorasib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; sotorasib is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including simvastatin.
    Tacrolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
    Telaprevir: (Contraindicated) The concurrent use of simvastatin and telaprevir is contraindicated due to the potential for serious/life-threatening reactions. Telaprevir is an inhibitor of CYP3A4, which is responsible simvastatin metabolism. Coadministration may result in large increases in simvastatin serum concentrations, which could cause adverse events such as myopathy and rhabdomyolysis.
    Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Contraindicated) Telithromycin is contraindicated during simvastatin therapy. Telithromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, therapy with simvastatin must be suspended during telithromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin. Pharmacokinetic studies have reported increased simvastatin concentrations due to CYP3A4 inhibition by telithromycin. When the two drugs were coadministered, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in the AUC, a 15-fold increase in the active metabolite Cmax, and a 12-fold increase in the active metabolite AUC. In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4-fold increase in AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. Increased serum concentrations of HMG-CoA reductase inhibitors are associated with myopathy. Additionally, simvastatin is a substrate for organic anion transport protein (OATP) and telithromycin may act as an inhibitor for the hepatic organic anion transport protein (OATP) uptake transporters OATP1B1 and OATP1B3.
    Telmisartan; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
    Tepotinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with tepotinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; tepotinib is a P-gp inhibitor.
    Teriflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
    Tesamorelin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
    Tezacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Ticagrelor: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Tipranavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Tocilizumab: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
    Trandolapril; Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
    Tucatinib: (Contraindicated) Concurrent use of simvastatin and tucatinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism by verapamil.
    Viloxazine: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
    Voclosporin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; voclosporin is a P-gp and OATP1B1 inhibitor.
    Voriconazole: (Contraindicated) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Warfarin: (Moderate) 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. (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, 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.
    Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.

    PREGNANCY AND LACTATION

    Pregnancy

    Ezetimibe; simvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. If the patient becomes pregnant while taking this ezetimibe; simvastatin, discontinue therapy immediately and inform the patient of the potential hazard to the fetus.[29596] 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.[24910] 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. Ezetimibe; Simvastatin should only be administered to females of child-bearing potential, including adolescents at least 1-year post-menarche, when such patients are highly unlikely to conceive and have been informed of the potential hazards.[29596]

    Ezetimibe; simvastatin is contraindicated for use in breast-feeding women. 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, and there may be other adverse effects to the nursing infant. The importance of continued ezetimibe; simvastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or to discontinue therapy.[29596] If pharmacotherapy is necessary for 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.[30812] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin 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. When used in combination with 10—80 mg of either simvastatin, combined use with ezetimibe achieved LDL-reductions of approximately > 51% compared to 36% with simvastatin monotherapy.
    •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.
    •Simvastatin: Like lovastatin, simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin's several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, cholesterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL. Simvastatin decreases serum total cholesterol (serum total-C), LDL-cholesterol, VLDL, triglycerides (TG), and apolipoprotein B (Apo-B), while increasing HDL-C. Simvastatin is administered in the evening hours since there is evidence for diurnal variation in the hepatic synthesis of cholesterol. HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

    PHARMACOKINETICS

    The combination of ezetimibe; simvastatin is administered orally. No clinically significant pharmacokinetic interactions have been noted when ezetimibe was co-administered with the HMG-CoA reductase inhibitors studied (e.g., simvastatin). Concomitant administration of ezetimibe has no significant effect on the bioavailability of these statins; the bioavailability of total ezetimibe is also unaffected. The ezetimibe; simvastatin product is bioequivalent to the drugs coadministered separately.
    Ezetimibe: 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. Following absorption, 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 co-administration has no significant effect on specific probe drugs known to be metabolized by cytochrome P-450 enzymes (CYP1A2, CYP2D6, CYP2C8/9 and CYP3A4 isoenzymes). In addition, cimetidine (a non-specific cytochrome P-450 inhibitor) has no effect on the bioavailability of ezetimibe or total ezetimibe. 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 (T½) of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. Following 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.
    Simvastatin: Simvastatin is an inactive prodrug. It is the methylated derivative of lovastatin and, like lovastatin, must be activated in the liver. Both simvastatin and the active metabolite are strongly bound to plasma proteins (95%). Simvastatin and lovastatin are lipophilic, while pravastatin is hydrophilic. Being lipophilic, simvastatin is taken up by cells other than hepatocytes and, unlike pravastatin, simvastatin penetrates the CNS. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. The half-life (T½) of simvastatin is 1.9 hours

    Oral Route

    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%.
    Simvastatin: Absorption is about 85%, but bioavailability is less than 5%. Absorption is not significantly reduced if taken before a low-fat meal; the drug can be administered with or without food. To optimize the action of simvastatin, it should be administered in the evening hours or at bedtime. Peak plasma concentrations are reached in 1.3—2.4 hours.