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    HMG-CoA Reductase Inhibitors (Statins)

    DEA CLASS

    Rx

    DESCRIPTION

    Oral HMG Co-A reductase inhibitor; used for hypercholesterolemia or hypertriglyceridemia; reduces LDL, total cholesterol, TG, and apolipoprotein B; increases HDL; improves mortality in patients with CAD; more potent than fluvastatin or pravastatin; FDA-approved for stroke prophylaxis and homozygous familial hypercholesterolemia.

    COMMON BRAND NAMES

    FloLipid, Zocor

    HOW SUPPLIED

    FloLipid Oral Susp: 1mL, 4mg, 8mg
    Simvastatin/Zocor Oral Tab: 5mg, 10mg, 20mg, 40mg, 80mg

    DOSAGE & INDICATIONS

    For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; and for reduction in cardiovascular mortality, including myocardial infarction prophylaxis and stroke prophylaxis.
    Oral dosage
    Adults

    Initially, 10 to 20 mg PO once daily in the evening. Patients with homozygous familial hypercholesterolemia or patients with coronary heart disease (CHD) or risk factors for CHD should start at a dose of 40 mg PO once daily in the evening. The usual dosage range is 5 to 40 mg PO once daily (mean LDL reduction range: 26 to 47%). Adjust dosage based on serum lipid determinations performed after four weeks of therapy and periodically thereafter. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. NOTE: The 80 mg/day dose should only be used in patients who have taken 80 mg chronically (e.g. at least 12 months) without evidence of myopathy. Patients who are taking 40 mg and are unable to achieve desired LDL reduction should be switched to an alternative agent and not be titrated to 80 mg.

    Adolescents and Children 10 years and older

    10 mg PO once daily in the evening. The recommended dosage range is 10 to 40 mg/day PO. Doses more than 40 mg/day PO have not been studied. Females should be at least 1 year post menarche. Adjust dosage at intervals of four weeks or more to attain the target LDL and lipid goals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Simvastatin is FDA-approved for the treatment of heterozygous familial hypercholesterolemia and is recommended for hyperlipidemia when either: 1) the LDL remains 190 mg/dL or more, or 2) the LDL remains 160 mg/dL or more and there is an increased risk for cardiovascular disease (e.g., positive family history of premature cardiovascular disease or two or more other risk factors are present). In a randomized, placebo controlled trial of pediatric patients with heterozygous familial hypercholesterolemia (n = 173), mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 30.9%, 40.7%, and 8.7%, respectively, after 48 weeks of treatment with simvastatin 40 mg/day PO. In a study of pediatric patients with total cholesterol more than 300 mg/dL after six months of diet modification, 16 patients younger than 17 years received a mean simvastatin dose of 16 mg daily for two years. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 25.5%, 37.3%, and 8.8%, respectively, and mean HDL concentrations were increased by 22.5%.

    Children younger than 10 years†

    An initial dose of 5 mg PO once daily titrated up to 10 to 20 mg PO once daily has been used in small studies. Although pharmacologic therapy is not routinely recommended for patients younger than 10 years of age, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a study of pediatric patients with total cholesterol more than 300 mg/dL after six months of diet modification, patients younger than 10 years of age (specific ages not reported) were started on simvastatin 5 mg PO once daily. Doses were increased, if necessary, to 10 mg PO once daily after four weeks and then increased further after an additional four weeks to 20 mg PO once daily. Sixteen patients younger than 17 years received a mean simvastatin dose of 16 mg daily for two years. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 25.5%, 37.3%, and 8.8%, respectively, and mean HDL concentrations were increased by 22.5%. In a study of pediatric patients with hyperlipidemia secondary to kidney disorders (n = 25 including three patients younger than 10 years, [4 years, 5 years, and 10 years]), an initial dose of 5 mg PO once daily was administered to patients weighing less than 30 kg, and an initial dose of 10 mg PO once daily to patients 30 kg or more. Doses were doubled after one month. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 23.3%, 33.7%, and 21%, respectively, after three months of treatment.

    For slowing the progression of coronary atherosclerosis†.
    Oral dosage
    Adults

    Initially, 20 to 40 mg PO once daily in the evening. The usual dosage range is 20 to 40 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In the Multicenter Anti-Atheroma Study (MAAS), 381 patients were treated with diet and either simvastatin 20 mg/day PO or placebo for a period of four years. Treatment with simvastatin reduced hyperlipidemia and slowed the progression of coronary atherosclerosis based on quantitative coronary angiography. NOTE: The 80 mg/day dose should only be used in patients who have taken 80 mg chronically (e.g. 12 months or more) without evidence of myopathy. Patients who are taking 40 mg and are unable to achieve desired LDL reduction should be switched to an alternative agent and not be titrated to 80 mg. Also, Chinese patients taking lipid-modifying doses of niacin-containing products should receive doses lower than 80 mg/day.

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

    Dosage not established. 40 to 80 mg PO once daily for 14 to 21 days has been used.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

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

    Adolescents

    40 mg/day PO.

    Children

    10 to 12 years: 40 mg/day PO.
    Less than 10 years: Safety and efficacy have not been established; however, doses up to 20 mg/day PO have been included in some study protocols.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Contraindicated in patients with active hepatic disease or with unexplained or persistent hepatic transaminase elevations.

    Renal Impairment

    The initial dose for adult patients with severe renal impairment is 5 mg PO once daily in the evening; close monitoring is advised. Dosage adjustments are not recommended for adult patients with mild to moderate renal impairment. Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available.
     
    Intermittent hemodialysis
    The hemodialyzability of simvastatin and its metabolites is unknown.

    ADMINISTRATION

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

    Oral Administration

    Avoid administration with grapefruit juice to avoid potential increases in drug serum concentrations.
    As peak cholesterol synthesis occurs in the early morning hours, evening dosing is recommended.

    Oral Solid Formulations

    Administer without regard to food once daily in the evening.

    Oral Liquid Formulations

    Shake the bottle well. Measure dosage with an oral syringe or calibrated measuring device.
    Administer on an empty stomach once daily in the evening.
    Storage: Use within 30 days of opening the bottle; store at room temperature (20 to 25 degrees C or 68 to 77 degrees F). Do not freeze or refrigerate.

    STORAGE

    FloLipid:
    - Avoid exposure to heat
    - Do not freeze
    - Do not refrigerate
    - Do not use more than 30 days after opening
    - Store at or below 77 degrees F
    Zocor:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Simvastatin is contraindicated in any patient with simvastatin hypersensitivity or hypersensitive to any component of the medication.

    Alcoholism, cholestasis, ethanol ingestion, hepatic decompensation, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Simvastatin is contraindicated in patients with certain types of hepatic disease, specifically acute liver failure and decompensated cirrhosis (hepatic decompensation). Elevations in serum transaminases have been reported with simvastatin therapy, including persistent increases to more than 3 times the upper limit of normal (ULN). In most cases, the serum transaminase elevations occurred soon after therapy initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or following a brief interruption in therapy. Fatal and non-fatal hepatic failure have rarely been reported with postmarketing use of statins, including simvastatin. Patients who consume large amounts of alcohol or have a history of liver disease, including cholestasis, hepatic encephalopathy, hepatitis, or jaundice, are at an increased risk for hepatic injury. In addition, patients should minimize ethanol ingestion while receiving simvastatin therapy, and simvastatin should be avoided in patients with alcoholism. Consider assessing liver enzymes prior to initiation of 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). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, therapy should be promptly discontinued.

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

    Simvastatin may cause myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) more than 10 times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with elevations in creatine phosphokinase (CPK) and may be accompanied by acute renal failure secondary to myoglobinuria; rare fatalities have occurred. Simvastatin should be discontinued immediately in any patient who develops myopathy, elevations in CPK, or signs of rhabdomyolysis. Since the risk of myopathy and rhabdomyolysis is dose-related, careful monitoring is needed at times of therapy initiation and at dose increases. The risk of myopathy, including rhabdomyolysis, is greater in patients receiving 80 mg/day compared to lower doses or other statin therapies. Therefore, the 80 mg dose is restricted to patients who have taken 80 mg/day chronically (e.g. 12 months or more) without evidence of myopathy. The risk is highest during the first year of treatment. Predisposing risk factors for myopathy and/or rhabdomyolysis include advanced age, females, renal disease or renal insufficiency, hypotension, acute infection, endocrine disease such as uncontrolled hypothyroidism, electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. Simvastatin may need to be temporarily withheld in patients experiencing these conditions acutely. The risk of developing myopathy is also increased when HMG-CoA reductase inhibitors are used in combination with CYP3A4 inhibitors or drugs that have an independent risk of myopathy; some drugs are contraindicated for use with simvastatin for this reason. In addition, the manufacturer suggests a lower maximum dosage of simvastatin when used with some drugs known to increase the risk of myopathy. Simvastatin is contraindicated in organ transplant patients receiving cyclosporine because of an increased risk of rhabdomyolysis and renal failure. If a patient who is stabilized on the 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 gram/day or more 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. Because simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin is administered to patients with severe renal impairment; such patients require lower initial doses and should be closely monitored.

    Asian patients

    Chinese patients taking lipid-modifying doses of niacin-containing products (1 gram/day or more of niacin) should not receive 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 simvastatin 40 mg or ezetimibe; simvastatin 10/40 mg coadministered with extended-release niacin 2 g/day. It is unknown if this increased risk of myopathy observed in Chinese patients applies to other Asian patients.[28605]

    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. 

    Diabetes mellitus

    If simvastatin is initiated in a patient with diabetes mellitus, increased monitoring of blood glucose control may be warranted. Increased 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 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with 1 or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or A1C greater than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, CI 0.21 to 1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

    Pregnancy

    Simvastatin therapy should be discontinued once pregnancy is identified in most patients.  Alternatively, consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or with established cardiovascular disease. Based on the mechanism of action, simvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant women and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy.[28605] In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Temporary discontinuation of lipid-lowering therapy, such as simvastatin, should have minimal impact on the long-term therapy of primary hyperlipidemia, as atherosclerosis is a chronic process. Advise pregnant patients and patients of child-bearing potential, including female adolescents at least 1 year post-menarche, of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.[28605]

    Geriatric

    Because advanced age (65 years or more) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in geriatric patients. Some older adults 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 to 78 years compared with adults aged 18 to 30 years. However, long-term therapy with 20 mg to 80 mg/day PO of simvastatin has been used safely in geriatric patients in clinical trials, with no differences in safety compared to younger adult 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. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications.

    Breast-feeding

    Simvastatin is not recommended for use in breast-feeding women. There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. 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 simvastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or to discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    Children, infants

    Safety and efficacy of simvastatin have not been established in infants and children less than 10 years of age. The long-term efficacy of statin 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 is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.

    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

    atrial fibrillation / Early / 5.7-5.7
    cirrhosis / Delayed / 0-1.0
    hepatic failure / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-0.1
    myoglobinuria / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    myasthenia gravis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 2.2-6.6
    gastritis / Delayed / 4.9-4.9
    edema / Delayed / 2.7-2.7
    elevated hepatic enzymes / Delayed / 0.4-1.0
    memory impairment / Delayed / 0-1.0
    amnesia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    myopathy / Delayed / 0.1-0.6
    myasthenia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    infection / Delayed / 3.2-9.0
    headache / Early / 2.5-7.4
    abdominal pain / Early / 5.9-7.3
    nausea / Early / 5.4-5.4
    vertigo / Early / 4.5-4.5
    insomnia / Early / 4.0-4.0
    myalgia / Early / 3.7-3.7
    sinusitis / Delayed / 2.3-2.3
    dyspepsia / Early / Incidence not known
    flatulence / Early / Incidence not known
    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    drowsiness / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    fever / Early / Incidence not known
    lichen planus-like eruption / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    rash / Early / Incidence not known
    malaise / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    dizziness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abrocitinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with abrocitinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; abrocitinib is a P-gp inhibitor.
    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.
    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.
    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.
    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.
    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.
    Capmatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with capmatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; capmatinib 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.
    Carvedilol: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.
    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.
    Cimetidine: (Moderate) Use HMG-CoA reductase inhibitors with caution with concomitant drugs that may decrease the levels or activity of endogenous steroids, such as cimetidine. Evaluate patients with signs and symptoms of endocrine dysfunction appropriately. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
    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 CYP3A; ciprofloxacin is a moderate CYP3A 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).
    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.
    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 CYP3A 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 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.
    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 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) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate and encorafenib is an OATP1B1 inhibitor.
    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.
    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: (Moderate) 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.
    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.
    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: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
    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.
    Futibatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
    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.
    Gilteritinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    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) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
    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 CYP3A 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.
    Lasmiditan: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lasmiditan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; lasmiditan is a P-gp inhibitor.
    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.
    Levoketoconazole: (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 CYP3A 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.
    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.
    Maribavir: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with maribavir is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; maribavir is a P-gp inhibitor.
    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.
    Midostaurin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
    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 CYP3A inhibitor; simvastatin is a sensitive CYP3A 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.
    Mitapivat: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with mitapivat is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; mitapivat is a P-gp inhibitor.
    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.
    Nanoparticle Albumin-Bound 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.
    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: (Moderate) Monitor for reduced cholesterol-lowering efficacy of simvastatin if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
    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.
    Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and simvastatin is contraindicated. Discontinue use of simvastatin at least 12 hours before, during, and 5 days after treatment with ritonavir-boosted nirmatrelvir. Coadministration may increase simvastatin exposure resulting in increased toxicity. Simvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A 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.
    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.
    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.
    Pacritinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pacritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pacritinib is a P-gp inhibitor.
    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.
    Pretomanid: (Major) Avoid coadministration of pretomanid with simvastatin, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
    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).
    Propafenone: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
    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.
    Selpercatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with selpercatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; selpercatinib is a P-gp inhibitor.
    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.
    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.
    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 CYP3A 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 CYP3A 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.
    Vonoprazan; 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.
    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.
    Voxelotor: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voxelotor is necessary. Simvastatin is a sensitive CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
    Warfarin: (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

    Simvastatin therapy should be discontinued once pregnancy is identified in most patients.  Alternatively, consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or with established cardiovascular disease. Based on the mechanism of action, simvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant women and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy.[28605] In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Temporary discontinuation of lipid-lowering therapy, such as simvastatin, should have minimal impact on the long-term therapy of primary hyperlipidemia, as atherosclerosis is a chronic process. Advise pregnant patients and patients of child-bearing potential, including female adolescents at least 1 year post-menarche, of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.[28605]

    Simvastatin is not recommended for use in breast-feeding women. There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. 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 simvastatin therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or to discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    MECHANISM OF ACTION

    Mechanism of Action: 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 total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL. In one head-to-head study of simvastatin vs. pravastatin involving 291 patients, simvastatin produced slightly greater improvements in total, LDL, and HDL cholesterol and triglycerides after 6 weeks. Both drugs were given in a dose of 10 mg PO once daily. It should be noted that higher doses can produce more dramatic results. These agents should be administered at bedtime 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

    Simvastatin is administered orally. It is an inactive prodrug, 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 absorbed dose is excreted in the feces and 13% in the urine. The half-life is 1.9 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, OATP1B1
    Simvastatin is a substrate of CYP3A4 and CYP2D6 hepatic metabolism. It has multiple significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and toxicity including myopathy and rhabdomyolysis. The risk of myopathy is increased by high concentrations of HMG-CoA reductase inhibitory activity in plasma and is dose-related. Any patient receiving a drug known to increase simvastatin serum concentrations or increase the risk of myopathy should be carefully monitored for potential myalgia, myopathy, myasthenia, and/or rhabdomyolysis. It does not affect the metabolism CYP3A4 substrates. Simvastatin acid is also a substrate of the transport protein OATP1B1. Coadministration with inhibitors of OATP1B1 may lead to increased plasma concentrations of simvastatin acid.

    Oral Route

    Oral absorption is 60% to 85%, but bioavailability is less than 5%. Peak plasma concentrations are reached in 1.3 to 2.4 hours. Absorption is not significantly reduced if taken before a low-fat meal. In a food effect study for the oral suspension, administration with a high fat meal (about 540 calories and 56% fat) resulted in an 18% decrease in simvastatin AUC and 44% increase in beta-hydroxyacid simvastatin (active form) AUC compared to exposures observed in the fasted state.