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    HMG-CoA Reductase Inhibitors/Statins

    DEA CLASS

    Rx

    DESCRIPTION

    Most potent, oral HMG-CoA reductase inhibitor
    Approved for primary hypercholesterolemia, hyperlipoproteinemia and/or hypertriglyceridemia, heterozygous familial hypercholesterolemia (for patients 8 to 17 years), homozygous familial hypercholesterolemia (for patients 7 years and older), and primary prevention of cardiovascular disease
    Limited metabolism; less potential for CYP3A4 drug interactions compared to simvastatin or lovastatin

    COMMON BRAND NAMES

    Crestor, Ezallor

    HOW SUPPLIED

    Crestor/Rosuvastatin/Rosuvastatin Calcium Oral Tab: 5mg, 10mg, 20mg, 40mg
    Rosuvastatin Oral Cap Coated Pellets: 5mg, 10mg, 20mg, 40mg

    DOSAGE & INDICATIONS

    For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control.
    For slowing the progression of atherosclerosis (e.g., carotid, coronary).
    Oral dosage (rosuvastatin tablets)
    Adults

    The usual starting dose is 10 mg PO once daily. A lower starting dosage of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg once daily. The overall dosage range is 5 to 40 mg PO once daily. Doses of 5 mg, 10 mg, 20 mg, and 40 mg per day reduce LDL-cholesterol by 45%, 52%, 55%, and 63%, respectively. Intensive lipid-lowering with 40 mg once daily has been shown to reduce the progression of carotid and coronary atherosclerosis in clinical trials (ASTEROID and METEOR studies).[33273] [33274] However, 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who require further LDL-reduction after receiving 20 mg/day. Adjust the initial dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[27988]

    For reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations, and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson types IIa or IIb); or to treat Fredrickson Type IV (hypertriglyceridemia, increased VLDL); or to treat primary dysbetalipoproteinemia (Type III hyperlipoproteinemia).
    Oral dosage (rosuvastatin tablets)
    Adults

    The usual starting dose is 10 mg PO once daily. A lower starting dose of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg PO once daily. The overall dosage range is 5 to 40 mg PO once daily. Doses of 5 mg, 10 mg, 20 mg, and 40 mg PO per day reduce LDL-cholesterol by 45%, 52%, 55%, and 63%, respectively. A dosage of 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who require further LDL-reduction after receiving 20 mg/day. The manufacturer originally intended to seek approval for an 80 mg dose; however, 2 patients developed renal toxicity while receiving this dose. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the reduction of total cholesterol, LDL-cholesterol, nonHDL-cholesterol, and apolipoprotein B concentrations in patients with homozygous familial hypercholesterolemia (HoFH).
    Oral dosage (rosuvastatin tablets)
    Adults

    The usual starting dose is 20 mg PO once daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Rosuvastatin may be used as an adjunct to other lipid-lowering therapy (e.g., LDL apheresis) when available. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[27988]

    Children and Adolescents 7 to 17 years

    20 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Oral dosage (rosuvastatin capsules)
    Adults

    The usual starting dose is 20 mg PO once daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Maximum dose is 40 mg once daily and used in patients unable to achieve LDL-C goals with 20 mg/day. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Rosuvastatin may be used as monotherapy or an adjunct to other lipid-lowering therapy (e.g., LDL apheresis) when available. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the reduction of total cholesterol, LDL-cholesterol, and apolipoprotein B concentrations in pediatric patients with heterozygous familial hypercholesterolemia (HeFH).
    NOTE: Rosuvastatin is indicated for patients with HeFH who, after an adequate trial of diet therapy, have LDL-C higher than 190 mg/dL or LDL-C higher than 160 mg/dL and have a positive family history of premature cardiovascular disease or two or more other CVD risk factors.
    Oral dosage (rosuvastatin tablets)
    Children and Adolescents 10 to 17 years

    5 to 20 mg PO once daily is the usual dosage range. Individualize dosage based on the goals of therapy. Dosage adjustments should be made at intervals of 4 weeks or more. Doses above 20 mg/day PO have not been studied in this population. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    Children 8 to 9 years

    5 to 10 mg PO once daily is the usual dosage range. Individualize dosage based on the goals of therapy. Dosage adjustments should be made at intervals of 4 weeks or more. Doses above 10 mg/day PO have not been studied in this population. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of hypertriglyceridemia or primary dysbetalipoproteinemia (Type III hyperlipoproteinemia).
    Oral dosage (rosuvastatin capsules)
    Adults

    The usual starting dose is 10 mg to 20 mg PO once daily. A lower starting dose of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg PO once daily. The overall dosage range is 5 to 40 mg PO once daily.  A dosage of 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who have not reached their LDL-C goal with 20 mg/day. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For primary prevention of cardiovascular disease including myocardial infarction prophylaxis and stroke prophylaxis, and to reduce the risk of arterial revascularization procedures in patients without evidence of coronary heart disease but who have risk factors for cardiovascular disease.
    NOTE: Increased risk of cardiovascular disease is based on age (50 years and older in men and 60 years and older in women), elevated C-reactive protein concentrations (greater than or equal to 2mg/L), and the presence of at least one additional cardiovascular disease risk factor (e.g.,hypertension, low HDL-C concentrations, smoking, or family history of premature coronary heart disease).
    Oral dosage (rosuvastatin tablets)
    Adults

    The usual starting dose is 10 to 20 mg PO daily, with a dose range of 5 to 40 mg PO daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Dosage adjustments should be made at 2 to 4-week intervals to achieve target goals for LDL-cholesterol. The dose used in the JUPITER study was 20 mg PO once daily. JUPITER was a randomized, double-blind, placebo-controlled multicenter trial assessing 17,802 men and women with LDL-C concentrations less than 130 mg/dL and C-reactive protein concentrations (CRP) greater than or equal to 2 mg/L. Patients were followed for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[27988] [34555]

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO.

    Geriatric

    40 mg/day PO.

    Adolescents

    20 mg/day PO (rosuvastatin tablets). Safety and efficacy of rosuvastatin capsules have not been established.

    Children

    7 to 12 years: 20 mg/day PO (rosuvastatin tablets). Safety and efficacy of rosuvastatin capsules have not been established.
    1 to 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Not recommended in patients with hepatic disease (see Contraindications).

    Renal Impairment

    CrCl 30 ml/min or greater: No dosage adjustment needed.
    CrCl less than 30 ml/min: Initially, 5 mg PO once daily for patients not receiving dialysis. Maximum dosage is 10 mg PO once daily. Rosuvastatin serum concentrations are increased approximately 3-fold in patients with severe renal impairment (CrCl less than 30 ml/min) vs. patients with normal renal function.[27988][63844]
     
    Intermittent hemodialysisUntil further data are available for hemodialysis patients, it would be prudent to initiate dosage at the lower end of the dosage range (e.g., 5 mg PO once daily), and adjust dosage to attain target LDL and lipid goals. Although the manufacturer does not provide dosage adjustment recommendations for patients receiving hemodialysis, rosuvastatin serum concentrations are increased by approximately 50% in patients receiving hemodialysis vs. patients with normal renal function. According to the manufacturer, hemodialysis does not significantly enhance the clearance of rosuvastatin.

    ADMINISTRATION

    Oral Administration

    May administer without regard to food. Food may decrease the rate of absorption by 20%, but does not affect the overall bioavailability.[27113]
    Tablets and capsules should be swallowed whole.
    Instruct patients not to take 2 doses of rosuvastatin within 12 hours of each other.[27988]
    Evening or morning administration does not affect rosuvastatin pharmacokinetics or cholesterol-lowering effects.[27534]

    Oral Solid Formulations

    Capsules (e.g., Ezallor) administration
    Capsules should not be crushed or chewed.
    Capsules may be opened and the granules emptied onto one teaspoon of applesauce and immediately swallowed without chewing. Prepare just prior to administration; do not store for future use. Administer the entire dosage.
    Nasogastric tube administration: For administration via nasogastric (NG) tube, the capsule may be opened and granuales emptied into 60 mL catheter tipped syringe. Add 40 mL of water, replace the plunger, and shake vigorously for 15 seconds. It is acceptable if the granuales begin to dissolve. Administer through the NG tube (16 French or greater). Flush NG tube with 60 mL of water following rosuvastatin administration. Prepare just prior to administration; do not store for future use. Administer the entire dosage. Use of other liquids not recommended.

    STORAGE

    Crestor:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ezallor:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Rosuvastatin is contraindicated in patients with a known hypersensitivity to rosuvastatin or any component of the products. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin.

    Alcoholism, hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Rosuvastatin, like other HMG-CoA reductase inhibitors, is contraindicated in patients with active hepatic disease (e.g., hepatic encephalopathy, hepatitis, jaundice) or unexplained persistent elevations in serum aminotransferase concentrations. In addition, patients should minimize alcohol intake while receiving rosuvastatin therapy, and rosuvastatin should be avoided in patients with alcoholism. Assess liver enzymes prior to initiation of rosuvastatin 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.[49066] 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 rosuvastatin, therapy should be interrupted. If an alternate etiology is not found, do not restart rosuvastatin.[27988] [63844]

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

    Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level but increase in a dose-dependent manner with 40 mg/day having the highest risk. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK). The current labeling recommends that the 40 mg/day dose of rosuvastatin be reserved only for those patients who have not achieved their LDL-C goal utilizing 20 mg PO once daily; do not exceed a maximum dose of 40 mg/day in any patient due to an increased risk for myopathy, rhabdomyolysis and renal dysfunction with higher dosages. Rosuvastatin should be discontinued immediately in any patient who develops myopathy, elevations in creatine kinase (CK), or evidence of drug-induced rhabdomyolysis or a decrease in renal function. Predisposing risk factors for myopathy include advanced age (65 years or more), renal disease or renal insufficiency, females, hypotension, acute infection, endocrine disease (including uncontrolled hypothyroidism), electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of developing myopathy is also increased when HMG-CoA reductase inhibitors are used in combination with selected drugs, such as fibrates, lipid-modifying doses of niacin, gemfibrozil, itraconazole, certain protease inhibitors, cyclosporine, and colchicine. The drug may need to be temporarily withheld during acute medical conditions or temporary prescribing of interacting agents to help mitigate risks.[27988] Since rosuvastatin undergoes minimal hepatic metabolism, the potential for drug interactions is expected to be less than with 'statins' metabolized by CYP3A4 isoenzymes such as atorvastatin, cerivastatin, lovastatin, and simvastatin.[27113] [27114] Rosuvastatin should be used with caution in patients with pre-existing significant renal impairment who are generally at a higher risk of developing rhabdomyolysis during therapy with HMG-CoA reductase inhibitors. Patients receiving the highest rosuvastatin dosage of 40 mg/day were found to have an increased frequency of hematuria and proteinuria (1.3%) compared to those on lower dosages or other HMG CoA-reductase inhibitors. In patients who have unexplained persistent proteinuria or hematuria during routine urinalysis testing, reduce the rosuvastatin dosage. Relative to other statins, a significant percentage (28%) of rosuvastatin is excreted renally. Rosuvastatin serum concentrations are increased approximately 3-fold in patients with severe renal impairment (i.e., creatinine clearance or CrCl less than 30 mL/minute not on hemodialysis) and thus a lower rosuvastatin daily dosage is recommended for these patients. Hemodialysis does not appreciably remove the drug.[27988]

    Asian patients

    Use caution in prescribing rosuvastatin to Asian patients. Pharmacokinetic studies show an approximate 2-fold elevation in median exposure in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore compared with Caucasians residing in North America and Europe. The contribution of environmental and genetic factors to the difference observed has not been determined. However, these increases should be considered when making rosuvastatin dosing decisions for Asian patients of Japanese and Chinese ancestry and consider lower starting and maximum doses.

    Diabetes mellitus

    If rosuvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose control may be warranted. Increased hemoglobin A1C, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes mellitus should be considered when initiating rosuvastatin 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

    Rosuvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Counsel females of reproductive potential to use effective contraception during rosuvastatin treatment. Rosuvastatin should be discontinued as soon as pregnancy is confirmed. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. It has been hypothesized that lipophilic statins (e.g., simvastatin, lovastatin) have a higher affinity for the embryotic and extra-hepatic tissues. A review of case reports examined the use of several statins during pregnancy and the correlation of birth defects. The study suggested that more highly lipophilic statins resulted in more adverse birth defect outcomes, yet further studies are needed to establish this correlation. At this time, there are no well-controlled studies of rosuvastatin use in pregnant women. In a prospective review of about 100 pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during rosuvastatin treatment. Rosuvastatin may cause fetal harm if administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with rosuvastatin.[27988] [63844]The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of rosuvastatin on the pituitary-gonadal axis in pre-menopausal females, are unknown. Patients treated with rosuvastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately.[27988]

    Breast-feeding

    Rosuvastatin is contraindicated during breast-feeding. Limited data indicate rosuvastatin is excreted into human breast milk. There are no data on 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; other adverse effects to a nursing infant are possible. The importance of continued rosuvastatin therapy to the mother should be considered in deciding whether to discontinue breast-feeding or discontinue the medication.[27988] [63844] If pharmacotherapy is necessary for the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.[30812] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Because advanced age (65 years or more) is a risk factor for myopathy and/or rhabdomyolysis, rosuvastatin should be prescribed with caution in the geriatric patient. During clinical trials, no significant differences in rosuvastatin safety or efficacy between older and younger adult patients were identified. In general, some geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors; monitor antilipemic response. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications.

    Children, infants

    The safe and effective use of rosuvastatin tablets in infants and children younger than 7 years has not been established. Safety and efficacy of rosuvastatin capsules have not been established in pediatric patients.[63844] During clinical trials, there was no detectable effect of rosuvastatin on growth, body mass index, or sexual maturation in children and adolescents older than 10 years.[27988] 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 are 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.[54722] [55759] 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.[33319] [54722]

    ADVERSE REACTIONS

    Severe

    proteinuria / Delayed / 1.3-1.3
    immune-mediated necrotizing myopathy / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    rhabdomyolysis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    myoglobinuria / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 2.4-3.3
    diabetes mellitus / Delayed / 2.8-3.0
    elevated hepatic enzymes / Delayed / 1.1-2.2
    hematuria / Delayed / 1.3-1.3
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    myasthenia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    confusion / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known

    Mild

    myalgia / Early / 2.0-12.7
    arthralgia / Delayed / 3.8-10.1
    headache / Early / 5.5-8.5
    dizziness / Early / 4.0-4.0
    diarrhea / Early / 3.4-3.4
    nausea / Early / 2.4-3.4
    dyspepsia / Early / 3.4-3.4
    asthenia / Delayed / 2.0-2.7
    abdominal pain / Early / 2.4-2.4
    pruritus / Rapid / 1.0
    rash / Early / 2.0
    muscle cramps / Delayed / Incidence not known
    fever / Early / Incidence not known
    insomnia / Early / Incidence not known
    nightmares / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    malaise / Early / Incidence not known
    flushing / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and rosuvastatin may increase rosuvastatin exposure and increase the risk of rosuvastatin toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Rosuvastatin is a BCRP substrate.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
    Antacids: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Aprepitant, Fosaprepitant: (Minor) Use caution if rosuvastatin and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of rosuvastatin. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Rosuvastatin is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Atazanavir: (Major) When possible, concurrent use of rosuvastatin and atavanavir should be avoided. If rosuvastatin must be used concurrently with atazanavir, limit the rosuvastatin dosage to 10 mg/day. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) When possible, concurrent use of rosuvastatin and atavanavir should be avoided. If rosuvastatin must be used concurrently with atazanavir, limit the rosuvastatin dosage to 10 mg/day. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 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.
    Calcium Carbonate: (Major) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Calcium Carbonate; Magnesium Hydroxide: (Major) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Calcium Carbonate; Risedronate: (Major) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Calcium Carbonate; Simethicone: (Major) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Cimetidine: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Clarithromycin: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
    Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and rosuvastatin, a substrate of OAT protein (OATP), may result in altered clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OATP substrates.
    Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP.
    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).
    Colchicine; Probenecid: (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).
    Cyclosporine: (Major) Do not exceed 5 mg/day of rosuvastatin in adults when coadministered with cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when rosuvastatin is used concomitantly with cyclosporine. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. The rosuvastatin AUC was increased 7-fold in the presence of cyclosporine.
    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.
    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: (Major) Avoid coadministration of darolutamide with rosuvastatin as concurrent use increased rosuvastatin exposure by approximately 5-fold in drug interaction studies. If concomitant use is unavoidable, closely monitor for rosuvastatin-related adverse reactions and consider a rosuvastatin dose-reduction. Rosuvastatin is a BCRP substrate; darolutamide is a BCRP inhibitor.
    Darunavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicisat.
    Darunavir; Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicisat.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicisat.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Dosage adjustments of rosuvastatin may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in elevated rosuvastatin serum concentrations. Adult doses of rosuvastatin must be limited to no more than 10 mg/day when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. (Major) Due to CYP3A4 inhibition by ritonavir, the risk of myopathy (including rhabdomyolysis) may be increased when ritonavir is given in combination with rosuvastatin. If coadministration is necessary, use the lowest possible dose of rosuvastatin. Alternatively, consider using pravastatin or fluvastatin; however, fluvastatin is partially metabolized (about 20%) by CYP3A4 and is generally recommended to be used cautiously with protease inhibitors.
    Drospirenone; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Elagolix: (Moderate) Elagolix may reduce the exposure (AUC) of rosuvastatin. Monitor lipid panel as clinically indicated and adjust rosuvastatin dose if indicated by treatment target goal and clinical response. During a drug interaction study, use of rosuvastatin (20 mg once daily) with elagolix (300 mg tiwce daily) resulted in 20% to 30% decrease in the exposure (AUC) of rosuvastatin. Peak concentration (Cmax) was minimally affected. Rosuvastatin is not extensively metabolized. The major metabolite, N-desmethyl rosuvastatin, is formed by CYP2C9 and has approximately 1/6 to 1/2 the activity of the parent compound. Elagolix does not affect CYP2C9. Rosuvastatin is a substrate for hepatic organic anion-transporting polyprotein 1B1 (OATP1B1); elagolix is also a substrate for the OATP1B1 transporter. The mechanism of the interaction is not clear.
    Elbasvir; Grazoprevir: (Moderate) Studies have shown plasma concentrations of rosuvastatin are increased when administered concurrently with elbasvir; grazoprevir. If these drugs are use together, the daily dose of rosuvastatin should not exceed 10 mg. Rosuvastatin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for rosuvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of rosuvastatin. Rosuvastatin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
    Eltrombopag: (Moderate) Use caution and monitor for signs of rosuvastatin toxicity if this drug is coadministered with eltrombopag. In clinical trials, a 50% dose reduction of rosuvastatin was recommended. Eltrombopag is an inhibitor of OATP1B1 and BCRP, and rosuvastatin is a substrate of both of these transporters. In a clinical study, administration of a single dose of rosuvastatin with eltrombopag increased plasma rosuvastatin AUC by 55% and the Cmax by 103%.
    Eluxadoline: (Moderate) Close monitoring for adverse effects, such as rhabdomyolysis and myopathy, is advised when eluxadoline is administered concurrently with rosuvastatin. Eluxadoline is an inhibitor of the organic anion-transporting peptide (OATP1B1) and the breast cancer resistance protein (BCRP); rosuvastatin is a substrate of both transporters. Use of these drugs together results in a 40% increase in the exposure (AUC) and a 18% increase in the maximum plasma concentration (Cmax) of rosuvastatin. Administer the lowest effect rosuvastatin dose and monitor for adverse effects.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with rosuvastatin as there is a potential for decreased rosuvastatin concentrations. Alternatively, when elvitegravir is boosted with cobicistat, the concentration of rosuvastatin may be increased due to inhibition of OATP by cobicistat. In one pharmacokinetic study, the Cmax and AUC of rosuvastatin were increased by 89% and 38%, respectively, when given concurrently with cobicistat and elvitegravir. Patients may experience a decreased antilipemic effect elvitegravir and rosuvastatin are coadministered. If elvitegravir is boosted with cobicistat, patients may be at increased risk for side effects of rosuvastatin. Rosuvastatin is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Moderate) Caution is warranted when elvitegravir is administered with rosuvastatin as there is a potential for decreased rosuvastatin concentrations. Alternatively, when elvitegravir is boosted with cobicistat, the concentration of rosuvastatin may be increased due to inhibition of OATP by cobicistat. In one pharmacokinetic study, the Cmax and AUC of rosuvastatin were increased by 89% and 38%, respectively, when given concurrently with cobicistat and elvitegravir. Patients may experience a decreased antilipemic effect elvitegravir and rosuvastatin are coadministered. If elvitegravir is boosted with cobicistat, patients may be at increased risk for side effects of rosuvastatin. Rosuvastatin is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Moderate) Caution is warranted when elvitegravir is administered with rosuvastatin as there is a potential for decreased rosuvastatin concentrations. Alternatively, when elvitegravir is boosted with cobicistat, the concentration of rosuvastatin may be increased due to inhibition of OATP by cobicistat. In one pharmacokinetic study, the Cmax and AUC of rosuvastatin were increased by 89% and 38%, respectively, when given concurrently with cobicistat and elvitegravir. Patients may experience a decreased antilipemic effect elvitegravir and rosuvastatin are coadministered. If elvitegravir is boosted with cobicistat, patients may be at increased risk for side effects of rosuvastatin. Rosuvastatin is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Erythromycin: (Minor) Erythromycin is generally associated with an increased risk of myopathy with HMG-CoA reductase inhibitors. This interaction is likely due to CYP3A4 inhibition of statins which are CYP3A4 substrates; however, rosuvastatin is not substantially metabolized, and is less likely to be significantly affected by CYP3A4 inhibitors such as erythromycin. However, other mechanisms, such as an effect on OATP1B1, may be involved. Rosuvastatin is an OATP1B1 substrate. Coadministration of a single dose of rosuvastatin (80 mg) with erythromycin results in 31% and 20% decrease in Cmax and AUC of rosuvastatin, respectively. The clinical significance of this interaction has not been established, monitor for effectiveness of rosuvastatin and for myopathy and adjust treatment as clinically indicated.
    Erythromycin; Sulfisoxazole: (Minor) Erythromycin is generally associated with an increased risk of myopathy with HMG-CoA reductase inhibitors. This interaction is likely due to CYP3A4 inhibition of statins which are CYP3A4 substrates; however, rosuvastatin is not substantially metabolized, and is less likely to be significantly affected by CYP3A4 inhibitors such as erythromycin. However, other mechanisms, such as an effect on OATP1B1, may be involved. Rosuvastatin is an OATP1B1 substrate. Coadministration of a single dose of rosuvastatin (80 mg) with erythromycin results in 31% and 20% decrease in Cmax and AUC of rosuvastatin, respectively. The clinical significance of this interaction has not been established, monitor for effectiveness of rosuvastatin and for myopathy and adjust treatment as clinically indicated.
    Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Desogestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Etonogestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Levonorgestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norelgestromin: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norethindrone: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norgestimate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Ethinyl Estradiol; Norgestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.1 to 1.3-fold increase in the AUC and maximal concentrations of norgestrel. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of norgestrel, such as breast tenderness, nausea, headache, or fluid retention. (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Etravirine: (Moderate) Concomitant use of etravirine and rosuvastatin has no effect on the serum concentration of rosuvastatin; however, the risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors.
    Fenofibrate: (Moderate) Clinical practice guidelines state the concurrent use of fenofibrate and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
    Fenofibric Acid: (Moderate) Clinical practice guidelines state the concurrent use of fenofibric acid and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
    Fosamprenavir: (Major) Fosamprenavir increases rosuvastatin plasma concentrations. If these drugs are to be coadministered, use the lowest possible dose of rosuvastatin, or consider treatment with an alternative HMG-CoA reductase inhibitor such as fluvastatin or pravastatin.
    Fostamatinib: (Moderate) Monitor for rosuvastatin toxicities that may require rosuvastatin dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; rosuvastatin is a substrate for BCRP. Coadministration of fostamatinib with rosuvastatin increased rosuvastatin AUC by 95% and Cmax by 88%.
    Gemfibrozil: (Major) Clinical practice guidelines state the concurrent use of gemfibrozil and rosuvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. Initiate rosuvastatin at a reduced dosage of 5 mg/day not to exceed 10 mg/day if coadministered with gemfibrozil. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Glecaprevir; Pibrentasvir: (Major) Do not exceed a maximum rosuvastatin dose of 10 mg when coadministered with glecaprevir due to an increased risk of myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporters OATP1B, OATP1B3, and BRCP; glecaprevir is an inhibitor of these transporters. Coadministration may increase the plasma concentrations of rosuvastatin. In drug interaction studies, coadministration of rosuvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of rosuvastatin. (Major) Do not exceed a maximum rosuvastatin dose of 10 mg when coadministered with pibrentasvir due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of rosuvastatin. Rosuvastatin is a substrate of the drug transporters OATP1B, OATP1B3, and BRCP; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of rosuvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of rosuvastatin.
    Indinavir: (Moderate) Use caution and the lowest rosuvastatin dose necessary if it must be coadministered with indinavir. The risk of developing myopathy/rhabdomyolysis increases when rosuvastatin is used concomitantly with CYP3A4 inhibitors such as indinavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and protease inhibitor therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Itraconazole: (Moderate) Itraconazole modestly increases the AUC of rosuvastatin by 28% and 39% in healthy volunteers receiving 80 mg and 10 mg rosuvastatin, respectively. A potential mechanism for this interaction is inhibition of the breast cancer resistance protein (BCRP) by itraconazole; rosuvastatin is a BCRP substrate..
    Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with rosuvastatin. Taking these drugs together may significantly increase rosuvastatin plasma concentrations, potentially resulting in myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP); ledipasvir is a BCRP inhibitor.
    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: (Moderate) Closely monitor for rosuvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a rosuvastatin dose reduction if administered with letermovir. Do not exceed a rosuvastatin dose of 5 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with rosuvastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in rosuvastatin plasma concentration.
    Lopinavir; Ritonavir: (Major) Due to CYP3A4 inhibition by ritonavir, the risk of myopathy (including rhabdomyolysis) may be increased when ritonavir is given in combination with rosuvastatin. If coadministration is necessary, use the lowest possible dose of rosuvastatin. Alternatively, consider using pravastatin or fluvastatin; however, fluvastatin is partially metabolized (about 20%) by CYP3A4 and is generally recommended to be used cautiously with protease inhibitors. (Major) When rosuvastatin was coadministered with lopinavir; ritonavir in healthy volunteers, the Cmax and AUC of rosuvastatin was increased 5-fold and 2-fold, respectively. When possible, concurrent use of rosuvastatin and lopinavir; ritonavir should be avoided. If rosuvastatin must be used concurrently with lopinavir; ritonavir, limit the rosuvastatin adult dosage to 10 mg/day. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); lopinavir is OATP1B1 inhibitor.
    Lovastatin; Niacin: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. 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 rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. 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 rosuvastatin immediately if myopathy is diagnosed or suspected.
    Mestranol; Norethindrone: (Minor) Mestranol is converted to ethinyl estradiol. When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Nelfinavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased with anti-retroviral protease inhibitors, such as nelfinavir, are used in combination with most HMG-CoA reductase inhibitors. Concomitant use of nelfinavir and rosuvastatin is expected to increase rosuvastatin concentrations; the manufacturer of nelfinavir suggests using the lowest possible dose of rosuvastatin if these drugs are to be coadministered. If treatment with an HMG-CoA reductase inhibitor is needed, the manufacturer of nelfinavir suggests using pravastatin or fluvastatin, which are less significantly metabolized by CYP3A4.
    Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. 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 rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. 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 rosuvastatin immediately if myopathy is diagnosed or suspected.
    Niacin; Simvastatin: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. 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 rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. 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 rosuvastatin immediately if myopathy is diagnosed or suspected.
    Norgestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.1 to 1.3-fold increase in the AUC and maximal concentrations of norgestrel. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of norgestrel, such as breast tenderness, nausea, headache, or fluid retention.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to rosuvastatin. Rosuvastatin 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Dosage adjustments of rosuvastatin may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in elevated rosuvastatin serum concentrations. Adult doses of rosuvastatin must be limited to no more than 10 mg/day when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. (Major) Due to CYP3A4 inhibition by ritonavir, the risk of myopathy (including rhabdomyolysis) may be increased when ritonavir is given in combination with rosuvastatin. If coadministration is necessary, use the lowest possible dose of rosuvastatin. Alternatively, consider using pravastatin or fluvastatin; however, fluvastatin is partially metabolized (about 20%) by CYP3A4 and is generally recommended to be used cautiously with protease inhibitors.
    Omeprazole; Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Oritavancin: (Moderate) Rosuvastatin is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated rosuvastatin plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of rosuvastatin toxicity, such as muscle aches, muscle pain or tenderness, general weakness or fatigue, side or back pain, or decreased urination.
    Osimertinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including rhabdomyolysis and myopathy, if coadministration with osimertinib is necessary. Rosuvastatin is a BCRP substrate and osimertinib is a BCRP inhibitor. Concomitant use increased the AUC of rosuvastatin by 35% and the Cmax by 72%.
    Ponatinib: (Major) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and rosuvastatin, an ABCG2 (BCRP) substrate, may increase the exposure of rosuvastatin.
    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).
    Red Yeast Rice: (Severe) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
    Regorafenib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with regorafenib is necessary. Rosuvastatin is a BCRP substrate and regorafenib is a BCRP inhibitor. Coadministration with regorafenib increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and 4.6-fold, respectively.
    Ritonavir: (Major) Due to CYP3A4 inhibition by ritonavir, the risk of myopathy (including rhabdomyolysis) may be increased when ritonavir is given in combination with rosuvastatin. If coadministration is necessary, use the lowest possible dose of rosuvastatin. Alternatively, consider using pravastatin or fluvastatin; however, fluvastatin is partially metabolized (about 20%) by CYP3A4 and is generally recommended to be used cautiously with protease inhibitors.
    Rolapitant: (Moderate) Avoid the concurrent use of rosuvastatin and rolapitant if possible; if coadministration is necessary, use the lowest effective dose of rosuvastatin and monitor for rosuvastatin-related adverse effects. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as rosuvastatin. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    Saquinavir: (Major) The concurrent use of saquinavir boosted with ritonavir and rosuvastatin should be avoided if possible due to the potential for myopathies, including rhabdomyolysis. Coadministration of saquinavir boosted with ritonavir and rosuvastatin results in an increased plasma concentration of rosuvastatin.The combination saquinavir/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. If coadministered, use the lowest possible dose of rosuvastatin with careful clinical monitoring,
    Segesterone Acetate; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
    Simeprevir: (Moderate) Coadministration of rosuvastatin with simeprevir, an inhibitor of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, results in increased rosuvastatin plasma concentrations. If these drugs are given together, initiate rosuvastatin therapy at 5 mg once daily; do not exceed 10 mg once daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Sofosbuvir; Velpatasvir: (Major) Do not exceed a rosuvastatin dose of 10 mg daily with coadministration of velpatasvir as this may significantly increase the serum concentrations of rosuvastatin, which may increase the risk of myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, while velpatasvir inhibits both BCRP and OATP1B1.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with rosuvastatin. Taking these drugs may significantly increase systemic exposure to rosuvastatin, which may increase the risk of myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptides (OATP1B1/1B3) transporters, while voxilaprevir inhibits both BCRP and OATP1B1/1B3. (Major) Do not exceed a rosuvastatin dose of 10 mg daily with coadministration of velpatasvir as this may significantly increase the serum concentrations of rosuvastatin, which may increase the risk of myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, while velpatasvir inhibits both BCRP and OATP1B1.
    Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and rosuvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of rosuvastatin of 5 mg/day is recommended.
    Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and rosuvastatin due to the potential for increased plasma concentrations of rosuvastatin increasing the risk of adverse effects. Rosuvastatin dose adjustment may be needed with coadministration. Rosuvastatin is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
    Tedizolid: (Moderate) If possible, stop use of rosuvastatin temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for rosuvastatin-associated adverse events. In clinical trials involving healthy adults, multiple doses of oral tedizolid (200 mg PO once daily) increased the Cmax and AUC of rosuvastatin (10 mg single PO dose) by approximately 55% and 70%, respectively. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering rosuvastatin with telaprevir due to the potential for rosuvastatin-related adverse events. When used in combination, the plasma concentrations of rosuvastatin may be elevated.
    Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Coadministration of rosuvastatin with inhibitors of OATP, such as telithromycin may theoretically result in increased concentrations of rosuvastatin.
    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.
    Tipranavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when tipranavir is given in combination with most HMG-CoA reductase inhibitors. If rosuvastatin is to be used concomitantly with tipranavir (in the FDA approved dosage regimen), use the lowest possible dose with careful monitoring, or consider an alternative HMG-CoA reductase inhibitor that is less significantly metabolized by CYP3A4 (i.e., fluvastatin, pravastatin).
    Tolvaptan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of rosuvastatin due to increased rosuvastatin exposure and potential for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the BCRP and OATP1B1 transporters. Tolvaptan is a BCRP inhibitor and the oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Warfarin: (Moderate) Addition of rosuvastatin to warfarin therapy has resulted in significant increases in the INR (> 4, baseline 2 to 3), without a change in warfarin plasma concentrations. INR should be monitored at baseline prior to rosuvastatin initiation, and frequently following initiation of rosuvastatin therapy and subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Rosuvastatin has not been associated with bleeding or with changes in INR in patients not taking oral anticoagulants.

    PREGNANCY AND LACTATION

    Pregnancy

    Rosuvastatin is contraindicated for use during pregnancy because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Counsel females of reproductive potential to use effective contraception during rosuvastatin treatment. Rosuvastatin should be discontinued as soon as pregnancy is confirmed. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Treatment should be immediately discontinued as soon as pregnancy is recognized. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. It has been hypothesized that lipophilic statins (e.g., simvastatin, lovastatin) have a higher affinity for the embryotic and extra-hepatic tissues. A review of case reports examined the use of several statins during pregnancy and the correlation of birth defects. The study suggested that more highly lipophilic statins resulted in more adverse birth defect outcomes, yet further studies are needed to establish this correlation. At this time, there are no well-controlled studies of rosuvastatin use in pregnant women. In a prospective review of about 100 pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidence of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population.

    Rosuvastatin is contraindicated during breast-feeding. Limited data indicate rosuvastatin is excreted into human breast milk. There are no data on 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; other adverse effects to a nursing infant are possible. The importance of continued rosuvastatin therapy to the mother should be considered in deciding whether to discontinue breast-feeding or discontinue the medication.[27988] [63844] If pharmacotherapy is necessary for the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.[30812] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Rosuvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Due to its unique structural binding sites and relative hydrophilicity, rosuvastatin has a high affinity for HMG-CoA reductase and is selective for hepatic cells with minimal uptake by nonhepatic tissues. In a rat hepatocyte model, rosuvastatin was found to be 7-fold more potent than atorvastatin; in a model using human HMG-CoA reductase, rosuvastatin was 8-fold more potent than pravastatin.[27110] Rosuvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B while increasing HDL. During a Phase II study, rosuvastatin doses of 1 to 80 mg lowered LDL cholesterol by 34 to 65%.[27113] Evening or morning administration does not affect rosuvastatin pharmacokinetics or antilipemic effects.[27113]
     
    HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

    PHARMACOKINETICS

    Rosuvastatin is administered orally. Unlike prodrugs, such as lovastatin or simvastatin, the majority of HMG-CoA reductase inhibitory activity (90%) in plasma is associated with the parent compound. Evening or morning dosing does not affect pharmacokinetic parameters or cholesterol-lowering effects.[27534] Rosuvastatin is about 88% bound to plasma proteins.[27113]
     
    Rosuvastatin appears to be metabolized to a limited extent to an N-desmethyl metabolite (7-fold less potent than rosuvastatin) and a 5S-lactone product.[27113] In human hepatocytes, the in vitro formation of the N-desmethyl metabolite is inhibited by sulphaphenazole, and to a lower extent by omeprazole, which suggests some metabolism by CYP2C9 and CYP2C19 isoenzymes.[27115] Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin. Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism of rosuvastatin via the CYP3A4 isoenzyme.[27113] [27114] In addition, hepatic metabolism is a minor pathway for rosuvastatin elimination, which suggests that clinically significant drug interactions via metabolism pathways may be limited.[27113] In vivo studies have demonstrated that azole antifungals (itraconazole, ketoconazole, fluconazole) and erythromycin have minimal or no effects on the pharmacokinetics of rosuvastatin (see Drug Interactions). Rosuvastatin is eliminated primarily unchanged via the fecal route (90%, including unabsorbed drug), and approximately 10% of the dose is eliminated renally.[27113] Approximately 72% of an absorbed dose is excreted via the bile and about 28% is excreted renally.[27113] Rosuvastatin has a plasma half-life of about 19 to 20 hours.[27113] [63844]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19
    In human hepatocytes, the in vitro formation of the N-desmethyl metabolite of rosuvastatin is inhibited by sulphaphenazole, and to a lower extent by omeprazole, which suggests some metabolism by CYP2C9 and CYP2C19 isoenzymes.[27115] However, hepatic metabolism is a minor pathway for elimination, which suggests that clinically significant drug interactions with rosuvastatin via inhibition of the drug's metabolism may be limited.[27113] Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism of rosuvastatin via the CYP3A4 isoenzyme.[27113] [27114] [27988]

    Oral Route

    The bioavailability of rosuvastatin is approximately 20%, with peak rosuvastatin plasma concentrations reached within 3 to 5 hours after oral dosing. Food reduces absorption rate by 20%, but does not affect overall bioavailability.