AHFS Class:

• HMG-CoA Reductase Inhibitors 24:06.08

Generic Name(s):

• Rosuvastatin Calcium

Rosuvastatin calcium, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent.1,3,15,16

Reduction in Risk of Cardiovascular Events

Primary Prevention

Rosuvastatin is used as an adjunct to diet and lifestyle modifications in adults without clinical evidence of coronary heart disease (CHD) who have an increased risk of cardiovascular disease based on age, high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or greater, and at least one additional cardiovascular disease risk factor; the drug is used to reduce the risk of stroke or myocardial infarction (MI) and the risk of undergoing arterial revascularization procedures in such patients.1,400

Rosuvastatin was evaluated in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study in 17,802 patients (men 50 years of age or older and women 60 years of age or older) without clinical evidence of cardiovascular disease who had LDL-cholesterol concentrations of less than 130 mg/dL and hsCRP concentrations of 2 mg/L or greater.1,15 Results of JUPITER demonstrated that therapy with rosuvastatin (20 mg daily) for a mean of 2 years reduced the risk of major cardiovascular events (i.e., composite of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina or an arterial revascularization procedure) by 44% compared with placebo.1,15 Aside from reducing the risk of the primary composite end point, rosuvastatin also substantially reduced the risk of certain individual components of the primary end point (i.e., nonfatal MI, nonfatal stroke, arterial revascularization procedure), as well as the risk of any (fatal and nonfatal) MI and stroke.1,15 However, there were no treatment differences among the rosuvastatin and placebo groups for death secondary to cardiovascular causes or hospitalization for unstable angina.1 At one year, rosuvastatin increased HDL-cholesterol concentrations and reduced LDL-cholesterol, hsCRP, total cholesterol, and serum triglyceride concentrations compared with placebo.1 In a post hoc subgroup analysis of 1405 patients with hsCRP concentrations of 2 mg/L or greater and no other traditional risk factors (smoking, blood pressure of at least 140/90 mm Hg or taking antihypertensives, low HDL-cholesterol concentrations) other than age, there was no substantial treatment benefit associated with rosuvastatin after adjustment for high HDL-cholesterol concentrations.1

Reducing Progression of Coronary Atherosclerosis

Rosuvastatin is used as an adjunct to dietary therapy to slow the progression of atherosclerosis in adults.1

The METEOR study evaluated rosuvastatin in patients with elevated LDL-cholesterol concentrations and subclinical atherosclerosis (as determined by carotid intimal-medial thickness [cIMT]) who were at low risk (Framingham risk less than 10% over 10 years) for symptomatic coronary artery disease.1,16 Therapy with rosuvastatin (40 mg daily) for 2 years slowed progression of atherosclerosis (as determined by B-mode ultrasound of the rate of change in mean maximum cIMT) compared with placebo.1,16 However, rosuvastatin did not induce disease regression.16

Secondary Prevention

Rosuvastatin also is used for secondary prevention† in patients with established atherosclerotic cardiovascular disease (ASCVD), defined as acute coronary syndrome (ACS), history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD).400 Extensive evidence demonstrates that statins can substantially reduce the risk of ASCVD.336,337,338,400,401,402,403

Patients with Chronic Kidney Disease

The potential benefits of rosuvastatin in patients with chronic kidney disease, a population at high risk of cardiovascular disease, were evaluated in the AURORA study, which was a randomized, double-blind study in 2776 patients undergoing hemodialysis.386 In this study, therapy with rosuvastatin 10 mg daily for a median duration of 3.8 years did not substantially reduce the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with placebo.386

Patients with HIV Infection

Guidelines for the use of statin therapy in patients with human immunodeficiency virus (HIV) infection were developed by the Department of Health and Human Services in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and HIV Medicine Association.503 These experts recommend at least moderate intensity statin therapy (i.e., pitavastatin 4 mg, atorvastatin 20 mg, or rosuvastatin 10 mg daily) for patients 40-75 years of age with HIV who have low-to-intermediate (<20%) 10-year ASCVD risk estimates.503 When 10-year ASCVD risk estimates are <5%, initiating at least moderate intensity statin therapy (i.e., pitavastatin 4 mg, atorvastatin 20 mg, or rosuvastatin 10 mg daily) may be considered although the absolute benefit of such treatment may be modest; the decision to initiate a statin should take into account the presence or absence of HIV-related factors that can increase ASCVD risk.503 Data are insufficient to recommend for or against statin therapy as primary prevention of ASCVD in patients less than 40 years of age with HIV.503

Clinical Perspective

The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400,401,402 There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary or primary prevention in high-risk patients.336,337,338,400,401,402,403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400,401,402

When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk ≥7.5%.400,401

The guideline states that patients with clinical ASCVD (defined as those with ACS, history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or PAD, including those with aortic aneurysm) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.400 Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400 The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.400 AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).400 If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.400

Intensity of Statin Therapy

The appropriate intensity of a statin should be used to reduce the risk of ASCVD.400 Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, rosuvastatin 20-40 mg daily is considered to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%) and rosuvastatin 5-10 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400

Combination Antilipemic Therapy

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be useful in certain high-risk patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration ≥55 mg/dL or non-HDL-cholesterol ≥85 mg/dL).400,403 If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.400,403

A 2022 consensus decision pathway published by the ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.403 In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.403 If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.403

In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.403 In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD , ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.403 If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.403

A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.406 Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.406 When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.406

Dyslipidemias

Rosuvastatin is used as an adjunct to diet for the management of primary hyperlipidemia or mixed dyslipidemia (including heterozygous familial hypercholesterolemia [HeFH]), hypertriglyceridemia, primary dysbetalipoproteinemia, and/or homozygous familial hypercholesterolemia (HoFH).1,2,3,4,5,6,1

Primary Hyperlipidemia or Mixed Dyslipidemia

Adults

Rosuvastatin is used as an adjunct to diet in adults to reduce LDL-cholesterol in the management of primary hyperlipidemia or mixed dyslipidemia (including HeFH).1 Efficacy of rosuvastatin for such use has been established in placebo-controlled studies and in comparative studies with other statins (e.g., atorvastatin, pravastatin, simvastatin).1,2,3,4,6

Reductions in total cholesterol and LDL-cholesterol concentrations achieved with usual dosages of rosuvastatin substantially exceed those with placebo or compared with baseline values.1,2,3,4,5,6 In a dose-ranging study in patients with primary hyperlipidemia, mean reductions in total cholesterol averaged 33, 36, 40, or 46% with rosuvastatin dosages of 5, 10, 20, or 40 mg, respectively, compared with 5% with placebo; corresponding reductions in LDL-cholesterol concentrations were 45, 52, 55, or 63%, respectively, versus 7% with placebo, while increases in HDL-cholesterol averaged 13, 14, 8, or 10%, respectively, versus 3% with placebo.1

In a 6-week comparative study in more than 2200 patients (approximately 50% were women and about 30% were 65 years of age or older) with primary hyperlipidemia, reductions in LDL-cholesterol concentrations in patients receiving rosuvastatin (10 mg daily) exceeded those with atorvastatin (10 mg daily), pravastatin (10, 20, or 40 mg daily), or simvastatin (10, 20, or 40 mg daily).1,3 LDL-cholesterol reductions from baseline averaged 46, 52, or 55% with rosuvastatin 10, 20, or 40 mg, respectively, daily in these patients.1,3

Rosuvastatin alone or combined with extended-release niacin improved the atherogenic lipid profile in patients with mixed dyslipidemia and low HDL-cholesterol concentrations.5,6 In a 24-week, randomized, double-blind study, LDL-cholesterol reductions averaged 48, 0.1, 42, or 36% in patients receiving rosuvastatin 40 mg daily, extended-release niacin 2 g daily, rosuvastatin 40 mg plus extended-release niacin 1 g daily, or rosuvastatin 10 mg plus extended-release niacin 2 g daily, respectively; HDL-cholesterol concentrations with these regimens were increased by 11, 12, 17, or 24%, respectively.5,6 Reductions in triglyceride concentrations and increases in HDL-cholesterol concentrations were similar with the highest dosage of rosuvastatin (40 mg daily) or extended-release niacin (2 g daily) given as monotherapy.5 Patients receiving rosuvastatin had a lower incidence of treatment-related adverse effects than those receiving niacin-containing regimens.5

Rosuvastatin alone or combined with ezetimibe improved the atherogenic lipid profile in patients with hypercholesterolemia.21,22,23 Pooled data from 3 randomized, double-blind trials conducted in Korea indicate that rosuvastatin (5, 10, or 20 mg daily) in combination with ezetimibe (10 mg daily) produced greater reductions in LDL-cholesterol, total cholesterol, and triglycerides compared to rosuvastatin (5, 10, or 20 mg daily) monotherapy in patients with hypercholesterolemia.21,22,23 When ezetimibe/rosuvastatin was compared to rosuvastatin alone, reductions in LDL-cholesterol were 57-59% and 44-49%, total cholesterol 39-40% and 30-33%, and triglycerides 20-23% and 12-13%, respectively.21,22 In addition, significantly more patients on rosuvastatin in combination with ezetimibe met LDL-cholesterol goals compared to those receiving rosuvastatin alone.21,22,23

Pediatric Patients

Rosuvastatin is used as an adjunct to diet to decrease LDL-cholesterol in the management of HeFH in children ≥8 years of age.1

Efficacy and safety of rosuvastatin in pediatric patients with HeFH were evaluated in a double-blind, placebo-controlled study and an open-label, uncontrolled study.1 In the controlled study (which was followed by a 40-week, open-label, dose-titration phase), 176 children and adolescents 10-17 years of age with HeFH (mean baseline LDL-cholesterol concentration of 233 mg/dL) were randomized to receive either rosuvastatin (5, 10, or 20 mg daily) or placebo for 12 weeks; after 12 weeks of the double-blind phase, all patients entered an open-label phase and received rosuvastatin for an additional 40 weeks.1 Treatment with rosuvastatin resulted in substantial reductions in concentrations of total cholesterol, LDL-cholesterol (primary end point), and apolipoprotein B (apo B) compared with placebo during the 12-week, double-blind phase.1 Mean reductions in total cholesterol averaged 30, 34, or 39% with rosuvastatin dosages of 5, 10, or 20 mg, respectively, compared with 0% with placebo; corresponding reductions in LDL-cholesterol concentrations were 38, 45, or 50%, respectively, versus 1% with placebo, and in apo B concentrations were 32, 38, or 41%, respectively, versus 2% with placebo.1 Changes in concentrations of triglycerides and HDL-cholesterol were similar in patients receiving rosuvastatin and in those receiving placebo.1

In the open-label study (Hypercholesterolaemia in Children and Adolescents taking Rosuvastatin Open Label [CHARON]), 175 children and adolescents 8-17 years of age with HeFH (defined as a documented genetic defect in the LDL receptor or in apo B) and a mean baseline LDL-cholesterol concentration of 236 mg/dL received rosuvastatin at an initial dosage of 5 mg once daily, titrated to a maximum tolerated dosage of 10 mg daily (in patients 8-9 years of age) or 20 mg daily (in patients 10-17 years of age).1 The observed reductions in LDL-cholesterol concentrations from baseline were consistent across age groups and with previous experience in controlled trials of adults and pediatric patients.1,375 At 24 months, LDL-cholesterol concentrations were reduced from baseline by approximately 35-43%; 48, 46, or 32% of patients receiving rosuvastatin dosages of 5, 10, or 20 mg daily, respectively, achieved the LDL-cholesterol goal of less than 110 mg/dL.375

Homozygous Familial Hypercholesterolemia

Adults

Rosuvastatin is used as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or alone, if such therapies are not available, to reduce LDL-cholesterol in adults with HoFH.1 In an open-label, forced-titration study in 40 patients with HoFH, therapy with rosuvastatin (20-40 mg daily [titrated at a 6-week interval]) decreased LDL-cholesterol concentrations by a mean of 22%.1,6 Approximately 33% of patients achieved additional (at least 6%) LDL-cholesterol lowering with an increase in the rosuvastatin dosage from 20 to 40 mg daily.1 Among the 27 patients with LDL-cholesterol reductions of 15% or greater, the mean LDL-cholesterol reduction achieved was 30%; among the 13 patients with LDL-cholesterol reductions of less than 15%, 3 had no change or an increase in LDL-cholesterol concentrations.1 LDL-cholesterol reductions of 15% or greater were observed in 3 of 5 patients with known receptor-negative status.1

Pediatric Patients

Rosuvastatin is used as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or alone, if such therapies are not available, to decrease LDL-cholesterol in children ≥7 years of age with HoFH.1 Rosuvastatin is designated an orphan drug by the FDA for treatment of pediatric HoFH.24 In a double-blind, placebo-controlled crossover study in 14 pediatric patients 6 years of age or older with HoFH (mean baseline LDL-cholesterol concentration of 481 mg/dL, 50% receiving apheresis, 57% receiving ezetimibe), treatment with rosuvastatin 20 mg daily for 6 weeks resulted in substantial reductions in concentrations of LDL-cholesterol (22.3%), total cholesterol (20.1%), triglycerides (30.4%), non-HDL-cholesterol (22.9%), and apo B (17.1%) compared with placebo.1,376

Hypertriglyceridemia

Rosuvastatin is used as an adjunct to diet in the treatment of adults with hypertriglyceridemia.1

In a 6-week, double-blind, placebo-controlled study in patients with primary hypertriglyceridemia (baseline triglyceride concentrations of 273-817 mg/dL), triglyceride concentrations were reduced by a median of 21, 37, 37, or 43% with rosuvastatin dosages of 5, 10, 20, or 40 mg daily, respectively, and increased by a median of 1% with placebo.1

Primary Dysbetalipoproteinemia

Rosuvastatin is used as an adjunct to diet for the treatment of adults with primary dysbetalipoproteinemia (Fredrickson type III).1,14

In a double-blind, crossover study in 32 patients with primary dysbetalipoproteinemia (genotypes 27 apo E2/E2 and 4 apo-E mutation [Arg145Cys]), treatment with rosuvastatin (10 or 20 mg daily) for 6 weeks resulted in reductions in concentrations of non-HDL-cholesterol (48 or 56%, respectively), total cholesterol (43 or 48%, respectively), triglycerides (40 or 43%, respectively), combined intermediate-density lipoprotein (IDL)- and very low-density lipoprotein (VLDL) cholesterol (47 or 56%, respectively), and circulating remnant lipoproteins.1,14

Clinical Perspective

Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of clinical ASCVD; other major risk factors include cigarette smoking, hypertension, diabetes, age, HeFH, chronic kidney disease (eGFR 15-59 mL/minute per 1.73 m²), history of heart failure, and other lipoprotein abnormalities.400,403 Therefore, the goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.400 Clinical studies have demonstrated that rosuvastatin 20-40 mg daily is considered to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%) and rosuvastatin 5-10 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400

The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of clinical ASCVD.400,401,402

When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥190 mg/dL, adults 40-75 years of age with diabetes mellitus, adults 40-75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40-75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70-189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher.400,401

There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.336,337,338,400,401,402,403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400,401,402

Combination Antilipemic Therapy

An ACC expert committee update on nonstatin drug therapies recommends that adults without clinical ASCVD with baseline LDL-cholesterol concentrations greater than 190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 inhibitor if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).403 Individuals with LDL-cholesterol concentrations greater than 190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as HeFH or HoFH.403 Current treatments for patients with familial hypercholesterolemia include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran) among other options.403

Hypertriglyceridemia

Patients with moderate or severe hypertriglyceridemia (fasting or non-fasting triglyceride levels 175-499 mg/dL or fasting levels ≥500 mg/dL, respectively) generally are at increased risk of ASCVD and pancreatitis (especially in patients with fasting levels ≥500 mg/dL).400,403 The AHA/ACC cholesterol management guideline recommends assessment and modification of lifestyle (obesity and metabolic syndrome), secondary disorders (e.g., diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.400 Initiation or intensification of statin therapy may be considered in adults 40-75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of ≥7.5%.400 Experts state statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes from triggering acute hypertriglyceridemic pancreatitis.400

Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations of serum LDL-cholesterol concentrations (often in excess of 400-500 mg/dL).407,408 Such extreme elevations, when left untreated, can lead to premature ASCVD as early as childhood; management of the condition requires referral to a lipid specialist and is focused on the aggressive reduction of LDL-cholesterol concentrations to slow ASCVD development.407,408 The treatment of HoFH often requires the use of multiple therapies, including pharmacologic and non-pharmacologic approaches, to reduce LDL-cholesterol concentrations.408 Current treatments for patients with HoFH include dietary lifestyle modifications with maximally tolerated dosages of high-intensity statins, ezetimibe, and PCSK9 inhibitors.403,408,409 In patients with HoFH who do not achieve target reductions in LDL-cholesterol levels, other options such as evinacumab and lomitapide can be added to therapy with or without lipoprotein apheresis.408,409

Pediatric Patients

In addition to early identification of children with familial hypercholesterolemia, dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.400,404 Evidence from randomized controlled trials coupled with the increased risk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents at ages ≥10 years who have familial hypercholesterolemia.400

In children and adolescents ≥10 years of age with an LDL-cholesterol level persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with familial hypercholesterolemia and who do not respond adequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statin therapy.400 Experts state that statins may be considered as early as 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a) and in the context of informed shared decision-making and counseling with the patient and family.400,404 Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to the LDL-cholesterol lowering response and tolerability.400,404 Some experts recommend a target LDL-cholesterol level <130 mg/dL or ≥50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.404

General

Pretreatment Screening

• Obtain baseline liver enzyme tests (e.g., AST, ALT).1
• Obtain baseline hepatic panel in appropriate patients with chronic stable liver disease (including non-alcoholic fatty liver disease).400
• Obtain baseline fasting lipid panel.400

Patient Monitoring

• Perform fasting lipid panel periodically 4-12 weeks after statin initiation or dose adjustment; monitoring should continue every 3-12 months thereafter as clinically indicated.1,400
• Periodically reinforce adherence to lifestyle modifications.400 Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of atherosclerotic cardiovascular disease (ASCVD).400
• Perform repeat liver function tests (e.g., AST, ALT, total bilirubin, alkaline phosphatase) when clinically indicated (i.e., symptoms suggesting hepatotoxicity); routine monitoring in the absence of symptoms is not recommended.1,400
• Monitor hepatic panel in appropriate patients with chronic stable liver disease (including non-alcoholic fatty liver disease).400
• Obtain creatine kinase (CK) levels in patients with severe statin-associated muscle weakness; routine monitoring in the absence of symptoms is not recommended.400

Administration

Rosuvastatin is administered orally as a single dose at any time of day, with or without food.1 Rosuvastatin tablets should be swallowed whole.1

If a dose of rosuvastatin is missed, resume treatment with the next dose; patients should not take an extra dose.1

Store tablets at 20-25°C; excursions permitted to 15-30°C.1 Protect from moisture.1

Dosage

Dosage of rosuvastatin calcium is expressed in terms of rosuvastatin.1

Reduction in Risk of Cardiovascular Events

For the reduction of risk of cardiovascular events the recommended dosage range of rosuvastatin in adults is 5-40 mg daily.1

The American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk.400 The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.400 The AHA/ACC guideline panel considers rosuvastatin 20-40 mg daily to be a high-intensity statin and rosuvastatin 5-10 mg daily to be a moderate-intensity statin.400

Dyslipidemias

Dosage in Adults

The dosage range of rosuvastatin in adults is 5-40 mg once daily.1

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

The recommended dosage range of rosuvastatin for the management of heterozygous familial hypercholesterolemia (HeFH) in children 8 to less than 10 years of age is 5-10 mg once daily.1

The recommended dosage range of rosuvastatin for the management of HeFH in children and adolescents ≥10 years of age is 5-20 mg once daily.1

Homozygous Familial Hypercholesterolemia

The recommended dosage of rosuvastatin in children and adolescents ≥7 years of age with homozygous familial hypercholesterolemia (HoFH) is 20 mg once daily.1

Dosage Modification for Concomitant Therapy

Special Populations

Asian Patients

The manufacturer recommends that an initial rosuvastatin dosage of 5 mg once daily be considered in Asian patients.1 The benefits versus risks when treating such patients without adequate control at rosuvastatin dosages up to 20 mg daily should be considered.1

Renal Impairment

In patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m²) who are not undergoing hemodialysis, rosuvastatin should be initiated at a dosage of 5 mg once daily, and dosage should not exceed 10 mg once daily.1 There are no dosage adjustment recommendations for patients with mild and moderate renal impairment.1

Hepatic Impairment

The manufacturer makes no specific dosage recommendations at this time for patients with hepatic impairment.1 Rosuvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1 Rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.1

Geriatric Patients

Although there are no specific dosage recommendations for geriatric patients, caution is recommended when rosuvastatin is used.1 Dose selection in geriatric patients (≥65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1

Pharmacogenomic Considerations

Rosuvastatin initial dosage adjustments may be needed based on the patient's solute carrier organic anion transporter (SLCO) 1B1 SLCO1B1 and/or ABCG2 phenotypes.500 In patients with Asian ancestry, the manufacturer recommends an initial rosuvastatin dosage of 5 mg once daily.1

SLCO1B1 decreased or possible decreased function phenotype: No dosage adjustment recommended.500SLCO1B1 poor function phenotype: Initial dosage ≤20 mg/day500

ABCG2 decreased function phenotype: No dosage adjustment recommended.500ABCG2 poor function phenotype: Initial dosage ≤20 mg/day.500

SLCO1B1 decreased or possible decreased function and ABCG2 decreased function phenotype: No dosage adjustment recommended.500SLCO1B1 decreased or possible decreased function and ABCG2 poor function phenotype: Initial dosage ≤10 mg/day.500SLCO1B1 poor function and ABCG2 decreased function phenotype: Initial dosage ≤20 mg/day.500SLCO1B1 poor function and ABCG2 poor function phenotype: Initial dosage ≤10 mg/day.500

Contraindications

• Acute liver failure or decompensated cirrhosis.1
• Known hypersensitivity to rosuvastatin or any component of the formulation.1 Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported.1

Warnings/Precautions

Musculoskeletal Effects

Myopathy, manifested as muscle pain, tenderness, or weakness associated with elevated creatine kinase and rhabdomyolysis, may occur.1 Acute kidney injury secondary to myoglobinuria and rare fatalities have been reported in patients receiving statins, including rosuvastatin.1 These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily).1

Rosuvastatin should be used with caution in patients with predisposing factors for myopathy (e.g., advanced age [65 years or older], renal impairment, inadequately treated hypothyroidism, higher rosuvastatin dosage).1 The risk of myopathy may be increased when rosuvastatin is used concomitantly with some other antilipemic agents (niacin or certain fibric-acid derivatives [i.e., gemfibrozil]), colchicine, or drugs that can increase exposure of rosuvastatin.1 The concomitant use of rosuvastatin with cyclosporine or gemfibrozil is not recommended.1 Rosuvastatin dosage modifications are recommended for patients taking certain antiviral medications (e.g., sofosbuvir/velpatasvir, glecaprevir/pibrentasvir), darolutamide, and regorafenib.1

AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400

Rosuvastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.1 Muscle symptoms and CK elevations may resolve if rosuvastatin is discontinued.1 Rosuvastatin therapy should be temporarily withheld in any patient experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).1

Immune-Mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.1 The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.1 Additional neuromuscular and serologic testing may be necessary and treatment with immunosuppressive agents may be required in patients who develop IMNM.1

Discontinue rosuvastatin if IMNM is suspected.1

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including rosuvastatin.1 These increases usually appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved with continued therapy or after temporary interruption of therapy.1 In a pooled analysis of placebo-controlled studies, increases in serum aminotransferase concentrations exceeding 3 times the upper limit of normal (ULN) occurred in 1.1% of patients receiving rosuvastatin compared with 0.5% of those receiving placebo.1 Marked persistent increases of hepatic aminotransferases have also occurred with rosuvastatin.1 There have been rare postmarketing reports of fatal and nonfatal hepatic failure in patients receiving statins, including rosuvastatin.1

Consider liver enzyme tests prior to initiation of rosuvastatin therapy and repeat as clinically indicated.1 Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious statin-related liver injury.200 The AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver enzyme tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not recommended.400

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, rosuvastatin therapy should be promptly interrupted.1

Rosuvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of chronic liver disease.1 The drug is contraindicated in patients with acute liver failure or decompensated cirrhosis.1

Proteinuria and Hematuria

Transient dipstick-positive proteinuria and microscopic hematuria (not associated with worsening renal function) have been reported in patients receiving rosuvastatin.1 These findings occurred more frequently in patients receiving rosuvastatin 40 mg compared with lower doses of rosuvastatin or comparator statins in clinical trials.1 Although the clinical importance of this finding is not known, dosage reduction should be considered in patients receiving rosuvastatin who have unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.1

Hyperglycemic Effects

Increases in glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including rosuvastatin.1,200 Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus.1,200 In the JUPITER study, a higher incidence of diabetes mellitus was reported in patients receiving rosuvastatin (2.8%) compared with those receiving placebo (2.3%).1 In addition, mean HbA_1c was increased by 0.1% in patients receiving rosuvastatin compared with those receiving placebo, and the number of patients with an HbA_1c greater than 6.5% also was significantly higher among those receiving rosuvastatin.1,15

AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus; because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.400

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit.405 This determination was based on several factors including safety signals from animal data.405 In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin (rosuvastatin is a hydrophilic statin)1,501 during the first trimester.400 Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm.405 More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.405 The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.405 While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.400,405 FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests that there is limited potential for statins to cause malformations and other adverse embryofetal effects.405 Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.405 While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia [HoFH] or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.400,405,402 Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.405

Lactation

Limited data indicate that rosuvastatin is distributed into human milk; however, the effects of the drug on breast-fed infants or milk production are not known.1 Because of the potential for serious adverse reactions from rosuvastatin in nursing infants, the drug is not recommended in nursing women.1 Women who require rosuvastatin therapy should not breast-feed their infants.1 Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.400,405,402

Females and Males of Reproductive Potential

In male and female rat fertility studies, no adverse effect on fertility was observed with oral rosuvastatin 50 mg/kg per day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC).1 Spermatidic giant cells were observed in the testicles of dogs and monkeys treated with oral rosuvastatin 30 mg/kg per day; vacuolation of seminiferous tubular epithelium was also observed in monkeys.1 Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area; similar findings have been seen with other statins.1

AHA/ACC cholesterol management guideline states women (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contraception.400

Pediatric Use

Safety and efficacy of rosuvastatin have not been established in pediatric patients younger than 8 years of age with heterozygous familial hypercholesterolemia (HeFH), younger than 7 years of age with HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH and HoFH).1

Safety and effectiveness of rosuvastatin have been established in pediatric patients 8 years of age and older with HeFH.1 Use of rosuvastatin in the pediatric population is based on a 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and a 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH.1 The observed reductions in LDL-cholesterol concentrations from baseline were consistent across age groups.1 In a population pharmacokinetic analysis of the 2 pediatric studies in patients with HeFH, rosuvastatin exposure appeared similar to or less than that observed in adults.1,377

Safety and effectiveness of rosuvastatin have been established in pediatric patients 7 years of age and older with HoFH.1 Use of rosuvastatin in the pediatric population is based on a randomized, placebo-controlled, cross-over study in 14 pediatric patients 7 years of age and older with HoFH.1 Substantial reductions in LDL-cholesterol (22.3%), total cholesterol (20.1%), non-HDL-cholesterol (22.9%), and apo B (17.1%) were observed with rosuvastatin compared with placebo in these patients.1

In studies evaluating rosuvastatin in the pediatric population, there were no detectable adverse effects on growth, weight, body mass index (BMI), or sexual maturation.1,375

Geriatric Use

Of the total number of patients receiving rosuvastatin in clinical studies, 31% were 65 years of age or older, and 6.8% were 75 years of age or older.1 Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1 Advanced age (≥65 years) is a risk factor for rosuvastatin-associated myopathy and rhabdomyolysis.1 There are no differences in plasma concentrations of rosuvastatin between geriatric (65 years of age or older) and younger patients.1

Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400

Monitor geriatric patients for development of myopathy.1

Hepatic Impairment

Plasma concentrations of rosuvastatin are modestly increased in patients with chronic alcoholic liver disease.1 Peak plasma concentrations and AUC of rosuvastatin are increased by 60 and 5%, respectively, in patients with Child-Pugh class A disease and by 100 and 21%, respectively, in patients with Child-Pugh class B disease compared with individuals with normal liver function.1

Rosuvastatin should be used with caution in patients with a history of liver disease (e.g., chronic alcoholic liver disease) and/or in patients who consume substantial amounts of alcohol.1 Rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis.1

Renal Impairment

Exposure to rosuvastatin (i.e., plasma concentrations) does not appear to be influenced by mild or moderate renal impairment (creatinine clearance of 30 mL/minute per 1.73 m² or greater).1 However, plasma concentrations of rosuvastatin were increased to a clinically important extent (about threefold) in patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m²) not undergoing hemodialysis compared with healthy individuals (creatinine clearance greater than 80 mL/minute per 1.73 m²).1 Steady-state plasma concentrations of rosuvastatin in patients undergoing chronic hemodialysis are approximately 50% higher than those in healthy individuals with normal renal function.1

In patients with severe renal impairment who are not undergoing hemodialysis, the recommended initial dosage is 5 mg daily; dosage should not exceed 10 mg daily.1

Renal impairment is a risk factor for myopathy and rhabdomyolysis; monitor all patients with renal impairment for development of myopathy.1

Asian Patients

Pharmacokinetic studies, including a large study conducted in the US, show an approximate twofold elevation in median exposure to rosuvastatin (peak plasma concentration and AUC) in Asian patients compared with white patients.1 Dosage of rosuvastatin should be adjusted in Asian patients.1 Increased systemic exposure and the benefits versus risks of rosuvastatin should be taken into consideration in such patients not adequately controlled at rosuvastatin dosages up to 20 mg daily.1

Pharmacogenomic Considerations

Genetic variation in the solute carrier organic anion transporter (SLCO) family member ( SLCO1B1 ), ABCG2 (also known as breast cancer resistance protein [BCRP]), and cytochrome P-450 (CYP) 2C9 genes alters systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.500 SLCO1B1 encodes a transporter ( SLCO1B1 ; alternative names include organic ion transporter protein [OATP] 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.500 ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and atorvastatin; CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).500

In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.500 Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.500

Pharmacogenetic test results may be used as the basis for changing to another statin type or dosage for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.500 Experts state statin therapy should neither be discontinued nor avoided based on SLCO1B1 , ABCG2 , or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.500

Patients with SLCO1B1 decreased or possible decreased function phenotypes or poor function phenotypes will have increased rosuvastatin exposure compared to those with normal function, which may translate to an increased risk of statin-associated musculoskeletal symptoms if dosage exceeds 20 mg per day.500 Patients with such phenotypes may require lower doses, or combination therapy (i.e., rosuvastatin plus a nonstatin guideline directed medical therapy); also consider disease- and population-specific (i.e., Asian ancestry) guidelines.500

Patients with ABCG2 decreased function phenotypes or poor function phenotypes will have increased rosuvastatin exposure compared to those with normal function, which may translate to increased lipid-lowering effects and unknown risk of statin-associated musculoskeletal symptoms.500 Patients with such phenotypes may require lower doses, an alternative statin, or combination therapy (i.e., rosuvastatin plus a nonstatin guideline directed medical therapy); also consider disease- and population-specific (i.e., Asian ancestry) guidelines.500

There is limited clinical or pharmacokinetic data regarding combinatorial phenotypes (e.g., ABCG2 decreased function plus SLCO1B1 decreased function).500 Such patients may require lower doses, an alternative statin, or combination therapy (i.e., rosuvastatin plus a nonstatin guideline directed medical therapy); also consider disease- and population-specific (i.e., Asian ancestry) guidelines.500

There are no data available regarding SLCO1B1 genotype effects on statin response or myopathy in pediatric patients.500

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving rosuvastatin include headache, nausea, myalgia, asthenia, and constipation.1

Rosuvastatin is minimally (approximately 10%) metabolized by cytochrome P-450 (CYP) isoenzyme 2C9.1,339 Clearance of rosuvastatin is not dependent on metabolism by CYP3A4 to a clinically important extent.1 Rosuvastatin is also a substrate for the organic anion transport protein (OATP) 1B1 and the breast cancer resistance protein (BCRP).1,501

Drugs Affecting Transport Systems

Concomitant use of rosuvastatin with drugs that are inhibitors of these transport proteins (e.g., cyclosporine, certain HIV and HCV protease inhibitors) may potentially result in increased plasma concentrations of rosuvastatin and an increased risk of myopathy and rhabdomyolysis.1 Clinicians should consult the relevant prescribing information of such drugs when concomitant use with rosuvastatin is being considered.1

Antacids

In a pharmacokinetic study, simultaneous administration of rosuvastatin (40 mg as a single dose) and an antacid containing aluminum hydroxide and magnesium hydroxide decreased rosuvastatin peak plasma concentration and AUC by 50%;1,17 such effects were considered clinically important.1 In contrast, when the antacid and rosuvastatin were administered 2 hours apart, rosuvastatin peak plasma concentration and AUC were decreased by 20%.1,17 Therefore, if rosuvastatin and an aluminum-magnesium hydroxide antacid are used concomitantly, the antacid should be administered at least 2 hours after rosuvastatin.1

Azole Antifungals

Fluconazole

Concomitant use of rosuvastatin (80 mg as a single dose) and fluconazole (200 mg once daily for 11 days) increased rosuvastatin peak plasma concentration and AUC by 1.1-fold.1

Itraconazole

Concomitant use of rosuvastatin (10 mg as a single dose) and itraconazole (200 mg once daily for 5 days) increased rosuvastatin peak plasma concentration and AUC by 1.4-fold.1 Concomitant use of a higher dose of rosuvastatin (80 mg as a single dose) and itraconazole (200 mg once daily for 5 days) increased rosuvastatin peak plasma concentration and AUC by 1.2- and 1.3-fold, respectively.1

Ketoconazole

Concomitant use of rosuvastatin (80 mg as a single dose) and ketoconazole (200 mg twice daily for 7 days) had no effect on rosuvastatin peak plasma concentration and AUC.1

Capmatinib

Concomitant use of rosuvastatin and capmatinib increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin (10 mg as a single dose) and capmatinib (400 mg twice daily) increased rosuvastatin peak plasma concentration and AUC by 3- and 2.1-fold, respectively; such effects were considered clinically important.1 If used concomitantly with capmatinib, dosage of rosuvastatin should not exceed 10 mg once daily.1

Colchicine

Myopathy, including rhabdomyolysis, has been reported in patients receiving various statins, including rosuvastatin, concomitantly with colchicine.1 The manufacturer states that the benefit of concomitant use of rosuvastatin with colchicine should be weighed against the increased risk of myopathy and rhabdomyolysis.1 Some experts state the combination is reasonable when clinically indicated.339,502 If concomitant use is necessary, monitor patients closely for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.1,339,502

Cyclosporine

Concomitant use of rosuvastatin and cyclosporine increases plasma rosuvastatin concentrations, which increases the risk of myopathy and rhabdomyolysis.1,339 Following concomitant use of rosuvastatin (10 mg once daily for 10 days) and cyclosporine (at a stable dosage of 75-200 mg twice daily), rosuvastatin peak plasma concentration and AUC were increased by 11- and 7.1-fold, respectively; such effects were considered clinically important.1,339 Concomitant use of rosuvastatin and cyclosporine should be avoided ; if concomitant use cannot be avoided, dosage of rosuvastatin should not exceed 5 mg once daily.1

Darolutamide

Concomitant use of rosuvastatin and darolutamide increases plasma rosuvastatin concentrations, which increases the risk of myopathy and rhabdomyolysis.1 Following administration of a single 5-mg dose of rosuvastatin in patients receiving darolutamide (600 mg twice daily for 5 days), rosuvastatin peak plasma concentration and AUC were increased by 5- and 5.2-fold, respectively; such effects were considered clinically important.1 If used concomitantly with darolutamide, dosage of rosuvastatin should not exceed 5 mg once daily.1

Digoxin

Concomitant use of rosuvastatin (40 mg once daily for 12 days) and digoxin (0.5 mg as a single dose) had no effect on digoxin peak plasma concentration and AUC.1

Dronedarone

Concomitant use of rosuvastatin (10 mg as a single dose) and dronedarone (400 mg twice daily) increased rosuvastatin AUC by 1.4-fold.1

Eltrombopag

Concomitant use of rosuvastatin (10 mg as a single dose) and eltrombopag (75 mg once daily for 5 days) increased rosuvastatin peak plasma concentration and AUC by 2- and 1.6-fold, respectively.1

Elvitegravir

Following concomitant use of rosuvastatin and cobicistat-boosted elvitegravir, rosuvastatin peak plasma concentration and AUC were increased by 89 and 38%, respectively.503 If these drugs are used concomitantly, experts recommend careful rosuvastatin titration to the lowest effective dosage while monitoring for adverse events.503

Enasidenib

Concomitant use of rosuvastatin and enasidenib increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin (10 mg as a single dose) and enasidenib (100 mg daily for 28 days) increased rosuvastatin peak plasma concentration and AUC by 3.7- and 2.4-fold, respectively.1 If used concomitantly with enasidenib, dosage of rosuvastatin should not exceed 10 mg once daily.1

Erythromycin

Concomitant use of rosuvastatin (80 mg as a single dose) and erythromycin (500 mg 4 times daily for 7 days) decreased rosuvastatin peak plasma concentration and AUC by 30 and 20%, respectively.1

Ezetimibe

Concomitant use of rosuvastatin (10 mg once daily for 14 days) and ezetimibe (10 mg once daily for 14 days) increased rosuvastatin peak plasma concentration and AUC by 1.2-fold.1

Febuxostat

Concomitant use of rosuvastatin and febuxostat increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin (10 mg as a single dose) and febuxostat (120 mg daily for 4 days) increased rosuvastatin peak plasma concentration and AUC by 2.1- and 1.9-fold, respectively; such effects were considered clinically important.1 If used concomitantly with febuxostat, dosage of rosuvastatin should not exceed 20 mg once daily.1

Fibric Acid Derivatives

Fibrates may cause myopathy when given alone.1 The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates and rosuvastatin.1

Fenofibrate

Concomitant use of rosuvastatin and fenofibrate increases the risk of myopathy and rhabdomyolysis.1 Following concomitant use of rosuvastatin (10 mg as a single dose) and fenofibrate (67 mg three times daily for 7 days), rosuvastatin peak plasma concentration was increased by 1.2-fold and AUC was unchanged; such effects were not considered clinically important.1 The manufacturers state that the benefit of concomitant use of rosuvastatin with fenofibrate should be weighed against the increased risk of myopathy and rhabdomyolysis.1 Some experts state that it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.339,400,502 If concomitant use is decided, monitor patients closely for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.1

Gemfibrozil

Concomitant use of rosuvastatin and gemfibrozil increases the risk of myopathy and rhabdomyolysis.1 Following concomitant use of rosuvastatin (80 mg as a single dose) and gemfibrozil (600 mg twice daily for 7 days), rosuvastatin peak plasma concentration and AUC were increased by 2.2- and 1.9-fold, respectively; such effects were considered clinically important.1 Concomitant use of rosuvastatin and gemfibrozil should be avoided ; if concomitant use cannot be avoided, rosuvastatin should be initiated at a dosage of 5 mg once daily and dosage of the statin should not exceed 10 mg once daily.1

Fostamatinib

Concomitant use of rosuvastatin and fostamatinib increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin (20 mg as a single dose) and fostamatinib (100 mg twice daily) increased rosuvastatin peak plasma concentration and AUC by 1.9- and 2-fold, respectively; such effects were considered clinically important.1 If used concomitantly with fostamatinib, dosage of rosuvastatin should not exceed 20 mg once daily.1

HCV Antivirals

Concomitant use of rosuvastatin with certain HCV antiviral agents has differing effects on exposure to rosuvastatin and increases the risk of myopathy and rhabdomyolysis.1 Rosuvastatin dosage adjustment or avoidance may be necessary.1

Concomitant use of rosuvastatin and the combination of sofosbuvir/velpatasvir/voxilaprevir has resulted in substantial increases in peak plasma concentrations (18.9-fold) and AUC (7.4-fold) of rosuvastatin, which increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of these drugs is not recommended.1

Concomitant use of ledipasvir/sofosbuvir and rosuvastatin also may substantially increase rosuvastatin exposure and is not recommended.1

Concomitant use of rosuvastatin (10 mg as a single dose) and simeprevir (150 mg daily for 7 days) increased rosuvastatin peak plasma concentration and AUC by 3.2- and 2.8-fold, respectively; such effects were considered clinically important.1 Concomitant use of rosuvastatin (10 mg as a single dose) and velpatasvir (100 mg daily) increased rosuvastatin peak plasma concentration and AUC by 2.6- and 2.7-fold, respectively; such effects were considered clinically important.1 Concomitant use of rosuvastatin (10 mg as a single dose) and elbasvir/grazoprevir (50/200 mg once daily) increased rosuvastatin peak plasma concentration and by AUC 5.5- and 2.3-fold, respectively; such effects were considered clinically important.1 Concomitant use of rosuvastatin (5 mg as a single dose) and glecaprevir/pibrentasvir (400/120 mg once daily) increased rosuvastatin peak plasma concentration and AUC by 5.6- and 2.2-fold, respectively; such effects were considered clinically important.1

Concomitant use of rosuvastatin and simeprevir or combinations of elbasvir/grazoprevir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir results in clinically important increased rosuvastatin exposure.1 If rosuvastatin is used concomitantly with simeprevir or the combination regimens described above, dosage of rosuvastatin should be initiated at 5 mg once daily and should not exceed 10 mg once daily.1

HIV Protease Inhibitors

Concomitant use of rosuvastatin with certain ritonavir-boosted HIV protease inhibitors has differing effects on exposure to rosuvastatin and may increase the risk of myopathy and rhabdomyolysis.1 Rosuvastatin dosage adjustment is advised if these drugs are used concomitantly.1

Concomitant use of rosuvastatin with certain cobicistat-boosted HIV protease inhibitors has differing effects on exposure to rosuvastatin.503 Experts recommend rosuvastatin dosage adjustment while monitoring for adverse events.503

Atazanavir

Concomitant use of rosuvastatin and ritonavir-boosted atazanavir increases the risk of myopathy and rhabdomyolysis.1 Following concomitant use of rosuvastatin (10 mg as a single dose) and ritonavir-boosted atazanavir (atazanavir 300 mg with ritonavir 100 mg once daily for 8 days), rosuvastatin peak plasma concentration and AUC were increased by 7- and 3.1-fold, respectively; such effects were considered clinically important.1 If used concomitantly with ritonavir-boosted atazanavir, rosuvastatin should be initiated at a dosage of 5 mg once daily and dosage of the statin should not exceed 10 mg once daily.1

Following concomitant use of rosuvastatin and cobicistat-boosted atazanavir, rosuvastatin peak plasma concentration and AUC were increased by 10.6- and 3.4-fold, respectively503 Experts recommend selecting the lowest effective rosuvastatin dosage, not to exceed 10 mg daily, while monitoring for adverse events.503

Darunavir

Following concomitant use of rosuvastatin (10 mg once daily for 7 days) and ritonavir-boosted darunavir (darunavir 600 mg with ritonavir 100 mg twice daily for 7 days), rosuvastatin peak plasma concentration and AUC were increased by 2.4- and 1.5-fold, respectively.1

Following concomitant use of rosuvastatin and cobicistat-boosted darunavir, rosuvastatin peak plasma concentration and AUC were increased by 3.8- and 1.9-fold, respectively503 Experts recommend selecting the lowest effective rosuvastatin dose, not to exceed 20 mg daily, while monitoring for adverse events.503

Fosamprenavir

Concomitant use of rosuvastatin and ritonavir-boosted fosamprenavir produces minimal to no change in exposure to rosuvastatin.1 Following concomitant use of rosuvastatin (10 mg as a single dose) and ritonavir-boosted fosamprenavir (fosamprenavir 700 mg with ritonavir 100 mg twice daily for 7 days), rosuvastatin peak plasma concentration and AUC were increased by 1.5- and 1.1-fold, respectively.1

Lopinavir

Concomitant use of rosuvastatin and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) increases the risk of myopathy and rhabdomyolysis.1 Following concomitant use of rosuvastatin (20 mg once daily for 7 days) and lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 17 days), rosuvastatin peak plasma concentration and AUC were increased by 5- and 2.1-fold, respectively; such effects were considered clinically important.1 If used concomitantly with lopinavir/ritonavir, rosuvastatin should be initiated at a dosage of 5 mg once daily and dosage of the statin should not exceed 10 mg once daily.1

Tipranavir

Concomitant use of rosuvastatin and ritonavir-boosted tipranavir produces minimal to no change in exposure to rosuvastatin.1 Following concomitant use of rosuvastatin (10 mg as a single dose) and ritonavir-boosted tipranavir (tipranavir 500 mg with ritonavir 200 mg twice daily for 11 days), rosuvastatin peak plasma concentration and AUC were increased by 2.2- and 1.4-fold, respectively.1

Lomitapide

Following concomitant use of rosuvastatin (20 mg as a single dose) and lomitapide (10 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 6 and 2%, respectively.374 Following concomitant use of rosuvastatin (20 mg as a single dose) and lomitapide (60 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 4 and 32%, respectively.374 Dosage adjustment of rosuvastatin is not required during concomitant use with lomitapide.374

Niacin

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of rosuvastatin and antilipemic dosages (1 g daily or higher) of niacin.1

The manufacturer states the benefit of concomitant use of rosuvastatin with lipid-modifying doses (≥1 g/day) of niacin should be weighed against the increased risk of myopathy and rhabdomyolysis.1 If concomitant use is decided, monitor patients closely for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.1

Omega-3-acid Ethyl Esters

Steady-state rosuvastatin concentrations are not altered by concomitant administration of rosuvastatin with omega-3-acid ethyl esters in healthy volunteers.505

Oral Contraceptives

Concomitant use of rosuvastatin (40 mg once daily for 28 days) and an oral contraceptive (ethinyl estradiol 0.035 mg with norgestrel 0.18, 0.215, and 0.25 mg once daily for 21 days) resulted in a 30% increase in ethinyl estradiol peak plasma concentration and AUC and a 20 and 30% increase in norgestrel peak plasma concentration and AUC, respectively.1

Regorafenib

Concomitant use of rosuvastatin and regorafenib increases plasma rosuvastatin concentrations, which may increase the risk of myopathy.1 Following administration of a single 5-mg dose of rosuvastatin in patients receiving regorafenib (160 mg every day for 14 days), peak plasma concentrations and AUC of rosuvastatin increased by 4.6- and 3.8-fold, respectively; such effects were considered clinically important.1 If used concomitantly with regorafenib, dosage of rosuvastatin should not exceed 10 mg once daily.1

Rifampin

Concomitant use of rosuvastatin (20 mg as a single dose) and rifampin (450 mg once daily for 7 days) did not affect rosuvastatin AUC.1

Tafamidis

Tafamadis may cause myopathy when given alone; concomitant use of rosuvastatin and tafamadis increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin (10 mg as a single dose) and tafamadis (61 mg twice daily on days 1-2, followed by once daily on days 3-9) increased rosuvastatin peak plasma concentration and AUC by 1.9- and 2-fold, respectively; such effects were considered clinically important.1 Concomitant use of rosuvastatin and tafamadis should be avoided.1 If concomitant use cannot be avoided, rosuvastatin should be initiated at a dosage of 5 mg once daily, dosage of the statin should not exceed 20 mg once daily, and the patient should be monitored for signs of myopathy and rhabdomyolysis.1

Teriflunomide

Concomitant use of rosuvastatin and teriflunomide increases the risk of myopathy and rhabdomyolysis.1 Concomitant use of rosuvastatin and teriflunomide increased rosuvastatin peak plasma concentration and AUC by 2.7- and 2.5-fold, respectively; such effects were considered clinically important.1 If used concomitantly with teriflunomide, dosage of rosuvastatin should not exceed 10 mg once daily.1

Warfarin

Rosuvastatin significantly increased the INR in patients receiving warfarin.1 Following concomitant use of rosuvastatin (40 mg once daily for 10 days) and warfarin sodium (25 mg as a single dose), AUC of R - or S -warfarin was unchanged or increased by 10%, respectively, while peak plasma concentrations of R - or S -warfarin were unchanged; such effects resulted in clinically important pharmacodynamic effects.1 Caution should be exercised when rosuvastatin is used concomitantly with anticoagulants.1 If rosuvastatin is used concomitantly with warfarin, obtain an INR prior to initiating rosuvastatin and monitor INR frequently enough after initiation, dose titration, or discontinuation to ensure that no substantial alteration in INR occurs.1,339 Once the INR is stable, monitor INR at regularly recommended intervals.1,339

Description

Rosuvastatin calcium is a synthetic heptenoic acid-derivative antilipemic agent.1,2 The drug is a selective, competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase (i.e., statin), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).1,2 Rosuvastatin reduces total and low-density lipoprotein (LDL)-cholesterol, apolipoprotein B (apo B), non-high-density lipoprotein (HDL)-cholesterol, and triglyceride concentrations, and increases HDL-cholesterol concentrations in patients with primary hyperlipidemia or mixed dyslipidemia.1,6 Rosuvastatin also reduces triglyceride concentrations in patients with primary hypertriglyceridemia.1,6 Other favorable effects of statins (pleiotropic effects) include an antiproliferative influence on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.501

Rosuvastatin is hydrophilic; peak plasma concentrations are reached in 3-5 hours, and both peak plasma concentration and AUC increase in an approximate dose-proportional manner.1 The absolute bioavailability of rosuvastatin is approximately 20%.1 Rosuvastatin AUC does not differ following evening or morning drug administration; AUC is also not affected by administration with food.1 Therapeutic response is generally achieved within 4 weeks and maintained during continued therapy.1 Rosuvastatin is 88% bound to plasma proteins, mostly albumin; such binding is reversible and independent of plasma concentrations.1

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite.1 The major metabolite is N -desmethyl rosuvastatin, which is formed principally by cytochrome P-450 (CYP) isoenzyme 2C9.1 Clearance of rosuvastatin is not dependent on metabolism by CYP3A4 to a clinically important extent.1 Based on in vitro studies, N -desmethyl rosuvastatin has approximately 17-50% of the HMG-CoA reductase inhibitory activity of the parent drug.1 The parent drug accounts for greater than 90% of the active plasma HMG-CoA reductase inhibitory activity.1 Rosuvastatin is a substrate for the organic anion transport protein (OATP) 1B1 and the breast cancer resistance protein (BCRP).1 Pharmacogenomics of statin therapy include genetic polymorphism of the OATP1B1 gene, which may affect rosuvastatin exposure.1 Higher plasma rosuvastatin concentrations have been reported in a limited number of patients with 2 reduced-function variant OATP1B1 alleles.1 The frequency of this genotype ( SLCO1B1 521 C/C) generally is less than 5% in most populations.1 The effect of this genetic variation on efficacy and safety of rosuvastatin has not been established.1 Rosuvastatin and its metabolites are mainly eliminated in feces (90%) following oral administration.1 The elimination half-life of rosuvastatin is approximately 19 hours.1 Following an IV dose, approximately 28% of total body clearance was via the renal route and 72% by the hepatic route.1 Pharmacokinetic differences were not observed among Caucasian, Hispanic, and Black or Afro-Caribbean groups; however a 2‑fold elevation in median exposure (peak plasma concentrations and AUC) was observed in Asian subjects when compared with a Caucasian control group.1

Advice to Patients

• Advise patients to read the manufacturer's patient information.1
• Advise patients of the importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.1,400
• Advise patients of the risk of myopathy and/or rhabdomyolysis; risk is increased with higher dosages or when used concomitantly with certain drugs.1 Advise patients of the importance of promptly reporting any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if manifestations persist after discontinuance of therapy.1
• Advise patients of the risk of adverse hepatic effects.1 Advise patients of the importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1
• Advise patients of the risk of increased glucose concentrations and development of type 2 diabetes.1,200
• Advise patients that rosuvastatin tablets may be administered once a day, at any time of day, with or without food.1 Advise patients to swallow tablets whole.1
• Advise patients to wait at least 2 hours after taking rosuvastatin to take an antacid that contains a combination of aluminum and magnesium hydroxide.1
• If a dose of rosuvastatin is missed, advise patients to take the next dose at the normal scheduled time; do not take an extra dose of rosuvastatin.1
• Advise females of reproductive potential of the risk to a fetus.1 Advise women to notify their clinician to discuss if rosuvastatin should be discontinued if they become pregnant or suspect pregnancy during therapy.1,405 Counsel women (including adolescents) of childbearing age who are sexually active to use a reliable form of contraception during therapy.400
• Advise women that breast-feeding is not recommended during therapy.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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