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CAMBER PHARMACE
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rosuvastatin calcium 10 mg tab (generic crestor)

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Uses

Rosuvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) for prevention of cardiovascular events and for the management of dyslipidemias.

Prevention of Cardiovascular Events

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults. There is extensive evidence demonstrating that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients). Because the relative reduction in ASCVD risk is correlated with the degree of low-density lipoprotein (LDL)-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. According to the ACC/AHA guidelines, rosuvastatin may be used for primary or secondary prevention in adults when moderate- or high-intensity statin therapy is indicated.(See Prevention of Cardiovascular Events under Dosage and Administration: Dosage.) Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Primary Prevention

Rosuvastatin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) in patients without clinical evidence of coronary heart disease (CHD) who have an increased risk of cardiovascular disease based on age (men 50 years of age or older, women 60 years of age or older), high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or greater, and at least one additional cardiovascular disease risk factor (e.g., hypertension, low high-density lipoprotein [HDL]-cholesterol concentrations, smoking, family history of premature CHD) to reduce the risk of stroke or myocardial infarction (MI) and to reduce the risk of undergoing arterial revascularization procedures.

The ACC/AHA cholesterol management guideline recommends statins as first-line therapy for primary prevention in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40-75 years of age with type 1 or 2 diabetes mellitus; and patients 40-75 years of age with LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. Before initiating statin therapy for primary prevention in patients without clinical ASCVD or diabetes mellitus, it is reasonable for clinicians and patients to discuss the potential for ASCVD risk reduction benefits, adverse effects, and drug interactions, as well as patient preferences for treatment.

In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) 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, 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. 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. However, there were no treatment differences among the rosuvastatin and placebo groups for death secondary to cardiovascular causes or hospitalization for unstable angina. At one year, rosuvastatin increased HDL-cholesterol concentrations and reduced LDL-cholesterol, hsCRP, total cholesterol, and serum triglyceride concentrations compared with placebo. 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 mmHg 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.

Reducing Progression of Coronary Atherosclerosis

Rosuvastatin is used as an adjunct to dietary therapy to slow the progression of atherosclerosis as part of a treatment strategy to lower total and LDL-cholesterol concentrations to target levels.

In the Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin (METEOR) study in 984 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, 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. However, rosuvastatin did not induce disease regression.

Intensity of Statin Therapy

The ACC/AHA cholesterol management guideline states that the appropriate intensity of a statin should be used to reduce the risk of ASCVD in patients most likely to benefit. Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the guideline expert panel, ACC/AHA considers rosuvastatin 5-10 mg daily to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30% to less than 50%) and rosuvastatin 20-40 mg daily to be a high-intensity statin (producing average LDL-cholesterol reductions of at least 50%). However, individual response may vary in clinical practice.

Combination Antilipemic Therapy

The ACC/AHA cholesterol management guideline states that nonstatin drugs may be useful adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, LDL-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events. 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.

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 Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA), a randomized, double-blind study in 2776 patients undergoing hemodialysis. 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.

Dyslipidemias

Rosuvastatin is used as an adjunct to dietary therapy for the management of primary hyperlipidemia or mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia, and/or homozygous familial hypercholesterolemia. Efficacy of rosuvastatin in patients with Fredrickson type I or V dyslipidemia has not been established.

Primary Hyperlipidemia or Mixed Dyslipidemia

Adults

Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in adults to reduce elevated total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), non-HDL-cholesterol, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hyperlipidemia or mixed dyslipidemia. Efficacy of rosuvastatin in patients with hyperlipidemia or mixed dyslipidemia has been established in placebo-controlled studies and in comparative studies with other statins (e.g., atorvastatin, pravastatin, simvastatin). Statins such as rosuvastatin also are used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy.

Reductions in total cholesterol and LDL-cholesterol concentrations achieved with usual dosages of rosuvastatin substantially exceed those with placebo or compared with baseline values. 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.

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). LDL-cholesterol reductions from baseline averaged 46, 52, or 55% with rosuvastatin 10, 20, or 40 mg, respectively, daily in these patients.

Rosuvastatin alone or combined with extended-release niacin improves the atherogenic lipid profile in patients with mixed dyslipidemia and low HDL-cholesterol concentrations. 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. 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. Patients receiving rosuvastatin had a lower incidence of treatment-related adverse effects than those receiving niacin-containing regimens. (See Musculoskeletal Effects under Cautions: Warnings/Precautions and also Drug Interactions: Niacin.)

Pediatric Patients

Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in children and adolescents 8-17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration exceeding 190 mg/dL or a serum LDL-cholesterol concentration exceeding 160 mg/dL and either a family history of premature cardiovascular disease or 2 or more other cardiovascular risk factors. The long-term effect of rosuvastatin therapy in childhood on reducing cardiovascular morbidity and mortality in adulthood has not been established. and also consult the most recent Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).

Efficacy and safety of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia were evaluated in a double-blind, placebo-controlled study and an open-label uncontrolled study. 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 heterozygous familial hypercholesterolemia (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. Treatment with rosuvastatin resulted in substantial reductions in concentrations of total cholesterol, LDL-cholesterol (primary end point), and apo B compared with placebo during the 12-week double-blind phase. 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. Changes in concentrations of triglycerides and HDL-cholesterol were similar in patients receiving rosuvastatin and in those receiving placebo. At the end of the 12-week double-blind phase, 12, 41, or 41% of patients receiving rosuvastatin dosages of 5, 10, or 20 mg achieved the LDL-cholesterol goal of less than 110 mg/dL compared with 0% of those receiving placebo. During the 40-week open-label phase, 71% of patients were titrated to the maximum rosuvastatin dosage of 20 mg daily and 41% of the patients achieved the LDL-cholesterol goal of less than 110 mg/dL.

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 heterozygous familial hypercholesterolemia (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). The observed reductions in LDL-cholesterol concentrations from baseline were consistent across age groups and consistent with previous experience in controlled trials of adults and pediatric patients. 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.

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 elevated total cholesterol, LDL-cholesterol, and apo B concentrations in adults with homozygous familial hypercholesterolemia. In an open-label, forced-titration study in 40 patients with homozygous familial hypercholesterolemia, therapy with rosuvastatin (20-40 mg daily [titrated at a 6-week interval]) decreased LDL-cholesterol concentrations by a mean of 22%. 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. 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. LDL-cholesterol reductions of 15% or greater were observed in 3 of 5 patients with known receptor-negative status.

Pediatric Patients

Rosuvastatin is used alone or in combination with other lipid-lowering therapies (e.g., LDL apheresis) to decrease elevated serum LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo B concentrations in children and adolescents 7-17 years of age with homozygous familial hypercholesterolemia as an adjunct to nondrug therapies (e.g., dietary management). In a double-blind, placebo-controlled crossover study in 14 children and adolescents 6 years of age or older with homozygous familial hypercholesterolemia (mean baseline LDL-cholesterol concentration of 416 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%), non-HDL-cholesterol (22.9%), and apo B (17.1%) compared with placebo.

Hypertriglyceridemia

Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) in the treatment of hypertriglyceridemia. 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. AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations.

Primary Dysbetalipoproteinemia

Rosuvastatin is used as an adjunct to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia (Fredrickson type III).

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.

For additional information on the role of rosuvastatin or other statins in the treatment of lipoprotein disorders, prevention of cardiovascular events, or other uses, see General Principles of Antilipemic Therapy and also Uses in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

General

Patients should be placed on a standard cholesterol-lowering diet before receiving rosuvastatin and should continue on this diet during treatment. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The manufacturer states that serum lipoprotein concentrations should be determined within 2-4 weeks following initiation and/or titration of rosuvastatin, and that dosage should be adjusted accordingly. The ACC/AHA cholesterol management guideline states that lipoprotein concentrations should be determined within 4-12 weeks following initiation of statin therapy (to determine the patient's response to therapy and adherence) and monitored every 3-12 months thereafter as clinically indicated.

Adherence to lifestyle modifications and to statin therapy are required for atherosclerotic cardiovascular disease (ASCVD) risk reduction and, thus, should be reinforced periodically.

Administration

Rosuvastatin is administered orally as a single dose at any time of day, with or without food; the tablets should be swallowed whole. Two doses of rosuvastatin should not be taken within 12 hours of each other.

Dosage

Dosage of rosuvastatin calcium is expressed in terms of rosuvastatin.

When initiating rosuvastatin therapy or switching from another statin, the appropriate initial dosage of rosuvastatin should be used; dosage may then be carefully adjusted according to individual requirements (i.e., percent reduction in low-density lipoprotein [LDL]-cholesterol concentration) and response.

Prevention of Cardiovascular Events

The ACC/AHA cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in patients most likely to benefit. Giving a maximally tolerated statin intensity should be emphasized over giving lower statin dosages and adding nonstatin drugs to address low HDL-cholesterol or high triglyceride concentrations, a strategy that has not yet been shown to reduce ASCVD risk. It should be noted that although dosages of 5 and 40 mg once daily are FDA-labeled dosages of rosuvastatin, these dosages were not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.

Primary Prevention

For primary prevention of cardiovascular disease in patients 21 years of age and older without clinical ASCVD who have primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater), the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (e.g., rosuvastatin 20-40 mg once daily) be initiated. In patients who are unable to tolerate high-intensity statin therapy, the maximum tolerated statin intensity should be used. The ACC/AHA cholesterol management guideline states that it is reasonable to intensify statin therapy to achieve at least a 50% reduction in LDL-cholesterol concentrations. In patients currently receiving the maximum intensity of statin therapy, addition of a nonstatin drug may be considered to achieve further reductions in LDL-cholesterol concentrations; however, the potential benefits and risks (e.g., adverse effects, drug interactions) of such combined therapy, along with patient preferences, should be considered.

For primary prevention of cardiovascular disease in patients 40-75 years of age with type 1 or 2 diabetes mellitus and LDL-cholesterol concentrations of 70-189 mg/dL, the ACC/AHA cholesterol management guideline recommends that moderate-intensity statin therapy (e.g., rosuvastatin 5-10 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 7.5% or higher, it is reasonable to consider high-intensity statin therapy (e.g., rosuvastatin 20-40 mg once daily) unless contraindicated. In patients with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.

For primary prevention of cardiovascular disease in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher, the ACC/AHA cholesterol management guideline recommends that moderate- (e.g., rosuvastatin 5-10 mg once daily) to high-intensity statin therapy (e.g., rosuvastatin 20-40 mg once daily) be initiated or continued. In those with an estimated 10-year ASCVD risk of 5 to less than 7.5%, it is reasonable to offer treatment with moderate-intensity statin therapy. Before initiating statin therapy for primary prevention of ASCVD in patients 40-75 years of age without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70-189 mg/dL, it is reasonable for clinicians and patients to discuss the potential benefits, adverse effects, drug interactions, and patient preferences for such therapy.

Secondary Prevention

For secondary prevention of cardiovascular disease in patients 21-75 years of age with clinical ASCVD, the ACC/AHA cholesterol management guideline recommends that high-intensity statin therapy (e.g., rosuvastatin 20-40 mg once daily) be initiated or continued unless contraindicated. In patients 21-75 years of age with clinical ASCVD who are at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, moderate-intensity statin therapy (e.g., rosuvastatin 5-10 mg once daily) should be given if tolerated. In patients older than 75 years of age with clinical ASCVD, use of statin therapy should be individualized based on the potential benefits, adverse effects, drug interactions, and patient preferences; it is reasonable to consider initiating or continuing moderate-intensity statin therapy in such patients if tolerated.

Dyslipidemias

General Dosage

The usual initial dosage of rosuvastatin in adults is 10-20 mg once daily. The dosage range of rosuvastatin in adults is 5-40 mg once daily. The maximum 40-mg daily dosage of rosuvastatin should be used only for those patients who have not achieved their LDL-cholesterol goal with the 20-mg daily dosage.

Following initiation and/or titration of rosuvastatin dosage, lipoprotein concentrations should be determined within 2-4 weeks and dosage adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

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

The recommended dosage range of rosuvastatin for the management of heterozygous familial hypercholesterolemia in children and adolescents 10-17 years of age is 5-20 mg once daily.

The maximum dosage of rosuvastatin in pediatric patients is 20 mg daily.

Homozygous Familial Hypercholesterolemia

The usual initial dosage of rosuvastatin in adults with homozygous familial hypercholesterolemia is 20 mg once daily.

The recommended dosage of rosuvastatin in children and adolescents 7-17 years of age with homozygous familial hypercholesterolemia is 20 mg once daily.

Concomitant Drug Therapy

In patients receiving concomitant cyclosporine, dosage of rosuvastatin should be limited.(See Drug Interactions: Cyclosporine.)

Concomitant use of rosuvastatin and gemfibrozil should be avoided; if concomitant use cannot be avoided, dosage of rosuvastatin should be limited.(See Gemfibrozil under Drug Interactions: Fibric Acid Derivatives.)

Caution is advised if rosuvastatin is used concomitantly with ritonavir-boosted atazanavir or with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir). Dosage of rosuvastatin should be limited.(Drug Interactions: HIV Protease Inhibitors.)

Caution is advised if rosuvastatin is used concomitantly with simeprevir. Dosage of rosuvastatin should be limited.(See Simeprevir under Drug Interactions: HCV Protease Inhibitors.)

Dosage Modification

The ACC/AHA cholesterol management guideline states that decreasing the statin dosage in adults may be considered when LDL-cholesterol concentrations are less than 40 mg/dL on 2 consecutive measurements; however, there are no data to suggest that LDL-cholesterol concentrations below 40 mg/dL would increase the risk of adverse effects.

Special Populations

Asian Patients

The manufacturer recommends that an initial rosuvastatin dosage of 5 mg once daily be considered in Asian patients.(See Asian Patients under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

In patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m) 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.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Hepatic Impairment

The manufacturer makes no specific dosage recommendations at this time for patients with hepatic impairment. (See Cautions: Contraindications and also Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Geriatric Patients

Although there are no specific dosage recommendations for geriatric patients, caution is recommended when rosuvastatin is used in these patients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

Active liver disease, including unexplained, persistent elevations in hepatic aminotransferase (transaminase) concentrations.

Pregnancy.(See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation.(See Lactation under Warnings/Precautions: Specific Populations, in Cautions.)

Known hypersensitivity to rosuvastatin or any ingredient in the formulation.(See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Serum cholesterol and triglyceride concentrations increase during normal pregnancy, and cholesterol products are essential for fetal development; therefore, suppression of cholesterol biosynthesis by rosuvastatin during pregnancy may cause fetal harm. Atherosclerosis is a chronic process, and discontinuance of antilipemic drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy. There is no known clinical benefit for continued use of antilipemic drugs during pregnancy.

Limited human data available to date have not identified an increased risk of major congenital malformations or miscarriage with the use of rosuvastatin during pregnancy; however, congenital anomalies following intrauterine exposure to other statins have been reported rarely. In animal studies, there were no adverse developmental effects when rosuvastatin was administered to rats and rabbits during the period of organogenesis at systemic exposures equivalent to the maximum recommended human dosage of 40 mg daily; decreased pup survival occurred at doses equivalent to or higher than the maximum recommended human dose.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Musculoskeletal Effects

Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving statins, including rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily).

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). 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]), cyclosporine, ritonavir-boosted atazanavir, the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), or simeprevir.(See Drug Interactions.)

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline does not recommend routine monitoring of CK concentrations in patients receiving statin therapy. However, the guideline states that it is reasonable to obtain baseline CK concentrations in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs) before initiating statin therapy. During statin therapy, it is reasonable to measure CK concentrations in adults experiencing muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).

The National Heart, Lung, and Blood Institute (NHLBI)-appointed expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that baseline CK concentrations should be obtained before initiating statin therapy in pediatric patients. In addition, routine monitoring for muscle toxicity is strongly recommended in children and adolescents receiving statin therapy.

Rosuvastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected. 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; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).(See Advice to Patients.)

and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org) and the Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at http://www.nhlbi.nih.gov).

Hepatic Effects

Increases in serum aminotransferase (i.e., AST [SGOT], ALT [SGPT]) concentrations have been reported in patients receiving statins, including rosuvastatin. These increases usually were transient and resolved or improved with continued therapy or after temporary interruption of therapy. 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. Jaundice has been reported in at least 2 patients but resolved following discontinuance of rosuvastatin therapy; a causal relationship to rosuvastatin has not been established. Although liver failure and irreversible liver disease have not been reported in clinical studies evaluating rosuvastatin, cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including rosuvastatin, during postmarketing surveillance.

Liver function tests should be performed prior to initiation of rosuvastatin therapy and repeated as clinically indicated (e.g., presence of manifestations suggestive of liver damage). Although the manufacturer previously recommended more frequent monitoring of liver function (i.e., at 12 weeks following initiation of therapy or any increase in dosage, then periodically [e.g., semiannually] thereafter), FDA concluded that serious statin-related liver injury is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious statin-related liver injury. The ACC/AHA cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function 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, the NHLBI expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that routine monitoring of hepatic function is strongly recommended in children and adolescents receiving statin therapy.

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, rosuvastatin therapy should be promptly interrupted. If an alternate etiology is not found, rosuvastatin therapy should not be restarted.

Rosuvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of chronic liver disease. The drug is contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.

Interactions with Coumarin-derivative Anticoagulants

Because rosuvastatin may potentiate the anticoagulant effects of coumarin-derivative anticoagulants, caution should be exercised when these agents are used concomitantly. If rosuvastatin is used concomitantly with coumarin-derivative anticoagulants, international normalized ratio (INR) should be stable before initiating rosuvastatin and should be monitored frequently enough during early therapy (or following adjustment of rosuvastatin dosage) to ensure that no substantial alteration in INR occurs.

Proteinuria and Hematuria

Transient dipstick-positive proteinuria and microscopic hematuria (not associated with worsening renal function) have been reported in patients receiving rosuvastatin. These findings occurred more frequently in patients receiving rosuvastatin 40 mg compared with lower doses of rosuvastatin or comparator statins in clinical trials. 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.

Endocrine Effects

Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including rosuvastatin. Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus. 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%). In addition, mean HbA1c was increased by 0.1% in patients receiving rosuvastatin compared with those receiving placebo, and the number of patients with an HbA1c greater than 6.5% also was substantially higher among those receiving rosuvastatin. Despite these findings, FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks. The ACC/AHA cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus according to current diabetes screening guidelines. If diabetes mellitus develops during statin therapy, patients should be encouraged to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of atherosclerotic cardiovascular disease (ASCVD).

Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, statins interfere with cholesterol synthesis and theoretically may blunt adrenal or gonadal steroid hormone production. Caution should be exercised if rosuvastatin is used concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones (e.g., ketoconazole, spironolactone, cimetidine).

Sensitivity Reactions

Hypersensitivity reactions, including rash, pruritus, urticaria, and angioedema, have been reported in patients receiving rosuvastatin.

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) has been reported rarely with all statins during postmarketing surveillance. This adverse CNS effect generally was nonserious and reversible, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks following discontinuance of statin therapy). Following review of available data (i.e., from the Adverse Event Reporting System [AERS] database, randomized clinical trials, observational studies, case reports), FDA concluded that cases of cognitive impairment did not appear to be associated with fixed or progressive dementia (e.g., Alzheimer's disease) or result in clinically important cognitive decline. Development of cognitive impairment did not appear to be associated with any specific statin, age of the patient, statin dosage, or concomitant drug therapy. Therefore, FDA continues to believe that the cardiovascular benefits of statins outweigh this small increased risk of cognitive impairment. The National Lipid Association (NLA) statin safety assessment task force recommends that patients experiencing manifestations consistent with cognitive impairment be evaluated and managed appropriately. The ACC/AHA cholesterol management guideline states that, in patients presenting with confusion or memory impairment, it is reasonable to evaluate the patient for statin as well as nonstatin causes (e.g., exposure to other drugs, systemic or neuropsychiatric causes).

Specific Populations

Pregnancy

Safety of rosuvastatin has not been established in pregnant women; there are no known benefits of therapy with the drug during pregnancy. (See Cautions: Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Rosuvastatin should be discontinued immediately if pregnancy is known or suspected. Women of childbearing potential should use effective contraception while receiving the drug.(See Advice to Patients.)

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. Because of the potential for serious adverse reactions from rosuvastatin in nursing infants, the drug is contraindicated in nursing women. Women who require rosuvastatin therapy should not breast-feed their infants.

Pediatric Use

Safety and efficacy of rosuvastatin have not been established in pediatric patients younger than 8 years of age.

In a randomized, double-blind, placebo-controlled study in children and adolescents 10-17 years of age (females were at least 1 year postmenarche) with heterozygous familial hypercholesterolemia, the adverse effect profile of rosuvastatin (5-20 mg daily for 12 weeks) generally was similar to that of placebo. However, elevations in serum CK concentrations exceeding 10 times the ULN were observed more frequently in children receiving rosuvastatin compared with those receiving placebo; 3% of children receiving rosuvastatin (2 receiving 10 mg daily and 2 receiving 20 mg daily) had increased CK concentrations exceeding 10 times the ULN compared with 0% of those receiving placebo. Although controlled clinical studies of rosuvastatin in children younger than 10 years of age with heterozygous familial hypercholesterolemia have not been conducted, the drug was evaluated in a 2-year, open-label study that included patients 8-17 years of age with heterozygous familial hypercholesterolemia; results of this study showed that safety and efficacy of rosuvastatin in this age group generally were similar to those observed in the adult population. In a population pharmacokinetic analysis of the 2 pediatric studies in patients with heterozygous familial hypercholesterolemia, rosuvastatin exposure appeared similar to or less than that observed in adults. In a 6-week double-blind, crossover study that was followed by 12 weeks of open-label treatment in children and adolescents 7-15 years of age with homozygous familial hypercholesterolemia, the safety profile of rosuvastatin (20 mg daily) was consistent with that in adults.

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

If rosuvastatin therapy is considered, the manufacturer states that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.(See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Geriatric Use

Of the 10,275 patients receiving rosuvastatin in clinical studies, 31% were 65 years of age or older, and 6.8% were 75 years of age or older. 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. Plasma concentrations of rosuvastatin were similar between geriatric (65 years of age or older) and younger patients.

Since geriatric patients (65 years of age and older) are at increased risk of myopathy, rosuvastatin should be used with caution in such patients.(See Musculoskeletal Effects under Cautions: Warnings/Precautions.) The ACC/AHA cholesterol management guideline states that initiation of statin therapy for primary prevention of ASCVD in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age.

Hepatic Impairment

Plasma concentrations of rosuvastatin are modestly increased in patients with chronic alcoholic liver disease. 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.

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. Rosuvastatin is contraindicated in patients with active liver disease, including unexplained, persistent elevations in hepatic aminotransferase concentrations.

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 m or greater). 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 m) not undergoing hemodialysis compared with healthy individuals (creatinine clearance greater than 80 mL/minute per 1.73 m). Steady-state plasma concentrations of rosuvastatin in patients undergoing chronic hemodialysis are approximately 50% higher than those in healthy individuals with normal renal function.

Dosage adjustments are required in patients with severe renal impairment who are not undergoing hemodialysis.(See Renal Impairment under Dosage and Administration: Special Populations.)

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 Caucasian patients. Dosage of rosuvastatin should be adjusted in Asian patients. Increased systemic exposure should be taken into consideration in such patients not adequately controlled at rosuvastatin dosages up to 20 mg daily.(See Asian Patients under Dosage and Administration: Special Populations.)

Common Adverse Effects

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

Drug Interactions

Rosuvastatin is minimally (approximately 10%) metabolized by cytochrome P-450 (CYP) isoenzyme 2C9. Clearance of rosuvastatin is not dependent on metabolism by CYP3A4 to a clinically important extent.

Drugs Affecting Transport Systems

Rosuvastatin is a substrate for the organic anion transport protein (OATP) 1B1 and the breast cancer resistance protein (BCRP). Concomitant use of rosuvastatin with drugs that are inhibitors of these transport proteins (e.g., cyclosporine, certain HIV protease inhibitors) may potentially result in increased plasma concentrations of rosuvastatin and an increased risk of myopathy. Clinicians should consult the relevant prescribing information of such drugs when concomitant use with rosuvastatin is being considered.

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 area under the plasma concentration-time curve (AUC) by 50%; such effects were considered clinically important. In contrast, when the antacid and rosuvastatin were administered 2 hours apart, rosuvastatin peak plasma concentration and AUC were decreased by 20%. Therefore, if rosuvastatin and an aluminum-magnesium hydroxide antacid are used concomitantly, the antacid should be administered at least 2 hours after rosuvastatin.

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.

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

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.

Colchicine

Myopathy, including rhabdomyolysis, has been reported in patients receiving various statins, including rosuvastatin, concomitantly with colchicine. Caution is advised if rosuvastatin is used concomitantly with colchicine.

Cyclosporine

Concomitant use of rosuvastatin and cyclosporine increases plasma rosuvastatin concentrations, which may increase the risk of myopathy. 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. If used concomitantly with cyclosporine, dosage of rosuvastatin should not exceed 5 mg once daily.

Digoxin

Concomitant use of rosuvastatin (40 mg once daily for 12 days) and digoxin (0.5 mg as a single dose) increased both peak plasma concentration and AUC of digoxin by 4%.

Dronedarone

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

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.

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.

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.

Fibric Acid Derivatives

Fenofibrate

Concomitant use of rosuvastatin and fenofibrate may increase the risk of myopathy. 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. However, the manufacturer states that caution is advised if rosuvastatin is used concomitantly with fenofibrate. The ACC/AHA cholesterol management guideline states that the combination of fenofibrate and low- or moderate-intensity statin therapy may be considered only if the benefits from atherosclerotic cardiovascular disease (ASCVD) risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risk of adverse effects.

Gemfibrozil

Concomitant use of rosuvastatin and gemfibrozil increases the risk of myopathy and/or rhabdomyolysis. 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. 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.

HCV Protease Inhibitors

Concomitant use of rosuvastatin with certain protease inhibitors has differing effects on exposure to rosuvastatin; in some cases, rosuvastatin exposure may be increased by up to threefold. Caution is advised if these drugs are used concomitantly.

Simeprevir

Concomitant use of rosuvastatin and simeprevir may increase the risk of myopathy. Following concomitant use of rosuvastatin (10 mg as a single dose) and simeprevir (150 mg once daily for 7 days), rosuvastatin peak plasma concentration and AUC were increased by 3.2- and 2.8-fold, respectively; such effects were considered clinically important. If used concomitantly with simeprevir, rosuvastatin should be initiated at a dosage of 5 mg once daily and dosage of the statin should not exceed 10 mg once daily.

HIV Protease Inhibitors

Concomitant use of rosuvastatin with certain ritonavir-boosted HIV protease inhibitors has differing effects on exposure to rosuvastatin; in some cases, rosuvastatin exposure may be increased by up to threefold. Caution is advised if these drugs are used concomitantly.

Atazanavir

Concomitant use of rosuvastatin and ritonavir-boosted atazanavir may increase the risk of myopathy. 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. 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.

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.

Fosamprenavir

Concomitant use of rosuvastatin and ritonavir-boosted fosamprenavir produces minimal to no change in exposure to rosuvastatin. 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.

Lopinavir

Concomitant use of rosuvastatin and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) may increase the risk of myopathy. 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. 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.

Tipranavir

Concomitant use of rosuvastatin and ritonavir-boosted tipranavir produces minimal to no change in exposure to rosuvastatin. 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.

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. 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. Dosage adjustment of rosuvastatin is not required during concomitant use with lomitapide.

Niacin

Concomitant use of rosuvastatin and antilipemic dosages (1 g daily or higher) of niacin may increase the risk of myopathy. Data from several large randomized studies indicate that concomitant use of niacin (1.5-2 g daily) with another statin (i.e., simvastatin 40-80 mg once daily, with or without ezetimibe) resulted in an increased risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, and bleeding.

Caution is advised if rosuvastatin is used concomitantly with antilipemic dosages of niacin.

Omega-3-acid Ethyl Esters

Concomitant administration of rosuvastatin (40 mg daily) with omega-3-acid ethyl esters (4 g daily) for 14 days did not affect the rate or extent of exposure to rosuvastatin at steady state.

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 25 or 26% increase in ethinyl estradiol peak plasma concentration or AUC, respectively, and a 23 or 34% increase in norgestrel peak plasma concentration or AUC, respectively.

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.

Warfarin

Rosuvastatin potentiates the effects of coumarin-derivative anticoagulants in prolonging prothrombin time (PT)/international normalized ratio (INR); the drug has been shown to substantially increase INR in patients receiving coumarin anticoagulants. 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 increased by 4 or 6%, respectively, while peak plasma concentration of R- or S-warfarin was decreased by 1% or unchanged, respectively; such effects resulted in clinically important pharmacodynamic effects. Caution should be exercised when rosuvastatin is used concomitantly with anticoagulants. If rosuvastatin is used concomitantly with coumarin-derivative anticoagulants, INR should be stable prior to initiating rosuvastatin and should be monitored frequently enough during early therapy (or following adjustment of rosuvastatin dosage) to ensure that no substantial alteration in INR occurs.

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