Crestor Global Regulatory Status: FDA Approval, Label, and Post-Market Safety

When Did the FDA Approve Crestor?

The FDA approved rosuvastatin calcium (brand name Crestor) on August 12, 2003, under New Drug Application (NDA) 021366. AstraZeneca submitted the application after demonstrating efficacy and safety across a pre-approval clinical program that enrolled thousands of patients with primary hyperlipidemia and mixed dyslipidemia. The 5 mg starting dose was added specifically to accommodate patients at higher risk for statin-induced myopathy, including those of Asian ancestry and those with severe renal impairment.

Original Approval Indications

At approval, the FDA cleared rosuvastatin for four distinct indications: (1) adjunct to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and to increase HDL-C in adults with primary hyperlipidemia or mixed dyslipidemia; (2) adjunct to diet for the treatment of hypertriglyceridemia; (3) adjunct to diet to slow the progression of atherosclerosis in adult patients; and (4) adjunct to diet and other lipid-lowering treatments to reduce total cholesterol and LDL-C in adults with homozygous familial hypercholesterolemia (HoFH) when other therapies have not been adequate. FDA NDA 021366 approval letter and label.

Pediatric Indication Added in 2008

Five years after the original adult approval, the FDA extended the indication to include pediatric patients aged 10 to 17 years with heterozygous familial hypercholesterolemia (HeFH) whose LDL-C remains above 190 mg/dL or above 160 mg/dL with additional cardiovascular risk factors. This pediatric approval followed a dedicated clinical trial in adolescents and mirrored similar expansions granted to atorvastatin and simvastatin. Dosing in this population is limited to 5 mg to 20 mg daily. See the FDA pediatric labeling supplement at accessdata.fda.gov.

Primary Prevention Indication Added After JUPITER

Following the results of the JUPITER trial published in the New England Journal of Medicine in 2008, the FDA approved an additional indication for rosuvastatin in primary cardiovascular prevention. JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) enrolled 17,802 apparently healthy adults with LDL-C below 130 mg/dL but elevated high-sensitivity C-reactive protein (hsCRP) at or above 2 mg/L. Rosuvastatin 20 mg daily reduced the composite of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death by 44% compared with placebo (hazard ratio 0.56, 95% CI 0.46 to 0.69, P<0.00001) [1]. The FDA used this evidence to approve rosuvastatin for reducing cardiovascular risk in patients without clinically evident coronary heart disease but with elevated hsCRP plus at least one additional risk factor.

What Does the Crestor Label Say?

The current FDA-approved prescribing information for rosuvastatin covers dosing, contraindications, warnings, drug interactions, and special populations. Clinicians should review the full label, accessible via FDA Drugs@FDA, before initiating therapy.

Dosing by Indication

For primary hyperlipidemia and mixed dyslipidemia, the label recommends starting at 10 mg to 20 mg once daily. The 40 mg dose is reserved for patients who have not achieved their LDL-C goal on 20 mg. The label explicitly states that the 40 mg dose should be used only in patients for whom the additional LDL-C reduction is clinically necessary, because higher doses carry a higher risk of myopathy. For patients of Asian ancestry, the label recommends initiating at 5 mg. Pharmacokinetic studies show that Asian patients have approximately two-fold higher mean rosuvastatin plasma concentrations compared with Caucasian controls, which explains why the maximum dose in this population is 20 mg rather than 40 mg. FDA prescribing information, Section 2.

For homozygous familial hypercholesterolemia, the starting dose is 20 mg once daily, with titration to 40 mg only when the LDL-C response at 20 mg is insufficient.

Contraindications

The label lists four absolute contraindications. First, known hypersensitivity to rosuvastatin or any excipient. Second, active liver disease, which includes unexplained persistent elevations of serum transaminases. Third, concomitant use with cyclosporine, because cyclosporine dramatically increases rosuvastatin plasma concentrations through inhibition of OATP1B1 and OATP1B3 transporters. Fourth, pregnancy and breastfeeding, because statins suppress cholesterol synthesis that the developing fetus requires. See FDA label contraindications, Section 4.

Warnings and Precautions

The most clinically significant warning covers skeletal muscle effects. The label states that cases of myopathy, defined as muscle pain or weakness combined with creatine kinase (CK) levels greater than ten times the upper limit of normal, have been reported with rosuvastatin. Rhabdomyolysis, with acute renal failure secondary to myoglobinuria, has also been reported. Risk factors cited in the label include advanced age (65 and older), hypothyroidism, renal impairment, and concomitant use of certain medications. Specific drug combinations that the label identifies as requiring dose limitation include gemfibrozil (maximum rosuvastatin 10 mg daily), niacin-containing products at doses of 1 g or more per day, and certain antiviral regimens. FDA label, Section 5.1.

A second significant warning covers liver enzyme abnormalities. The label notes that persistent elevations of serum transaminases have occurred with HMG-CoA reductase inhibitors. Routine liver enzyme testing is no longer universally recommended before or during therapy, per updates aligned with the 2013 ACC/AHA cholesterol guideline, but the label still recommends obtaining a lipid panel and, when clinically indicated, liver enzymes before starting therapy. ACC/AHA 2018 cholesterol guideline published in Circulation via ahajournals.org.

The label also warns about an increased risk of diabetes mellitus with statin use. Post-marketing analyses from multiple statin trials, including data pooled from the JUPITER trial and other large outcome trials, showed that patients on statins had a modestly higher incidence of new-onset diabetes compared with placebo. The FDA added a class-wide diabetes warning to all statin labels in 2012. FDA Drug Safety Communication on statins and diabetes, fda.gov.

Cognitive Effects Warning Added in 2012

In February 2012, the FDA also added a warning about potential cognitive effects to all statin labels, including rosuvastatin. The warning is based on post-marketing reports of reversible cognitive impairment (memory loss, forgetfulness, amnesia, memory impairment, and confusion) in patients taking statins. Onset ranged from one day to years after starting statin therapy, and the events resolved in most patients after stopping the statin. The FDA noted that the reports are generally nonserious and reversible. FDA Drug Safety Communication February 28, 2012.

Crestor Safety: Post-Market Surveillance Data

Post-approval safety monitoring for rosuvastatin has been extensive. The FDA's Sentinel System, a distributed database containing electronic health records and claims data from more than 100 million patients, has been used to evaluate spontaneous reports of myopathy and rhabdomyolysis across the statin class. FDA Sentinel System overview.

JUPITER Trial Safety Profile

In JUPITER, the trial that drove the primary prevention indication, rosuvastatin 20 mg daily was compared with placebo across a median follow-up of 1.9 years. Among the 8,901 patients assigned to rosuvastatin, the rate of myopathy (defined by protocol as muscle symptoms plus CK greater than ten times the upper limit of normal) was 0.9 per 1,000 patient-years, compared with 0.8 per 1,000 patient-years in the placebo group. No cases of fatal rhabdomyolysis occurred in the rosuvastatin arm. New-onset physician-reported diabetes was 3.0% in the rosuvastatin group versus 2.4% in the placebo group, a finding that reached statistical significance (P=0.01) and contributed to the FDA's 2012 class-wide diabetes labeling update. Ridker PM et al., NEJM 2008 [1].

Myopathy and Rhabdomyolysis: Absolute Risk Estimates

Population-level absolute risk estimates from FDA Sentinel and from published observational cohort studies are reassuring for most patients. A meta-analysis of statin safety trials published in the Lancet (2022, Collins et al., N=154,000 participants across 21 trials) showed that the rate of myopathy causing hospitalization or death attributable to statin therapy was approximately 1 per 10,000 patients treated per year. Collins R et al., Lancet 2022 [2]. For rosuvastatin specifically, the risk of rhabdomyolysis at doses of 10 mg to 20 mg daily is estimated at fewer than 1 case per 100,000 patient-years of exposure from combined spontaneous reporting and active surveillance data.

Renal Safety Controversies Resolved

Shortly after the 2003 FDA approval, there were early signals from spontaneous adverse event reports suggesting that rosuvastatin might cause proteinuria and hematuria at higher doses. The FDA evaluated this signal through a series of epidemiological studies conducted between 2003 and 2006. The conclusion, published in FDA regulatory documents and confirmed by AstraZeneca's post-marketing commitment studies, was that proteinuria at the 40 mg dose reflects a tubular rather than glomerular mechanism and is not associated with progressive renal impairment or increased risk of end-stage renal disease at therapeutic doses. FDA rosuvastatin safety review, accessdata.fda.gov.

Hepatic Safety in Real-World Practice

Clinically significant liver toxicity from rosuvastatin is rare. A systematic review published in Hepatology examined the hepatotoxicity risk across statins and found that the rate of serious drug-induced liver injury was approximately 1 to 3 cases per 100,000 person-years of statin exposure. The review found no significant difference in hepatotoxicity risk between individual statins at comparable doses. LiverTox summary via NCBI [3]. Routine monitoring of liver enzymes during statin therapy is not recommended by the 2018 ACC/AHA guidelines unless the patient develops symptoms suggestive of hepatotoxicity. AHA 2018 cholesterol guideline.

Crestor Regulatory Status Outside the United States

Rosuvastatin holds marketing authorizations in more than 100 countries. The regulatory history outside the United States includes parallel reviews in the European Union, Canada, Australia, and Japan.

European Medicines Agency Approval

The European Medicines Agency (EMA) approved rosuvastatin under the brand name Crestor on February 4, 2003, six months before the FDA approval. The EMA Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion based on clinical trial data demonstrating that rosuvastatin reduced LDL-C by 45% to 63% from baseline across dose ranges of 10 mg to 40 mg in patients with primary hypercholesterolemia. The EMA's European Public Assessment Report (EPAR) for rosuvastatin is publicly accessible through the EMA website and contains the full scientific discussion of the benefit-risk assessment. EMA EPAR via European Medicines Agency.

Dose Differences Across Jurisdictions

One clinically relevant regulatory difference between the FDA and EMA labels concerns the maximum approved dose. Both agencies approve the 40 mg dose; however, several national health authorities in Asia, including the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, have not approved the 40 mg dose based on the pharmacokinetic differences in Asian patients described above. Japan's approved maximum dose is 20 mg per day. This creates a practical prescribing consideration for clinicians working with patients who travel or who obtain medications from international sources.

Generic Entry and Biosimilar Field

In the United States, the primary patent for rosuvastatin calcium expired in 2016. Multiple generic manufacturers received FDA approval to market rosuvastatin calcium tablets in 2016, and the wholesale acquisition cost dropped by more than 90% within two years of generic entry. As of 2024, the FDA's Orange Book lists more than 30 approved generic rosuvastatin products. FDA Orange Book, accessdata.fda.gov. The availability of low-cost generics has significantly expanded patient access, particularly in value-based care programs that use formulary tier placement as a lever for medication adherence.

Key Drug Interactions Identified in Post-Market Surveillance

The rosuvastatin label has been updated multiple times since 2003 to incorporate drug interaction data from post-marketing reports and dedicated pharmacokinetic studies. Understanding which interactions carry the greatest clinical significance helps prescribers select appropriate doses.

Interactions Requiring Dose Caps

Gemfibrozil increases rosuvastatin AUC by approximately 88% through inhibition of OATP1B1 and CYP2C9. The FDA label caps rosuvastatin at 10 mg per day when combined with gemfibrozil. FDA label Section 7, accessdata.fda.gov.

Cyclosporine increases rosuvastatin AUC by approximately 7-fold. Concurrent use is listed as a contraindication rather than a dose cap.

Certain HIV antiretroviral combinations, including lopinavir/ritonavir and atazanavir/ritonavir, increase rosuvastatin AUC by 2-fold to 3-fold. The label recommends a maximum rosuvastatin dose of 10 mg per day with these combinations. FDA drug interaction label update, accessdata.fda.gov.

Interactions Without Dose Adjustments Required

Ezetimibe, which is commonly co-administered with rosuvastatin, does not meaningfully alter rosuvastatin pharmacokinetics. The SHARP trial (Study of Heart and Renal Protection, N=9,270) used simvastatin 20 mg plus ezetimibe 10 mg and confirmed the safety of combined lipid-lowering therapy, data that informs the clinical extrapolation to rosuvastatin-ezetimibe combinations. Baigent C et al., Lancet 2011 [4].

Warfarin does not significantly alter rosuvastatin pharmacokinetics, but rosuvastatin may modestly increase INR in patients taking warfarin. The label recommends monitoring INR when rosuvastatin is initiated in patients on warfarin. FDA label Section 7.3.

Special Populations: Label Guidance

Pregnancy and Lactation

Rosuvastatin is contraindicated during pregnancy. Cholesterol biosynthesis is required for normal fetal development, and statin use during pregnancy has been associated with fetal harm in animal studies. The FDA updated rosuvastatin's reproductive toxicity labeling under the 2015 Pregnancy and Lactation Labeling Rule (PLLR), removing the former "Category X" designation and replacing it with detailed narrative risk information. The label advises discontinuing rosuvastatin as soon as pregnancy is recognized. FDA PLLR update summary, fda.gov. Rosuvastatin should not be used during breastfeeding; it is unknown whether the drug is excreted in human milk, but animal studies show transfer into breast milk.

Renal Impairment

For patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2 who are not on hemodialysis), the label recommends starting at 5 mg once daily and not exceeding 10 mg per day. This recommendation is based on pharmacokinetic data showing that plasma rosuvastatin concentrations are approximately three times higher in patients with severe renal impairment compared with healthy volunteers. FDA label Section 8.6.

Older Adults

No specific dose adjustment is required solely based on age, but the label notes that elderly patients (65 and older) are at higher risk of myopathy. The 2018 ACC/AHA cholesterol guideline recommends clinicians use moderate-intensity statin therapy as the preferred starting strategy in patients 75 and older, defined as the dose range that achieves 30% to 50% LDL-C reduction. ACC/AHA 2018 cholesterol guideline, ahajournals.org. Rosuvastatin 10 mg achieves approximately 46% mean LDL-C reduction and fits within this moderate-intensity category.

Regulatory Timeline: Key Milestones

The following timeline consolidates FDA regulatory milestones for rosuvastatin that are relevant to prescribers and patients. This framework does not appear in any single FDA document; it is synthesized from NDA approval records, label revision histories at accessdata.fda.gov, and the FDA drug safety communications listed below.

• February 4, 2003: EMA approves rosuvastatin (Crestor) in the European Union.
• August 12, 2003: FDA approves rosuvastatin (NDA 021366) for adults with primary hyperlipidemia and mixed dyslipidemia at doses of 10 mg to 40 mg. FDA NDA 021366, accessdata.fda.gov.
• 2003 to 2006: FDA conducts active safety review of early post-marketing proteinuria and hematuria signals; AstraZeneca completes required post-market studies; FDA concludes the signal does not represent progressive nephrotoxicity at approved doses. FDA accessdata review documents.
• 2008: JUPITER trial results published in NEJM; 44% reduction in composite cardiovascular events over median 1.9 years in 17,802 patients. Ridker PM et al., NEJM 2008, pubmed.ncbi.nlm.nih.gov.
• 2008: FDA approves rosuvastatin for primary prevention of cardiovascular events in patients with elevated hsCRP plus additional risk factors, based on JUPITER data.
• 2008: FDA approves pediatric indication for heterozygous familial hypercholesterolemia in patients aged 10 to 17. FDA pediatric supplement, accessdata.fda.gov.
• February 2012: FDA adds class-wide warnings for cognitive effects and new-onset diabetes to all statin labels, including rosuvastatin. FDA Drug Safety Communication 2012, fda.gov.
• 2015: FDA updates rosuvastatin reproductive labeling under the new Pregnancy and Lactation Labeling Rule. FDA PLLR, fda.gov.
• 2016: Primary US patent expires; multiple FDA-approved generic rosuvastatin products enter the market. FDA Orange Book, accessdata.fda.gov.
• Ongoing: FDA Sentinel active surveillance monitors rosuvastatin and all statins for myopathy, rhabdomyolysis, hepatotoxicity, diabetes, and cognitive effects. FDA Sentinel, fda.gov.

ACC/AHA Guideline Positioning of Rosuvastatin

The 2018 ACC/AHA guideline on the management of blood cholesterol classifies statins by intensity based on the average expected LDL-C reduction [5]. Rosuvastatin appears in two intensity categories:

• High-intensity statins (expected LDL-C reduction 50% or greater): rosuvastatin 20 mg and 40 mg daily.
• Moderate-intensity statins (expected LDL-C reduction 30% to 50%): rosuvastatin 5 mg and 10 mg daily.

The guideline recommends high-intensity statin therapy for patients with established atherosclerotic cardiovascular disease (ASCVD), patients with LDL-C at or above 190 mg/dL, and patients aged 40 to 75 with diabetes and an estimated 10-year ASCVD risk at or above 7.5%. Rosuvastatin 20 mg to 40 mg is a direct option for each of these groups. ACC/AHA 2018 guideline, ahajournals.org.

The 2018 guideline also introduced the concept of risk-enhancing factors and, separately, coronary artery calcium (CAC) scoring to guide statin initiation decisions in patients at intermediate risk (10-year risk 7.5% to 20%). A patient with a CAC score above 100 Agatston units or above the 75th percentile for age, sex, and ethnicity is considered a candidate for statin therapy, with rosuvastatin 10 mg to 20 mg serving as a common choice given its LDL-C-lowering magnitude. ACC/AHA 2018 guideline, ahajournals.org.