Rosuvastatin

Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids.<ref name=AHFS2018/> It is recommended to be used with dietary changes, exercise, and weight loss.<ref name=AHFS2018/> It is taken orally (by mouth).<ref name=AHFS2018>Template:Cite web</ref>

Common side effects include abdominal pain, nausea, headaches, and muscle pains.<ref name=AHFS2018/> Serious side effects may include rhabdomyolysis, liver problems, and diabetes.<ref name=AHFS2018/> Use during pregnancy may harm the baby.<ref name=AHFS2018/> Like all statins, rosuvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.<ref name=AHFS2018/>

Rosuvastatin was patented in 1991 and approved for medical use in the United States in 2003.<ref name=AHFS2018/><ref name=Fis2006>Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2018/> In 2023, it was the twelfth most commonly prescribed medication in the United States, with more than 42Template:Nbspmillion prescriptions.<ref name="Top 300 of 2023">Template:Cite web</ref><ref>Template:Cite web</ref> In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023.<ref>Template:Cite web</ref>

Medical uses

File:Crestor Tablets (rosuvastatin).jpg

Rosuvastatin (marketed as Crestor) 10 mg tablets

The primary use of rosuvastatin is to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels in the blood.<ref name=AHFS2018/>

Effects on cholesterol levels

The effects of rosuvastatin on low-density lipoprotein (LDL) cholesterol are dose-related. Higher doses are more effective at improving the lipid profile of patients with hypercholesterolemia than milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin.<ref name="Jones-2003">Template:Cite journal</ref>

A meta-analysis showed that rosuvastatin can modestly increase the levels of high-density lipoprotein (HDL) cholesterol in the blood, similar to other statins.<ref name="pmid=18553127">Template:Cite journal</ref> A 2014 Cochrane review determined there was good evidence for rosuvastatin lowering non-HDL levels linearly with dose.<ref name="pmid25415541" />

Side effects and contraindications

Side effects are uncommon:<ref name=MedLine>Template:Cite web</ref>

• constipation
• heartburn
• dizziness
• sleeplessness
• depression
• joint pain
• cough
• memory loss or forgetfulness
• confusion

The following rare side effects are more serious. Like all statins, rosuvastatin can possibly cause myopathy, rhabdomyolysis:<ref name=MedLine/><ref name="Crestor FDA label" />

• muscle pain, tenderness, or weakness
• lack of energy
• fever
• chest pain
• jaundice: yellowing of the skin or eyes
• dark colored, or foamy urine
• pain in the upper right part of the abdomen
• nausea
• extreme tiredness
• weakness
• unusual bleeding or bruising
• loss of appetite
• flu-like symptoms
• sore throat, chills, or other signs of infection

Allergic reactions can develop:<ref name="Crestor FDA label" />

• rash
• hives
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness
• numbness or tingling in fingers or toes

Rosuvastatin has multiple contraindications, including hypersensitivity to rosuvastatin or any component of the formulation, active liver disease, elevation of serum transaminases, pregnancy, or breastfeeding.<ref name="Crestor FDA label">Template:Cite web</ref> Rosuvastatin is not prescribed nor used while pregnant, as it can cause serious harm to the fetus.<ref name="Crestor FDA label" /> With breastfeeding, it is unknown whether rosuvastatin is passed through breastmilk.<ref name="Crestor FDA label" /><ref name=LactMed>Template:Cite web</ref>

Dose adjustments needs to be considered in individuals with renal failure. In mild to moderate renal failure (CL_cr >30 to <60 mL/min/1.73 m²) a higher dose than 20mg daily is generally not recommended. Maximum dose of Rosuvastatin in patients with severe renal failure (CL_cr < 30 mL/min/1.73 m²) without hemodialysis is 10mg daily.<ref>Template:Cite journal</ref>

The risk of myopathy may be increased in Asian Americans: "Because Asians appear to process the drug differently, half the standard dose can have the same cholesterol-lowering benefit in those patients, though a full dose could increase the risk of side effects, a study by the drug's manufacturer, AstraZeneca, indicated."<ref>Template:Cite news</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Therefore, the lowest dose is recommended in Asians.<ref>Template:Cite web</ref>

Myopathy

As with all statins, there is a concern of rhabdomyolysis, a severe undesired side effect. The U.S. Food and Drug Administration (FDA) has indicated that "it does not appear that the risk [of rhabdomyolysis] is greater with Crestor than with other marketed statins", but has mandated that a warning about this side-effect, as well as a kidney toxicity warning, be added to the product label.<ref name="FDAlabel">Template:Cite web - This page is subject to change; the date reflects the last revision date.</ref><ref name="FDA Rosuvastatin Safety">Template:Cite web</ref>

Diabetes mellitus

Statins increase the risk of diabetes,<ref>Template:Cite journal</ref> consistent with FDA's review, which reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated people.<ref>Template:Cite web</ref>

Drug interactions

The following drugs can have negative interactions with rosuvastatin and should be discussed with the prescribing doctor:<ref name=MedLine/><ref name="Crestor FDA label" />

• Coumadin anticoagulants ('blood thinners', e.g. warfarin) can affect the removal of rosuvastatin
• Ciclosporin, colchicine
• Drugs that may decrease the levels or activity of endogenous steroid hormones, e.g., cimetidine, ketoconazole, and spironolactone
• Additional medications for high cholesterol such as clofibrate, fenofibrate, gemfibrozil, and niacin (when taken in lipid-modifying doses of 1 g/day and above)
• Specific protease inhibitors including atazanavir (when taken with ritonavir), lopinavir/ritonavir and simeprevir
• Alcohol intake should be reduced while on rosuvastatin to decrease the risk of developing liver damage<ref name="Crestor FDA label" />
• Aluminum and magnesium hydroxide antacids should not be taken within two hours of taking rosuvastatin<ref name="Crestor FDA label" />
• Coadministration of rosuvastatin with eluxadoline may increase the risk of rhabdomyolysis and myopathy<ref name = "Viberzi FDA label">Template:Cite web</ref>

Grapefruit juice negatively interacts with several specific drugs in the statin class, but it has little or no effect on rosuvastatin.<ref name="Bailey_2013">Template:Cite journal</ref>

Structure

Rosuvastatin has structural similarities with most other statins, e.g., atorvastatin, cerivastatin and pitavastatin, but unlike other statins, rosuvastatin contains sulfur (in sulfonyl functional group). Crestor is a calcium salt of rosuvastatin, i.e., rosuvastatin calcium,<ref name="FDAlabel"/> in which calcium replaces the hydrogen in the carboxylic acid group on the right of the skeletal formula at the top right of this page.

Mechanism of action

Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins.<ref name="ASTEROID">Template:Cite journal</ref>

Putative beneficial effects of rosuvastatin therapy on chronic heart failure may be negated by increases in collagen turnover markers as well as a reduction in plasma coenzyme Q₁₀ levels in patients with chronic heart failure.<ref>Template:Cite journal</ref>

Pharmacodynamics

The dose-related magnitude of rosuvastatin on blood lipids was determined in a Cochrane systematic review in 2014. Over the dose range of 1 to 80 mg/day, strong linear dose‐related effects were found; total cholesterol was reduced by 22.1% to 44.8%, LDL cholesterol by 31.2% to 61.2%, non-HDL cholesterol by 28.9% to 56.7%, and triglycerides by 14.4% to 26.6%.<ref name="pmid25415541">Template:Cite journal</ref>

Pharmacokinetics

Absolute bioavailability of rosuvastatin is about 20% and C_max is reached in 3 to 5 hours; administration with food did not affect the AUC according to the original sponsor submitted clinical study and as per product label.<ref name="Crestor FDA label" /> However, a subsequent clinical study has shown a marked reduction in rosuvastatin exposure when administered with food.<ref>Template:Cite journal</ref> It is 88% protein bound, mainly to albumin.<ref name=AHFS2018/> Fraction absorbed of rosuvastatin is frequently misquoted in the literature as approximately 0.5 (50%)<ref>Template:Cite journal</ref> due to a miscalculated hepatic extraction ratio in the original submission package subsequently corrected by the FDA reviewer.<ref>Template:Cite web</ref>

Rosuvastatin is metabolized mainly by CYP2C9, but is not extensively metabolized; approximately 10% is recovered as metabolite N-desmethyl rosuvastatin. It is excreted in feces (90%) primarily and the elimination half-life is approximately 19 hours.<ref name="Crestor FDA label" /><ref name=AHFS2018/>

Both AUC and C_max are approximately 2-fold higher in Asian patients compared to Caucasian patients given the same dose of rosuvastatin.<ref name="Crestor FDA label" />

Society and culture

Rosuvastatin is the international nonproprietary name (INN).<ref name="INN">Template:Cite web</ref>

Economics

Because low- to moderate dose statins are strongly recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of cardiovascular disease in adults aged 40–75 years who are at risk,<ref name=USPSTFstatins>Template:Cite journal</ref> the Patient Protection and Affordable Care Act (PPACA) in the United States requires most health insurance plans to cover the costs of these drugs without charging the insured patient a copayment or coinsurance, even if he or she has not yet reached his or her annual deductible.<ref name="AZHR">Template:Cite web</ref><ref name="HealthcareDotGovPreventiveCare">Template:Cite web</ref><ref name="KFFACApreventive">Template:Cite web</ref> Rosuvastatin 5 mg and 10 mg are examples of regimens meeting the USPSTF guideline;<ref name=USPSTFstatins/> however, insurers have discretion as to which low- and moderate-dose statin regimens to cover under this requirement,<ref name=ACApreventiveFAQ>Template:Cite web</ref> and some only cover other statins.<ref>Template:Cite web</ref>

The drug was billed as a "super-statin" during its clinical development; the claim was that it offered high potency and improved cholesterol reduction compared to rivals in the class. The main competitors to rosuvastatin are atorvastatin and simvastatin. However, people can also combine ezetimibe with either simvastatin or atorvastatin and other agents on their own, for somewhat similar augmented response rates. Template:As of some published information for comparing rosuvastatin, atorvastatin, and ezetimibe/simvastatin results are available, but many of the relevant studies are stillTemplate:When in progress.<ref name="ASTEROID"/>Template:Update inline

First launched in 2003, sales of rosuvastatin were $129Template:Nbspmillion and $908Template:Nbspmillion in 2003 and 2004 respectively, with a total patient treatment population of over 4Template:Nbspmillion by the end of 2004.Template:Citation needed Annual cost to the UK National Health Service (NHS) in 2018, for 5–40 mg rosuvastatin daily (of one person) was £24-40, compared to £10-20 for 20–80 mg simvastatin.<ref>Template:Cite web</ref>

In 2013, it was the fourth-highest-selling drug in the United States, accounting for approximately $5.2Template:Nbspbillion in sales.<ref>Template:Cite web</ref> In 2021, it was the thirteenth most commonly prescribed medication in the United States, with more than 32Template:Nbspmillion prescriptions.<ref name="Rosuvastatin - Drug Usage Statistics">Template:Cite web</ref>

Legal status

Rosuvastatin is approved in the United States for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia).<ref name="pill">Template:Cite web - NOTE: this is provider-oriented information and should not be used without the supervision of a physician.</ref> In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.<ref name="fdaap">Template:Cite report</ref>

Template:As of, rosuvastatin had been approved in 154 countries and launched in 56. Approval in the United States by the Food and Drug Administration (FDA) came on 13 August 2003.<ref>Template:Cite web</ref><ref name="FDAapproval">Template:Cite news</ref>

Patent protection and generic versions

The main patent that protected rosuvastatin (RE37,314, which expired in 2016) was challenged as an improper reissue of an earlier patent. This challenge was rejected in 2010, and thus, patent protection continued until 2016.<ref>Template:Cite webTemplate:Dead link</ref><ref>Template:Cite press release</ref><ref>Template:Cite news</ref><ref>Template:Cite news Template:Subscription required</ref><ref>Template:Cite press release</ref>

In April 2016, the FDA approved the first generic version of rosuvastatin (from Watson Pharmaceuticals Inc).<ref>Template:Cite web</ref> In July 2016, Mylan gained approval for its generic rosuvastatin calcium.<ref>Template:Cite press release</ref>

Debate and criticisms

In October 2003, several months after its introduction in Europe, Richard Horton, the editor of the medical journal The Lancet, criticized the way Crestor had been introduced. "AstraZeneca's tactics in marketing its cholesterol-lowering drug, rosuvastatin, raise disturbing questions about how drugs enter clinical practice and what measures exist to protect patients from inadequately investigated medicines," according to his editorial. The Lancet's editorial position is that the data for Crestor's superiority rely too much on extrapolation from the lipid profile data (surrogate end-points) and too little on hard clinical end-points, which are available for other statins that had been on the market longer. The manufacturer responded by stating that few drugs had been tested so successfully on so many patients. In correspondence published in The Lancet, AstraZeneca's CEO Tom McKillop called the editorial "flawed and incorrect" and slammed the journal for making "such an outrageous critique of a serious, well-studied medicine."<ref name="lancetoped">Template:Cite journal
Template:Cite journal</ref>

In 2004, the consumer interest organization Public Citizen filed a Citizen's Petition with the FDA, asking that Crestor be withdrawn from the US market. On 11 March 2005, the FDA issued a letter to Sidney M. Wolfe of Public Citizen both denying the petition and providing an extensive detailed analysis of findings that demonstrated no basis for concerns about rosuvastatin compared with the other statins approved for marketing in the United States.<ref name="FDA ruling">Template:Cite web</ref> In 2015, Wolfe explained why he thought that "the drug should have been withdrawn and why it should not be used", due to the incidence of rhabdomyolysis, renal problems, and significant increase in glycated hemoglobin (HbA_1C) and fasting insulin levels, and decreased insulin sensitivity in diabetic patients. Rosuvastatin indeed lowered cholesterol more than other statins, but Wolfe asked, "what about actually improving health, preventing heart attacks and strokes?"<ref name=wolfe>Template:Cite journal</ref>