Rosuvastatin

Rosuvastatin, sold under the trade name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids.[3] It is recommended to be used together with dietary changes, exercise, and weight loss.[3] It is taken by mouth.[3]

Rosuvastatin
Clinical data
Pronunciation/roʊˈsuːvəstætɪn/ roh-SOO-və-stat-in
Trade namesCrestor, Rosulip, Zuvamor, others
Other namesRosuvastatin calcium (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa603033
License data
Pregnancy
category
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability20%[2][3]
Protein binding88%[2][3]
MetabolismLiver: CYP2C9 (major) and CYP2C19-mediated; ~10% metabolized[2][3]
MetabolitesN-desmethyl rosuvastatin (major; 1/6–1/9 of rosuvastatin activity)[4]
Elimination half-life19 hours[2][3]
ExcretionFeces (90%)[2][3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.216.011
Chemical and physical data
FormulaC22H28FN3O6S
Molar mass481.539 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Common side effects include abdominal pain, nausea, headaches, and muscle pains.[3] Serious side effects may include rhabdomyolysis, liver problems, and diabetes.[3] Use during pregnancy may harm the baby.[3] Like all statins, rosuvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.[3]

Rosuvastatin was patented in 1991, and approved for medical use in the United States in 2003.[3][5] It is available as a generic medication.[3] In 2017, it was the 39th most commonly prescribed medication in the United States, with more than 19 million prescriptions.[6][7]

Medical uses
Rosuvastatin (marketed as Crestor) 10 mg tablets

The primary use of rosuvastatin is for prevention of cardiovascular disease in those at high risk and the treatment of abnormal lipids.[3]

Effects on cholesterol levels

The effects of rosuvastatin on low-density lipoprotein (LDL) cholesterol are dose-related. Higher doses were more efficacious in improving the lipid profile of patients with hypercholesterolemia than milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin.[8]

Meta-analysis showed that rosuvastatin is able to modestly increase levels of high-density lipoprotein (HDL) cholesterol as well, as with other statins.[9] A 2014 Cochrane review determined there was good evidence for rosuvastatin lowering non-HDL levels linearly with dose.[10] HDL increases by 7% with no dose effect noted.

Side effects and contraindications

Side effects are uncommon. The following side effects should be reported to the prescribing doctor if they persist or get worse:[11]

The following rare side effects are more serious. Like all statins, rosuvastatin can possibly cause myopathy, rhabdomyolysis. Stop taking rosuvastatin and contact the prescribing doctor if any of these occur:[11][4]

If any signs of an allergic reaction develop, contact an emergency medical service immediately:[4]

Rosuvastatin has multiple contraindications, conditions that warrant withholding treatment with rosuvastatin, including hypersensitivity to rosuvastatin or any component of the formulation, active liver disease, elevation of serum transaminases, pregnancy, or breastfeeding.[4] Rosuvastatin must not be taken while pregnant as it can cause serious harm to the baby.[4] In the case of breastfeeding, it is unknown whether rosuvastatin is passed through breastmilk but, due to the potential of disrupting the infant's lipid metabolism, patients should not breast feed while on rosuvastatin.[4][12]

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."[13][14][15] Therefore, the lowest dose is recommended in Asians.[16]

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.[17][18]

Diabetes mellitus

Statins increase the risk of diabetes,[19] consistent with FDA's review, which reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated people.[20]

Drug interactions

The following drugs can have negative interactions with rosuvastatin and should be discussed with the prescribing doctor:[11][4]

Structure

Rosuvastatin has structural similarities with most other synthetic statins, e.g., atorvastatin, cerivastatin and pitavastatin, but unlike other statins, rosuvastatin contains sulfur (in sulfonyl functional group).

Crestor is actually a calcium salt of rosuvastatin, i.e. rosuvastatin calcium,[17] 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
Further information: Statin

Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins.[22]

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.[23]

Pharmacodynamics

In a Cochrane systematic review the dose-related magnitude of rosuvastatin on blood lipids was determined. 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%.[24]

Pharmacokinetics

Absolute bioavailability of rosuvastatin is about 20% and Cmax 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.[4] However, a subsequent clinical study has shown a marked reduction in rosuvastatin exposure when administered with food.[25] It is 88% protein bound, mainly to albumin.[3] Fraction absorbed of rosuvastatin is frequently misquoted in the literature as approximately 0.5 (50%)[26] due to a miscalculated hepatic extraction ratio in the original submission package subsequently corrected by the FDA reviewer.[27] It is likely that closer to 0.25 (25%) of the administered dose is absorbed.

Rosuvastatin is metabolized mainly by CYP2C9 and 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.[4][3]

Society and culture

Rosuvastatin is the international nonproprietary name (INN).[28]

Cost

Under provisions of the Patient Protection and Affordable Care Act (PPACA) in the United States, there is no cost for adults aged 40–75 years for rosuvastatin 5 mg and 10 mg based on United States Preventive Services Task Force (USPSTF) recommendations.[29][30]

Indications and regulation

Rosuvastatin is approved in the United States for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia).[31] In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.[32]

As of 2004, rosuvastatin was 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.[33][34]

Patent protection and generic versions

The main patent protecting rosuvastatin (RE37,314 — due to expire in 2016) was challenged as being an improper reissue of an earlier patent. This challenge was rejected in 2010, confirming protection until 2016.[35][36][37][38]

In April 2016, the FDA approved the first generic version of rosuvastatin (from Watson Pharmaceuticals Inc).[39] In July 2016, Mylan gained approval for its generic rosuvastatin calcium.[40]

Marketing

The drug was billed as a "super-statin" during its clinical development; the claim was that it offers 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. As of 2006 some published information for comparing rosuvastatin, atorvastatin, and ezetimibe/simvastatin results is available, but many of the relevant studies are still in progress.[22]

First launched in 2003, sales of rosuvastatin were $129 million and $908 million in 2003, and 2004, respectively, with a total patient treatment population of over four million by the end of 2004. Annual cost to the UK National Health Service (NHS) in 2018 for 5–40 mg rosuvastatin daily was £24-40, compared to £10-20 for 20–80 mg simvastatin.[41]

In 2013, it was the fourth-highest selling drug in the United States, accounting for approximately $5.2 billion in sales.[42]

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 Sir Tom McKillop called the editorial "flawed and incorrect" and slammed the journal for making "such an outrageous critique of a serious, well-studied medicine."[43]

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, M.D. 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.[44]

References
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  • "Rosuvastatin". Drug Information Portal. U.S. National Library of Medicine.
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