Rosuvastatin

Rosuvastatin

Clinical data
Pronunciation	roh-SOO-və-sta-tin
Trade names	Crestor
AHFS/Drugs.com	Monograph
MedlinePlus	a603033
Pregnancy category	AU: D US: X (Contraindicated)
Routes of administration	By mouth (tablets)
ATC code	C10AA07 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	20%[1]
Protein binding	88%[1]
Metabolism	Liver: CYP2C9 (major) and CYP2C19-mediated; ~10% metabolized[1]
Metabolites	N-desmethyl rosuvastatin (major; 1/6–1/9 of rosuvastatin activity)[2]
Biological half-life	19 hours[1]
Excretion	Faeces (90%)[1]
Identifiers
IUPAC name (3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
CAS Number	287714-41-4 Y
PubChem (CID)	446157
IUPHAR/BPS	2954
DrugBank	DB01098 Y
ChemSpider	393589 N
UNII	413KH5ZJ73 Y
KEGG	D01915 N
ChEBI	CHEBI:38545 N
ChEMBL	CHEMBL1496 N
PDB ligand ID	FBI (PDBe, RCSB PDB)
ECHA InfoCard	100.216.011
Chemical and physical data
Formula	C22H28FN3O6S
Molar mass	481.539
3D model (Jmol)	Interactive image
SMILES OC(=O)C[C@H](O)C[C@H](O)\C=C\c1c(C(C)C)nc(N(C)S(=O)(=O)C)nc1c2ccc(F)cc2
InChI InChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1 N Key:BPRHUIZQVSMCRT-VEUZHWNKSA-N N
NY (what is this?)  (verify)

Rosuvastatin (marketed by AstraZeneca as Crestor) 10 mg tablets

Rosuvastatin (INN),^[3] marketed as Crestor, is a member of the drug class of statins, used in combination with exercise, diet, and weight-loss to treat high cholesterol and related conditions, and to prevent cardiovascular disease.

It was developed by Shionogi. In 2013 Crestor was the fourth-highest selling drug in the United States, accounting for approx. $5.2 billion in sales.^[4] A generic version became available in the United States in 2016.^[5]

Medical uses

The primary use of rosuvastatin is for the treatment of dyslipidemia.^[6]

Effects on cholesterol levels

The effects of rosuvastatin on 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.^[7]

Meta-analysis showed that rosuvastatin is able to modestly increase levels of HDL cholesterol as well, as with other statins.^[8] A 2014 Cochrane review determined there was good evidence for rosuvastatin lowering non-HDL levels linearly with dose.^[9] 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:^[10]

• 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. Stop taking rosuvastatin and contact the prescribing doctor if any of these occur:^[10][11]

• 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

If any signs of an allergic reaction develop, contact an emergency medical service immediately:^[11]

• 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, 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.^[2] Rosuvastatin must not be taken while pregnant as it can cause serious harm to the unborn baby.^[11] 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.^[11][12]

Drug interactions

The following drugs can have negative interactions with rosuvastatin and should be discussed with the prescribing doctor:^[10][2]

• Coumarin 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 in order to decrease risk of developing liver damage^[11]
• Aluminum and magnesium hydroxide antacids should not be taken within two hours of taking rosuvastatin^[11]
• Coadministration of rosuvastatin with eluxadoline may increase the risk of rhabdomyolysis and myopathy^[13]:8

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,^[14] 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.^[15]

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.^[16]

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.^[2] However, a subsequent clinical study has shown a marked reduction in rosuvastatin exposure when administered with food.^[17] It is 88% protein bound, mainly to albumin.^[18] Fraction absorbed of rosuvastatin is frequently misquoted in the literature as approximately 0.5 (50%)^[19] due to a miscalculated hepatic extraction ratio in the original submission package subsequently corrected by the FDA reviewer.^[20] 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.^[2][18]

Society and culture

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).^[21] In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.^[22]

As of 2004, rosuvastatin had been approved in 154 countries and launched in 56. Approval in the United States by the FDA came on August 12, 2003.^[23]

The results of the JUPITER trial (2008) suggested rosuvastatin may decrease the relative risk of heart attack and stroke in patients without hyperlipidemia, but with elevated levels of highly sensitive C-reactive protein. This could strongly impact medical practice by placing many patients on statin prophylaxis who otherwise would have been untreated.^[24][25] As a result of this clinical trial, the FDA approved rosuvastatin for the primary prevention of cardiovascular events.^[22]

The AURORA trial randomized 2776 patients undergoing hemodialysis due to kidney damage to receive either rosuvastatin or placebo. The randomized, double-blind study (2005 to 2009) found no difference in the two groups in the primary end-point, a combination of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke. The study found no difference in all-cause mortality among this population at a mean follow-up of 3.8 years.^[26]

FDA advisory for East Asian patients

According to the FDA, the risk of myopathy during rosuvastatin therapy 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.^[27]

Therefore, physicians should start Asian-American or East Asian patients at the lowest dose level.^[28]

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.^{[29][30][31][32]}

In April 2016 the FDA approved the first generic version of rosuvastatin (from Watson Pharmaceuticals Inc).^[33]

In July 2016 Mylan gained approval for its generic rosuvastatin calcium.^[34]

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 (Lipitor) and simvastatin (Zocor). However, people can also combine ezetimibe with either rosuvastatin 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.^[15]

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 4 million by the end of 2004. Typical per patient costs to the UK NHS are £18.03–26.02/month (compared to £0.85–1.37/month for simvastatin).

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."^[35]

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 March 11, 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.^[36]

Myopathy

As with all statins, there is a concern of rhabdomyolysis, a severe undesired side effect. The 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.^[14]

Diabetes mellitus

Statins increase the risk of diabetes,^[37] consistent with FDA's review of the JUPITER trial, which reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients.^[38]

References

References

• "Annual Report and Form 20-F, Information 2004" (PDF). AstraZeneca PLC. 2005. 
• "Annual Report and Form 20-F, 2003" (PDF). AstraZeneca PLC. 2004. Archived from the original (PDF) on 2005-05-13. Retrieved 2005-03-20. 
• "Highlights of Prescribing Information" (PDF). AstraZeneca PLC. 2008. Retrieved 2009-03-11. 
• McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, Smith G, Warwick M (2001). "Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor". Am J Cardiol. 87 (5A): 28B–32B. doi:10.1016/S0002-9149(01)01454-0. PMID 11256847. 

External links

• "Rosuvastatin (Crestor) Information". eMedicineHealth. 
• Rosuvastatin, U.S. National Library of Medicine Drug Information Portal
• Crestor Official Site