Rosuvastatin

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Rosuvastatin
Rosuvastatin structure.svg
Rosuvastatin-3D-balls.png
Clinical data
Pronunciation/rˈsvəstætɪn/ roh-SOO-və-stat-in
Trade namesCrestor, Rosulip, Zuvamor, others
Other namesRosuvastatin calcium (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa603033
License data
Pregnancy
category
  • AU: D
  • US: X (Contraindicated)
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%[1][2]
Protein binding88%[1][2]
MetabolismLiver: CYP2C9 (major) and CYP2C19-mediated; ~10% metabolized[1][2]
MetabolitesN-desmethyl rosuvastatin (major; 1/6–1/9 of rosuvastatin activity)[3]
Elimination half-life19 hours[1][2]
ExcretionFeces (90%)[1][2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.216.011 Edit this at Wikidata
Chemical and physical data
FormulaC22H28FN3O6S
Molar mass481.539 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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.[2] It is recommended to be used together with dietary changes, exercise, and weight loss.[2] It is taken by mouth.[2]

Common side effects include abdominal pain, nausea, headaches, and muscle pains.[2] Serious side effects may include rhabdomyolysis, liver problems, and diabetes.[2] Use during pregnancy may harm the baby.[2] Like all statins, rosuvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.[2]

Rosuvastatin was patented in 1991, and approved for medical use in the United States in 2003.[2][4] It is available as a generic medication.[2] In the United States, the wholesale cost per dose is less than US$0.15 as of 2018.[5] In the United Kingdom, it costs the NHS about £0.65 per dose as of 2018.[6] In 2016, it was the 37th most prescribed medication in the United States, with more than 19 million prescriptions.[7]

Medical uses[edit]

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.[2]

Effects on cholesterol levels[edit]

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.[medical citation needed]

Side effects and contraindications[edit]

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][12]

If any signs of an allergic reaction develop, contact an emergency medical service immediately:[12]

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.[3] Rosuvastatin must not be taken while pregnant as it can cause serious harm to the unborn baby.[12] 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.[12][13]

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."[14][15][16] Therefore the lowest dose is recommended in Asians.[17]

Myopathy[edit]

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.[18]

Diabetes mellitus[edit]

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[edit]

The following drugs can have negative interactions with rosuvastatin and should be discussed with the prescribing doctor:[11][3]

Structure[edit]

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,[18] 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[edit]

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[edit]

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[edit]

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.[3] 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.[2] 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.[3][2]

Society and culture[edit]

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

Indications and regulation[edit]

Rosuvastatin is approved in the United States for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia).[29] In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.[30]

As of 2004, rosuvastatin had been approved in 154 countries and launched in 56. Approval in the United States by the FDA came on 12 August 2003.[31]

Patent protection and generic versions[edit]

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.[32][33][34][35]

In April 2016, the FDA approved the first generic version of rosuvastatin (from Watson Pharmaceuticals Inc).[36] In July 2016, Mylan gained approval for its generic rosuvastatin calcium.[37]

Marketing[edit]

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[when?] 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.[citation needed] Annual cost to the UK National Health Service (NHS) in 2018 for 5-40mg rosuvastatin daily was £24-40, compared to £10-20 for 20-80mg simvastatin.[38]

In 2013, it was the fourth-highest selling drug in the United States, accounting for approx. $5.2 billion in sales.[39]

Debate and criticisms[edit]

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."[40]

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.[41]

References[edit]

  1. ^ a b c d e Aggarwal, RK; Showkathali, R (June 2013). "Rosuvastatin calcium in acute coronary syndromes". Expert Opinion on Pharmacotherapy. 14 (9): 1215–1227. doi:10.1517/14656566.2013.789860. PMID 23574635.
  2. ^ a b c d e f g h i j k l m n o p q "Rosuvastatin Calcium Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists (AHFS). Retrieved 24 December 2018.
  3. ^ a b c d e "Crestor (rosuvastatin calcium) Tablets. Full Prescribing Information" (PDF). AstraZeneca. Retrieved 29 November 2016.
  4. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 473. ISBN 9783527607495.
  5. ^ "NADAC as of 2018-12-19". Centers for Medicare and Medicaid Services (CMS). Retrieved 22 December 2018.
  6. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 203. ISBN 9780857113382.
  7. ^ "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  8. ^ Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW (2003). "Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial)". Am J Cardiol. 92 (2): 152–60. doi:10.1016/S0002-9149(03)00530-7. PMID 12860216.
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  10. ^ Adams, S. P.; Sekhon, S. S.; Wright, J. M. (November 2014). "Lipid-lowering efficacy of rosuvastatin". Cochrane Database Syst Rev. 11 (11): CD010254. doi:10.1002/14651858.CD010254.pub2. PMC 6463960. PMID 25415541.
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  21. ^ "Viberzi (eluxadoline) Tablets, for Oral Use, CIV. Full Prescribing Information". Actavis Pharma, Inc. Retrieved 29 November 2016.
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  25. ^ Li, Yunxia; Jiang, Xuehua; Lan, Ke; Zhang, Ruoqi; Li, Xue; Jiang, Qian (1 October 2007). "Pharmacokinetic Properties of Rosuvastatin After Single-Dose, Oral Administration in Chinese Volunteers: A Randomized, Open-Label, Three-Way Crossover Study". Clinical Therapeutics. 29 (10): 2194–2203. doi:10.1016/j.clinthera.2007.10.005. ISSN 0149-2918. PMID 18042475.
  26. ^ Bergman, Ebba; Lundahl, Anna; Fridblom, Patrik; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans (1 December 2009). "Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil". Drug Metabolism and Disposition. 37 (12): 2349–2358. doi:10.1124/dmd.109.029363. ISSN 1521-009X. PMID 19773540.
  27. ^ "Page 45 of FDA Drug Approval Package, Clinical Pharmacology Biopharmaceutics Review(s) (PDF)". Food and Drug Administration. 29 January 2004. Retrieved 22 June 2016.
  28. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 45" (PDF). World Health Organization. 2001. p. 50. Retrieved 29 November 2016.
  29. ^ "Core Data Sheet, Crestor Tablets" (PDF). AstraZeneca. June 17, 2003. Archived from the original (PDF) on May 8, 2005. Retrieved March 20, 2005. - NOTE: this is provider-oriented information and should not be used without the supervision of a physician.
  30. ^ http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/021366s016ltr.pdf
  31. ^ "FDA Approves New Drug for Lowering Cholesterol". Food and Drug Administration. 12 August 2003. Archived from the original on 7 February 2005. Retrieved 20 March 2005.
  32. ^ "AstraZeneca's Crestor patent upheld;No generic competition until 2016".[dead link]
  33. ^ "Crestor Patent Upheld By US Court" (Press release). AstraZeneca. 29 June 2010. Retrieved 25 April 2012.
  34. ^ Berkrot, Bill; Hals, Tom (29 June 2010). "U.S. judge rules AstraZeneca Crestor patent valid". Reuters. Retrieved 25 April 2012.
  35. ^ Starkey, Jonathan (1 July 2010). "AstraZeneca patent upheld". The News Journal. Wilmington, Delaware. Retrieved 25 April 2012. (subscription required)
  36. ^ "FDA approves first generic Crestor". Food and Drug Administration. 29 April 2016. Retrieved 3 May 2016.
  37. ^ "Mylan Launches Generic Crestor Tablets" (Press release). Mylan. July 2016.
  38. ^ "COST COMPARISON CHARTS" (PDF). REGIONAL DRUG AND THERAPEUTICS CENTRE (NEWCASTLE). August 2018.
  39. ^ "Top 100 Drugs for Q2 2013 by Sales". Retrieved 24 August 2013.
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    McKillop T (1 November 2003). "The statin wars". Lancet. 362 (9394): 1498. doi:10.1016/S0140-6736(03)14698-3. PMID 14602449.
  41. ^ "Docket No. 2004P-0113/CP1" (PDF). Food and Drug Administration.

External links[edit]

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