Rosuvastatin

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Rosuvastatin

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Rosuvastatin, whose commercial name is Crestor, is a new drug that reduces elevated LDL-cholesterol, total cholesterol, triglycerides and ApoB, and increases HDL-cholesterol. It is indicated for people with a high cholesterol concentration in the blood, or with a familial propensity for high cholesterol.

Last updated: June 21, 2004.

Drug Info:

Rosuvastatin

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Brand names: Crestor®

Chemical formula:



Rosuvastatin Calcium Oral tablet

What is this medicine?

ROSUVASTATIN (roe SOO va sta tin) is known as a HMG-CoA reductase inhibitor or 'statin'. It lowers cholesterol and triglycerides in the blood. This drug may also reduce the risk of heart attack, stroke, or other health problems in patients with risk factors for heart disease. Diet and lifestyle changes are often used with this drug.
 
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•frequently drink alcoholic beverages
•kidney disease
•liver disease
•muscle aches or weakness
•other medical condition
•an unusual or allergic reaction to rosuvastatin, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. You can take this medicine with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed.
 
Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for children as young as 10 years old for selected conditions, precautions do apply.
 
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

Do not take this medicine with any of the following medications:
•herbal medicines like red yeast rice
•other medicines for high cholesterol

This medicine may also interact with the following medications:
•alcohol
•antacids containing aluminum hydroxide or magnesium hydroxide
•cyclosporine
•niacin
•warfarin

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Visit your doctor or health care professional for regular check-ups. You may need regular tests to make sure your liver is working properly.

Tell your doctor or health care professional right away if you get any unexplained muscle pain, tenderness, or weakness, especially if you also have a fever and tiredness.

Avoid taking antacids containing aluminum, calcium or magnesium within 2 hours of taking this medicine.

This drug is only part of a total heart-health program. Your doctor or a dietician can suggest a low-cholesterol and low-fat diet to help. Avoid alcohol and smoking, and keep a proper exercise schedule.

Do not use this drug if you are pregnant or breast-feeding. Serious side effects to an unborn child or to an infant are possible. Talk to your doctor or pharmacist for more information.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•dark urine
•fever
•joint pain
•muscle cramps, pain
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•trouble passing urine or change in the amount of urine
•unusually weak or tired
•yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•constipation
•heartburn
•nausea
•stomach gas, pain, upset

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 20 and 25 degrees C (68 and 77 degrees F). Keep container tightly closed (protect from moisture). Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.


A statin used for the treatment of primary hypercholesterolaemia or mixed hyperlipidaemia (see hyperlipidaemia) that has not responded to dietary measures or exercise. It is available as tablets on prescription only.

Side effects:
see statins.

Precautions:
see statins. In addition, the maximum dosage should be reduced for people at risk of developing rhabdomyolysis (e.g. those with a history of muscle disorders), and rosuvastatin should be used with caution in people with kidney disease.

Interactions with other drugs:

Antacids reduce the absorption of rosuvastatin.
Anticoagulants the effects of oral anticoagulants are increased.
Erythromycin reduces the plasma concentration of rosuvastatin.
Protease inhibitors: increase the plasma concentration of rosuvastatin, and therefore the risk of muscle damage, and should not be taken with it.

See also statins.

Proprietary preparation:
Crestor.

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Rosuvastatin
Systematic (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
Clinical data
Trade names Crestor
AHFS/Drugs.com monograph
MedlinePlus a603033
Pregnancy cat. D (AU) X (US)
Legal status Prescription Only (S4) (AU) POM (UK) -only (US)
Routes oral
Pharmacokinetic data
Bioavailability 20%
Metabolism Liver
Half-life 19 h
Excretion Urine / Faeces
Identifiers
CAS number 287714-41-4 YesY
ATC code C10AA07
PubChem CID 446157
DrugBank DB01098
ChemSpider 393589 N
UNII 413KH5ZJ73 YesY
KEGG D01915 N
ChEBI CHEBI:38545 N
ChEMBL CHEMBL1496 N
Chemical data
Formula C22H28FN3O6S 
Mol. mass 481.539
SMILES eMolecules & PubChem
 N (what is this?)  (verify)

Rosuvastatin (marketed by AstraZeneca as Crestor) is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi.

Contents

Medical uses

The primary uses of rosuvastatin is for the treatment of dyslipidemia.[1] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.[1]

Structure

Rosuvastatin has structural similarities with most other synthetic statins, e.g., atorvastatin, cerivastatin, pitavastatin, but rosuvastatin unusually also contains sulfur.

Crestor is actually rosuvastatin calcium,[2] in which calcium replaces the hydrogen in the carboxylic acid group on the right of the 2 structure diagrams.

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.[3] Its approximate elimination half life is 19 h and its time to peak plasma concentration is reached in 3–5 h following oral administration.[4]

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.[5]

Indications and regulation

Rosuvastatin is approved for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia).[6] In February 2010, rosuvastatin was approved by the FDA for the primary prevention of cardiovascular events.[7]

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.[8]

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.[9][10] As a result of this clinical trial, the FDA approved rosuvastatin for the primary prevention of cardiovascular events.[7]

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.[11]

Effects on cholesterol levels

The effects of rosuvastatin on LDL cholesterol are dose-related. At the 10 mg dose, the average LDL cholesterol reduction was found to be 46% in one trial. Increasing the dose from 10 mg to 40 mg gave a modest additional 9% absolute reduction in LDL levels (55% below baseline levels).[12]

FDA advisory for 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.[13]

Therefore, physicians should start Asian patients at the lowest dose level.[14]

Marketing and competition

Patent protection

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. [15][16][17][18]

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. So far, some published information for comparing rosuvastatin, atorvastatin, and ezetimibe/simvastatin results is available, but many of the relevant studies are still in progress.[3]

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.[citation needed] Typical per patient costs to the UK NHS are £18.03-26.02/month (compared to £0.85-1.37/month for simvastatin).

Generic rosuvastatin is also produced by pharmaceutical companies in India and elsewhere, and often sold under its INN Rosuvastatin. It is marketed by Cipla Pharmaceuticals under the trade name Rosulip.

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."[19]

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.[20]

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.[2]

Diabetes mellitus

Statins increase the risk of diabetes,[21] 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.[22]

Notes

  1. ^ a b "Crestor". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/crestor.html. Retrieved 3 April 2011. 
  2. ^ a b "FDA Alert (03/2005) - Rosuvastatin Calcium (marketed as Crestor) Information". The Food and Drug Administration. March 14, 2005. Archived from the original on 2005-03-05. http://web.archive.org/web/20050305033448/http://www.fda.gov/cder/drug/infopage/rosuvastatin/default.htm. Retrieved 2005-03-20.  - This page is subject to change; the date reflects the last revision date.
  3. ^ a b Nissen SE, Nicholls SJ, Sipahi I, et al. (2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial" (PDF). JAMA 295 (13): 1556–65. doi:10.1001/jama.295.13.jpc60002. PMID 16533939. http://jama.ama-assn.org/cgi/reprint/jama;295/13/1556.pdf?ijkey=Md42dlk7z9TzyL8&keytype=finite. 
  4. ^ Retrieved from package insert on 2009-03-11
  5. ^ Ashton E, Windebank E, Skiba M, et al. (January 2010). "Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study". Int J Cardiol 146 (3): 404–7. doi:10.1016/j.ijcard.2009.12.028. PMID 20085851. http://linkinghub.elsevier.com/retrieve/pii/S0167-5273(10)00002-1. 
  6. ^ "Core Data Sheet, Crestor Tablets" (PDF). AstraZeneca PLC. June 17 2003. http://www.crestor.info/gUserFiles/CRESTOR_CDS_10_40_mg_FINAL_170603.pdf. Retrieved 2005-03-20.  - NOTE: this is provider-oriented information and should not be used without the supervision of a physician.
  7. ^ a b http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/021366s016ltr.pdf
  8. ^ "FDA Approves New Drug for Lowering Cholesterol". The Food and Drug Administration. August 12, 2003. Archived from the original on 2005-02-07. http://web.archive.org/web/20050207153150/http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01247.html. Retrieved 2005-03-20. 
  9. ^ Ridker PM, Danielson E, et al. (November 2008). "Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein". N. Engl. J. Med. 359 (21): 2195–207. doi:10.1056/NEJMoa0807646. PMID 18997196. 
  10. ^ Brendan M. Everett, MD, MPH; Robert J. Glynn, ScD; Jean G. MacFadyen, BA; Paul M Ridker, MD, MPH (2010). "Rosuvastatin in the Prevention of Stroke Among Men and Women With Elevated Levels of C-Reactive Protein". Circulation 121 (1): 143–150. doi:10.1161/CIRCULATIONAHA.109.874834. PMID 20026779. http://circ.ahajournals.org/cgi/reprint/121/1/143.pdf. 
  11. ^ Fellstrom BC, Jardine AG, et al. (April 2009). "Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis". N. Engl. J. Med. 360 (14): 1395–1407. doi:10.1056/NEJMoa0810177. PMID 19332456. http://content.nejm.org/cgi/content/short/360/14/1395?query=TOC. 
  12. ^ 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. 
  13. ^ FDA Advisory Targets Asian Patients (Los Angeles Times).
  14. ^ Asian-Americans Among Groups More at Risk of Serious Muscle Damage (WebMD).
  15. ^ "AstraZeneca's Crestor patent upheld;No generic competition until 2016". http://www.delawareonline.com/article/20100701/BUSINESS/7010316/1003/RSS01. [dead link]
  16. ^ AstraZeneca (June 29, 2010). "CRESTOR Patent Upheld By US Court". PR Newswire. United Business Media. http://www.prnewswire.com/news-releases/crestor-patent-upheld-by-us-court-97435724.html. Retrieved 2012-04-25. 
  17. ^ Berkrot, Bill; Tom Hals (June 29, 2010). "UPDATE 2-U.S. judge rules AstraZeneca Crestor patent valid". Reuters. http://www.reuters.com/article/2010/06/29/astrazeneca-crestor-idUSN2917115320100629. Retrieved 2012-04-25. 
  18. ^ Starkey, Jonathan (July 1, 2010). "AstraZeneca patent upheld". The News Journal (Wilmington, Delaware). http://pqasb.pqarchiver.com/delawareonline/access/2074695931.html?FMT=ABS&date=Jul+01%2C+2010. Retrieved 2012-04-25.  (Subscription required)
  19. ^ Horton, Richard (October 25 2003). "The statin wars: why AstraZeneca must retreat". Lancet 362 (9393): 1341. doi:10.1016/S0140-6736(03)14669-7. PMID 14585629. 
    McKillop T (November 1 2003). "The statin wars". Lancet 362 (9394): 1498. doi:10.1016/S0140-6736(03)14698-3. PMID 14602449. 
  20. ^ Food and Drug Administration. "Docket No. 2004P-0113/CP1" (PDF). http://www.fda.gov/ohrms/dockets/dockets/04p0113/04p-0113-pdn0001.pdf. 
  21. ^ Sattar, N; Preiss, D, Murray, HM, Welsh, P, Buckley, BM, de Craen, AJ, Seshasai, SR, McMurray, JJ, Freeman, DJ, Jukema, JW, Macfarlane, PW, Packard, CJ, Stott, DJ, Westendorp, RG, Shepherd, J, Davis, BR, Pressel, SL, Marchioli, R, Marfisi, RM, Maggioni, AP, Tavazzi, L, Tognoni, G, Kjekshus, J, Pedersen, TR, Cook, TJ, Gotto, AM, Clearfield, MB, Downs, JR, Nakamura, H, Ohashi, Y, Mizuno, K, Ray, KK, Ford, I (2010 Feb 27). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.". Lancet 375 (9716): 735–42. doi:10.1016/S0140-6736(09)61965-6. PMID 20167359. 
  22. ^ "FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs". http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm?utm_source=fda&utm_medium=website&utm_term=Statins&utm_content=f3&utm_campaign=HomePageSpotlight. 

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