Rosuvastatin
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| Rosuvastatin
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| Systematic (IUPAC) name | |
| 7-[4-(4-fluorophenyl) -6-(1-methylethyl)- 2-(methyl-methylsulfonyl-amino)- pyrimidin-
5-yl]- 3,5-dihydroxy-hept-6-enoic acid | |
| Identifiers | |
| CAS number | |
| ATC code | C10 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C22H28FN3O6S |
| Mol. mass | 481.539 |
| Pharmacokinetic data | |
| Bioavailability | 20% |
| Metabolism | Liver |
| Half life | 19 hours |
| Excretion | Urine / Faeces |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | oral |
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Overview
Rosuvastatin is a member of the drug class of statins, used to treat hypercholesterolemia and related conditions, and to prevent cardiovascular disease. It is currently being marketed by the pharmaceutical company AstraZeneca as Crestor.
Dosing
Rosuvastatin is available as Crestor in tablet form (5, 10, 20, or 40 mg) for oral administration. Tablets are pink, round or oval (40 mg), biconvex, film-coated, and imprinted with "ZD4522" and tablet strength.[1] Japanese approval is in the dose range of 2.5 mg to 20 mg; therefore, smaller dose tablet forms might also be available outside the United States. Note that 97% of worldwide sales have been at or below the 20 mg dose.
Mechanism of action
- Further information: Statin
Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar, yet higher efficacy, to other statins.[1]
Indications and regulation
Rosuvastatin is approved for the treatment of elevated LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia) and/or triglycerides (hypertriglyceridemia).[1]
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.[1]
Effects on cholesterol levels
The effects of rosuvastatin on LDL cholesterol are dose-related. At the 10mg 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 increase of an additional 9% absolute reduction in LDL levels (55% below baseline levels).[1]
Debate & criticisms
Several months after its introduction in Europe, Richard Horton, the editor of the medical journal The Lancet, criticized the way Crestor had been introduced to the marketplace. "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 relies too much on extrapolation from the lipid profile data and too little on hard clinical endpoints, which are available for other statins which had been on the market longer. The manufacturer responded by stating that few drugs had been tested so successfully in so many patients. In correspondence published in The Lancet, AstraZeneca's CEO Sir Tom McKillop called the editorial "flawed and incorrect" and criticized the journal for making "such an outrageous critique of a serious, well-studied medicine."[1]
In 2004, the consumer interest organisation 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 (a) denying the petition and (b) providing an extensive detailed analysis of findings which demonstrated no basis for concerns about rosuvastatin compared with the other statins approved for marketing in the United States; the full text of the FDA letter is available on-line: http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_CP.pdf[1].
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.[1] However, more recent, larger and more thorough reviews have actually demonstrated both slightly lower rates of myopathy for rosuvastatin than any of the other statins available within the United States and improved kidney function with all statin use, including rosuvastatin, see below.
Regarding myopathy and potential rhabdomyolysis, recent reviews of published data on all statins marketed in the US, and reviewed by the FDA, both pre and post-approval, have found that marked rises in the serum levels of muscle CK enzymes to 10 times normal or greater, the hallmark of serious muscle problems, remain very rare, 1:10,000 to 1:20,000 individuals. (For comparison, this incidence is about identical with that for acetaminophen (paracetamol), commonly purchased as Tylenol, an OTC agent about which most people rarely worry; accept as safe)
Cerivastatin, a statin recalled in 2001, was an exception; it had a higher myopathy response. For the statins still on the market in the US, reported toxicity levels has been highest for pravastatin, simvastatin next, atorvastatin next and rosuvastatin the lowest at similar milligram doses. Yet the efficacy of these agents to change blood LDLipoproteins levels, at the same milligram doses, is the exact opposite. So, from the standpoint of the rare but serious muscle toxicity events, rosuvastatin, as of mid-2005 has turned out to have the best therapeutic index of the currently available statins.
Renal effects
Recent reviews of published trial data, focusing on renal function, on placebo vs. statin, and tracking renal function over time have shown a small but distinct effect of statins to lessen renal dysfunction, when added to treatment (compared to placebo), and to slow the progression of further renal function decline over time. All the statins have a somewhat dose related response to increase urine protein levels. Because increased urine protein has long been relied upon as a warning sign of renal glomerular dysfunction, this increase as a result of statin treatment had been feared to indicate a negative effect on renal function.
However, all current evidence, see reference 6 and others, is that the increase in urinary protein is from the renal tubular cells, not the glomeruli, and is due to cholesterol synthesis inhibition within the tubular cells and is not associated with any decline in renal function. Instead, as mentioned above, clinical experience is that renal function, especially in those with partial renal failure, actually improves slightly and the rate of further decline decreases compared with those in the same trials who were randomized to the placebo agent.
Clinical Trial Data
More recent human controlled research trial data continues to be more promising. One of the most recent was a 2 year trial of rosuvastatin treatment, the ASTEROID trial, in reported in 2006 that when several hundred people were treated with Crestor at the highest currently approved dose of 40 mg a day, IVUS showed some reversal of atherosclerotic plaque within the coronary arteries.[1]
References
- Annual Report and Form 20-F, Information 2004 (PDF). AstraZeneca PLC (2005).
- Annual Report and Form 20-F, 2003 (PDF). AstraZeneca PLC (2004).
- 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. PMID 11256847.
Notes
External links
- Crestor web site, by AstraZeneca, and their Rosuvastatin Information site providing access to clinical trial information.
- Rosuvastatin (Crestor) Information. eMedicineHealth (10/16/2005).
- What Are Some Possible Side Effects of Crestor?. eMedicineHealth (10/16/2005).
FDA documents index
2005
- 11 March 2005: Letter from FDA to Public Citizen informing of the denial of Public Citizen's 4 March 2004 Citizen's Petition
- 8 March 2005: Letter from FDA to AstraZeneca regarding "false or misleading claims regarding the superiority of Crestor".
- 2 March 2005: FDA Public Health Advisory on Crestor (rosuvastatin), patient and healthcare provider information updated
- 2 March 2005: Letter from FDA to AstraZeneca mandating changes to prescription labeling
2004
- 21 December 2004: Letter from FDA to AstraZeneca regarding "false or misleading safety claims" in a print ad
- 4 November 2004: FDA Docket listing 2004P-0113, regarding Public Citizen's Citizens' Petition of 4 March 2004
- 15 September 2004: FDA Docket listing 2004P-0113, regarding Public Citizen's Citizens' Petition of 4 March 2004
- 1 September 2004: Letter from FDA to Public Citizen indicating that Public Citizen's 4 March 2004 Citizen's Petition is still under consideration.
- 4 June 2004: FDA Docket listing 2004P-0113, regarding Public Citizen's Citizens' Petition of 4 March 2004
- 18 May 2004: Letter from Public Citizen to FDA, update to Citizen's Petition of 4 March 2004
- 6 March 2004: FDA Docket listing 2004P-0113, regarding Public Citizen's Citizens' Petition of 4 March 2004
- 5 March 2004: Letter from FDA to Public Citizen acknowledging receipt of Citizen's Petition.
- 4 March 2004: Letter from Public Citizen to FDA petitioning for the immediate removal of Crestor from the market
2003
- 12 August 2003: Letter from FDA to AstraZeneca, approval letter
- 9 July 2003: Presentations to the Endocrinologoc (sic) and Metabolic Drugs Advisory Committee
Lipid modifying agents (C10) | |
|---|---|
| Statins | Atorvastatin • Cerivastatin • Fluvastatin • Lovastatin • Mevastatin • Pitavastatin • Pravastatin • Rosuvastatin • Simvastatin |
| Fibrates | Clofibrate • Bezafibrate • Aluminium clofibrate • Gemfibrozil • Fenofibrate • Simfibrate • Ronifibrate • Ciprofibrate • Etofibrate • Clofibride |
| Bile acid sequestrants | Colestyramine • Colestipol • Colextran • Colesevelam |
| Niacin and derivatives | Niceritrol • Niacin • Nicofuranose • Aluminium nicotinate • Nicotinyl alcohol • Acipimox |
| Other | Dextrothyroxine • Probucol • Tiadenol • Benfluorex • Meglutol • Omega-3-triglycerides • Magnesium pyridoxal 5-phosphate glutamate • Policosanol • Ezetimibe |
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Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
