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      Safety of Rosuvastatin: Update on 16,876 Rosuvastatin-Treated Patients in a Multinational Clinical Trial Program

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          Abstract

          Background: The safety and tolerability of rosuvastatin were assessed using data from 16,876patients who received rosuvastatin 5–40 mg in a multinational phase II/III /IIIb/IV program, representing 25,670 patient-years of continuous exposure to rosuvastatin. Methods: An integrated database, consisting of 33 trials whose databases were locked up to and including September 16, 2005, was used to examine adverse events and laboratory data. Results: In placebo-controlled trials, adverse events irrespective of causality assessment occurred in 52.1% of patients receiving rosuvastatin 5–40 mg (n = 931) and 51.8% of patients receiving placebo (n = 483). In all controlled clinical trials with comparator statins, rosuvastatin 5–40 mg was associated with an adverse event profile similar to profiles for atorvastatin 10–80 mg, simvastatin 10–80 mg, and pravastatin 10–40 mg. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal [ULN] on at least 2 consecutive occasions) were uncommon (≤0.2%) in the rosuvastatin and comparator statin groups. Elevated creatine kinase >10 times ULN occurred in ≤0.3% of patients receiving rosuvastatin or other statins. Myopathy (creatine kinase >10 times ULN with muscle symptoms) possibly related to treatment occurred in 0.03% of patients taking rosuvastatin at doses ≤40 mg. The frequency of dipstick-positive proteinuria at rosuvastatin doses ≤20 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. Both short- and long-term rosuvastatin treatment were associated with small increases in estimated glomerular filtration rate, with improvements appearing to be somewhat greater in those patients beginning treatment with greater renal impairment. In the phase II–IV program, no deaths were attributed to rosuvastatin; at doses of rosuvastatin ≤40 mg, 1 case of rhabdomyolysis occurred in a patient who received rosuvastatin 20 mg and concomitant gemfibrozil treatment. Conclusion: In summary, rosuvastatin was well tolerated by a broad range of patients with dyslipidemia, and its safety profile was similar to those of comparator statins investigated in the clinical program. (Nota bene: The clinical development program for rosuvastatin initially evaluated rosuvastatin doses up to 80 mg. Following completion of the phase III/IIIb program, a decision was made not to pursue marketing approval for the 80-mg dose because the additional lipid-modifying benefits of this dose did not justify the potential risks for use in the general population of patients with dyslipidemia.)

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          Most cited references 24

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          Statin-associated myopathy.

          Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia with and without elevated CK levels, muscle weakness, muscle cramps, and persistent myalgia and CK elevations after statin withdrawal. We performed a literature review to provide a clinical summary of statin-associated myopathy and discuss possible mediating mechanisms. We also update the US Food and Drug Administration (FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy were identified via a PubMed search through November 2002 and articles on statin clinical trials, case series, and review articles were identified via a PubMed search through January 2003. Adverse event reports of statin-associated rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature review found that reports of muscle problems during statin clinical trials are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. Cerivastatin was the most commonly implicated statin. Few data are available regarding the frequency of less-serious events such as muscle pain and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis and other adverse effects with statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications. Medications such as the fibrate gemfibrozil alter statin metabolism and increase statin plasma concentration. How statins injure skeletal muscle is not clear, although recent evidence suggests that statins reduce the production of small regulatory proteins that are important for myocyte maintenance.
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            Drug treatment of lipid disorders.

             Robert Knopp (1999)
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               G De Backer (2003)
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2007
                May 2007
                16 March 2007
                : 107
                : 4
                : 433-443
                Affiliations
                aDepartment of Pathological Biochemistry, University of Glasgow, Glasgow, UK; bCleveland Clinic Foundation, Cleveland, Ohio, and cAstraZeneca LP, Wilmington, Del., USA
                Article
                100908 Cardiology 2007;107:433–443
                10.1159/000100908
                17363845
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 8, References: 39, Pages: 11
                Categories
                Original Research

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