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

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.)

Cardiovascular Event Reduction and Adverse Events Among Subjects Attaining Low-Density Lipoprotein Cholesterol <50 mg/dl With Rosuvastatin

“…Lower targets for LDL-C remain controversial, will need to be evaluated in prospective settings, and may not be achievable among patients with very elevated LDL-C. Nonetheless, the JUPITER trial data provide reassurance regarding the safety of treating with rosuvastatin at very low levels of LDL-C. Safety findings among patients attaining LDL-C Ͻ50 mg/dl were consistent with the established safety profile of rosuvastatin (24). Elevation of ALT and dipstick proteinuria and hematuria were more frequent with rosuvastatin than with placebo, but within the rosuvastatin group, were not more frequent among subjects attaining LDL-C Ͻ50 mg/dl.…”

Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation

“…Evidence from a rosuvastatin clinical trials database suggests that treatmentrelated discontinuation rates were lower (2.9%) for patients receiving rosuvastatin 5-40 mg/day than for patients receiving placebo (4.3%). 73 However, in the 2-year open-label ASTEROID study (n = 507, all statin-naïve) discontinuation rates because of drug-related muscle pain or weakness for rosuvastatin 40 mg/day were 3.7%. 76 It is noteworthy that adverse events may be more common in clinical practice as trial participants are usually younger, healthier and more closely monitored than patients in usual clinical practice.…”

“…Although the evidence for the long-term safety of rosuvastatin is limited, a rosuvastatin clinical trials database (comprising data from 33 phase II/ III clinical trials) 73 suggests that rates of myopathy (< 0.03%), myositis (< 0.3%) and elevated ALT levels greater than three times the upper limit of normal (< 0.2%) are uncommon at doses of ≤ 40 mg/day. Although no deaths have been attributed to rosuvastatin (< 40 mg/day), one case of rhabdomyolysis has been found in a patient who received rosuvastatin 20 mg/day and concomitant gemfibrozil treatment.…”

Aleglitazar, a balanced PPARα/γ agonist, has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin

“…The doses of statins used in the current study are widely used and have well-characterised safety and tolerability profiles [14,15]. Co-administration of atorvastatin or rosuvastatin at these commonly used doses with aleglitazar had no apparent effect on the safety profile of any of the three compounds in healthy volunteers in this short-term study.…”