Safety of rosuvastatin: update on 16,876 rosuvastatin-treated patients in a multinational clinical trial program.

BACKGROUND: The safety and tolerability of rosuvastatin were assessed using data from 16,876 patients 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 (< or = 0.2%) in the rosuvastatin and comparator statin groups. Elevated creatine kinase > 10 times ULN occurred in < or = 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 < or = 40 mg. The frequency of dipstick-positive proteinuria at rosuvastatin doses < or = 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 < or = 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.)