Increased myopathy with combination use of ER niacin/laropiprant (Tredaptive®) and simvastatin 40mg in Chinese patients. Results from interim analysis of HPS2-THRIVE study

HSA has recently been informed by MSD of the results of an interim analysis from an ongoing study, HPS2-THRIVE, which suggest a higher incidence of myopathy observed in Chinese patients on concomitant extended release (ER) niacin/laropiprant 2g/40mg (Tredaptive®, MSD) and simvastatin 40mg (with or without ezetimibe) treatment as compared to Scandinavian and British patients.

ER niacin/laropiprant is a lipid-lowering agent indicated for the treatment of dyslipidemia.It contains a combination of ER niacin, a lipid-modifying agent and laropiprant, a potent, selective antagonist of the prostaglandin D₂(PGD₂) receptor subtype 1 (DP₁). Laropiprant is a novel agent that is added to the combination to suppress the PGD₂mediated flushing that is associated with the use of niacin. Tredaptive® has been licensed for use in Singapore since March 2009.

Myopathy

Myopathy and rhabdomyolysis are known adverse effects of HMG-CoA reductase inhibitors (statins), and the risk increases with higher doses and concomitant use of certain CYP3A4 inhibitors such as gemfibrozil and ciclosporin. Clinical trial data from 41,050 patients, whereby approximately 60% of them were treated with simvastatin for at least four years, showed that the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at the doses of 20, 40 and 80mg/day respectively.¹

HPS2-THRIVE study

HPS2-THRIVE is a double blind, randomised placebo controlled study to assess the long term clinical effects of increasing HDL-cholesterol with ER niacin/laropiprant in 25,000 patients with pre-existing atherosclerotic vascular disease who were,receiving simvastatin 40mg daily (plus ezetimibe 10mg daily, where indicated). This study, sponsored by Oxford University, is currently conducted in China, UK and Scandinavia. The study is currently in progress and is expected to be completed in 2012.

(i) Interim safety analysis

An interim analysis conducted by the independent safety monitoring committee revealed that the incidence of myopathy among approximately 4,700 UK/Scandinavian patients treated with Tredaptive® co-administered with either simvastatin 40mg or ezetimibe/simvastatin 10mg/40mg is similar to the overall incidence of 0.08% reported in the prescribing information for simvastatin 40mg.¹ However, in approximately 3,900 Chinese patients in the same treatment arm, the incidence of myopathy is higher than expected, with an approximate incidence of 0.9%. The risk of myopathywas not increased among 8,600 Chinese, UK, or Scandinavian patients in the control arm (placebo plus simvastatin 40mg or ezetimibe/simvastatin 10mg/40mg).

The events of myopathy among Chinese patients resolved with the discontinuation of therapy. No myopathy or rhabdomyolysis related deaths were observed in any patient cohort.

Baseline characteristics of randomised Chinese patients were similar to those of Scandinavian and UK patients except that they tended to be younger, diabetic, abstained from alcohol, had lower Body Mass Indexes (BMIs) and lower total cholesterol. 58% of the Chinese were statin naive as compared to 4% of the Scandinavia/UK patients at the time of screening. It was noted that the use of Traditional Chinese Medicines (TCMs) was more prevalent among Chinese patients with myopathy vis-à-vis all randomised Chinese patients (52.9% vs 37.5%). In addition, the following factors: age > 70 years, female gender and diagnosis of diabetes mellitus at baselinewere also found to be more prevalent among Chinese patients with myopathy than among the entire Chinese study population. No trend was observed with other variables such as alcohol use, BMI, type or extent of statin use prior to enrolment and the use of ezetimibe as a component of the background lipid-modifying therapy.

(ii) Conclusion

The reason for the higher rate of myopathy in HPS2-THRIVE in the Chinese cohort who were on concomitant Tredaptive® and simvastatin 40mg with or without ezetimibe 10mg remains unknown currently. HSA is working with the company to update the local product insert of Tredaptive® to highlight this interim data on myopathy gathered from the HPS2-THRIVE study.

HSA's advisory

HSA has not received any local reports of rhabdomyolysis or myopathy associated with Tredaptive® or in combination with statins to date. Physicians prescribing the combined therapy of Tredaptive® with statins are advised to carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months or therapy and when dosage of either drug is increased.

Healthcare professionals are strongly encouraged to report adverse reactions of myopathy associated with Tredaptive® or Tredaptive® with statins combination treatment to the Vigilance Branch of HSA. HSA will continue to monitor the development of this safety issue and update healthcare professionals when new information arises.

References

1. Singapore Package Insert for simvastatin (Zocor®, MSD)