Safety updates on statins

Important product safety information and risk of rhabdomyolysis with high dose simvastatin

HSA would like to draw the attention of healthcare professionals to important new safety information related to the class of statin products, in particular the safety product label changes initiated by the US Food and Drug Administration (FDA) as well as its re-analysis results from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial.

Statins are indicated for the treatment of hypercholesterolaemia in addition to diet and exercise. There are six different types of statins licensed in Singapore, namely atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin. These statins are marketed as single-ingredient products under both proprietary and generic brands. They are also marketed as combination products, such as Vytorin® by MSD containing simvastatin/ezetimibe and Caduet® by Pfizer containing amlodipine/atorvastatin.

Safety updates by the US FDA

(a) All statins

In February 2012, the US FDA announced several safety updates to the product labels of statin-containing products, including warnings on cognitive side effects and reports of increased blood glucose and glycosylated haemoglobin (HbA1c) levels.¹ Despite these new safety concerns, FDA has assessed that the cardiovascular benefits of statins outweigh the small increased risks.

Cognitive impairment

FDA's review took into consideration information from the Adverse Events Reporting System database, published medical literature (case reports and observational studies) and randomised clinical trials investigating the effects of statins on cognition. In general, cognitive side effects (eg, memory loss, confusion) observed were non-serious and were reversible within a few weeks after discontinuation of the statin therapy. The time to onset of the event was highly variable, ranging from one day to several years after statin exposure. The cases did not appear to be associated with fixed or progressive dementia, such as Alzheimer's disease. Further assessment also did not reveal an association between the adverse event and any specific statin, the age of the patient, the statin dose, or concomitant medication use. Nevertheless, the US product labels for statins were updated to provide healthcare professionals with this information for consideration when prescribing statins.

Increased fasting glucose and HbA1c

FDA's class labelling on increased fasting glucose and HbA1c stemmed from the review of clinical trial meta-analyses and epidemiological data from published literature, including the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, which reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients versus placebo-treated patients. Data from these studies suggest the possibility of a class effect of statins in increasing fasting plasma glucose and HbA1c.

(b) Simvastatin

Rhabdomyolysis and dose restrictions

In June 2011, FDA confirmed an increased risk of myopathy and rhabdomyolysis with high dose simvastatin (80mg) following a re-analysis of the SEARCH trial.² In this trial, the incidence of myopathy increased from 0.02% (one patient) among patients taking 20mg simvastatin daily to 0.9% (52 patients) among those taking simvastatin 80mg daily. In addition, 22 patients (0.4%) in the simvastatin 80mg group developed rhabdomyolysis vis-à-vis no cases of rhabdomyolysis in patients from the simvastatin 20mg group.

Local situation

To date, HSA has not received any local adverse reaction report on cognitive impairment and abnormal blood glucose levels associated with the use of statins. HSA has received one report of rhabdomyolysis in a patient taking high dose simvastatin (80mg). This patient was also on other concomitant medications such as aspirin, atenolol, clopidogrel, enalapril and omeprazole.

HSA has reviewed the information present on cognitive impairment, increased fasting glucose and HbA1c and rhabdomyolysis and is currently working with the companies of the various statin-containing products to strengthen the local package inserts (PIs) to include precautions and warnings on these safety issues. Healthcare professionals are advised to take into consideration the above safety issues when prescribing statins and are encouraged to report adverse drug reactions associated with the use of statin-containing products to the Vigilance Branch of HSA.

Summary of important safety label updates

Updates to all statins PI

• Post-marketing reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with statins. The reports are generally non-serious, and reversible upon statin discontinuation.

• Increases in HbA1c and fasting serum glucose levels have been reported with statins

Updates to simvastatin P

• Increased risk of myopathy and rhabdomyolysis with high dose simvastatin (80mg)

References

1. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

2. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm