The American Food and Drugs Administration (FDA) has approved an updated label containing a boxed warning about cancer risks for pimecrolimus (Elidel)® and tacrolimus (Protopic)®.
The FDA is taking this action to "ensure that healthcare providers and patients are aware of the possible long-term risks of these products". This follows rare reports of cancer in patients using these products, although at this time no causal relationship has been established.
Action: The safety of these products is still under review and as detailed here, clinicians should ensure these products are used as per the NICE Technology Appraisal and within the product licence. (Note: neither product is licensed for used in patients under 2 years old).
Summary of Product Characteristics for Tacrolimus
Summary of Product Characteristics for Pimecrolimus
The BMJ has published a paper this week that examines the impact that the National Service Framework for Coronary Heart Disease (NSF for CHD) has had on secondary prevention in older patients1.
The study examined the uptake of antiplatelet, antihypertensive and lipid-lowering drugs in patients aged 69 to 74 with CHD and compared uptake rates from before (data from 1998-2001) and after (data from 2003) the introduction of the NSF. The data were analysed by diagnosis (myocardial infarction or angina) and gender.
In all cases the proportion of patients being prescribed the above classes of drugs increased, in some cases doubling. However, despite these improvements there is still considerable opportunity for improvement, for example less than half of patients with a diagnosis of angina are prescribed a statin.
Action: The NSF for CHD has had a positive impact on the care of patients with CHD. The QOF will have driven these improvements further, however some quick audit work will identify any remaining areas for improvement.
- Ramsay SE et al. Secondary prevention of coronary heart disease in older patients after the national service framework: population based study. BMJ 2006;332:144-5
Pediatrics, the journal of the American Academy of Pediatrics has published a study1 examining the safety and tolerability of Pimecrolimus. Five if the six authors declare a conflict of interest stating they are either employed directly, consult for or receive grants from the manufacturer of pimecrolimus. The abstract and full paper are available online.
The study is an analysis of several sources of data including pharmacokinetic, double blind and open label studies. The study examined a total of 1133 patients, aged 3-23 months, who were followed up for a maximum of 2 years.
All but one of the studies was for 6 months or less with one longer term study lasting two years; one year blinded and one year open label follow up. Incidence Density rates were reported for adverse events that occurred in more than 1% of patients. The only adverse event that was statistically different was the increased risk of teething in patients using pimecrolimus, however there were tendencies to increased risk (although not significant) in several other areas.
The study separately examined skin infection rates and although there was little difference in the rate of bacterial infections of the skin there was an increased risk (again not significant) of viral and fungal skin infections.
The study also details that evidence of increased incidence of skin malignancies has not been seen in this study or in post marketing safety analyses. However, they also submit the conclusive evidence of safety with respect to this concern will only be available 5 to 10 years after product launch.
This study does go some way to reassuring prescribers of the safety of pimecrolimus however there is still a long way to go. Treatment withdrawals were not reported in this study and given that the paper states that 5million patients have been treated with pimecrolimus since launch a study of 1133 patients represents a very small cohort.
Action: Clinicians should continue to ensure that pimecrolimus is used within its product licence (Note: Pimecrolimus is not recommended for use in children under 2 years old) and the NICE Technology Appraisal recommendations.
- Paul C et al. Safety and Tolerability of 1% Pimecrolimus Cream Among Infants: Experience With 1133 Patients Treated for Up to 2 Years. Pediatrics 2006;117:e129-e131
The National Prescribing Centre has published MeReC Extra 20. This MeReC covers the findings of the PROactive Study and details changes to the handwriting requirements for controlled drug prescriptions.
PROactive has already been covered here. The NPC conclude "it remains uncertain whether pioglitazone reduces the risk of death, MI and stroke in patients with type 2 diabetes who are already at high risk of these events". They suggest that clinicians should focus upon the interventions that are known to be more important, namely reducing cardiovascular risks.
The publication also details changes in the handwriting requirements for controlled drug prescriptions. From November 2005 the handwriting requirement only applies to the signature of the prescriber, the rest of the prescription can be computer generated.
Action: All clinicians who are involved in the treatment of diabetes or who issue prescriptions for controlled drugs will benefit from reading this MeReC Extra.
Clinical Trials sometimes use surrogate endpoints as the measure of the primary outcome of the study. Surrogate endpoints are a proxy for what would ideally be measured but for limitations imposed by time, cost or ethical considerations.
However, these surrogate endpoints may not be an accurate predictor for the outcome we would ideally like to assess. This can have an impact upon the relevance and credibility of the study. Additionally, it may become clear later that, while the surrogate endpoint strongly and statistically indicated a benefit, the impact on a clinically important endpoint is not beneficial.
This happened with doxazosin in the ALLHAT Study. It was found that patients treated with doxazosin rather than the other study drugs were at higher risk of mortality despite effective blood pressure lowering in this and other studies.
For example, there are many studies demonstrating the efficacy of rosuvastatin in cholesterol related outcomes such as reductions in low-density cholesterol and triglycerides. However, there are currently no hard outcome data that show reductions in heart attacks, strokes or deaths. These data are available for other statins, such as simvastatin.