Dronedarone is an antiarrhythmic drug approved by the EMA in 2009 for the treatment of some types of atrial fibrillation. The EMA scientific report, to support the marketing authorization, states that the medicine is less effective but safer than amiodarone.
The pre-marketing experience for dronedarone did not highlight any risk of pulmonary, hepatic, ocular or central nervous system toxicity, raising hope in respect to the less favourable profile of amiodarone. After its commercialization, however, the drug was associated to serious issues of hepatic and pulmonar safety and for this reason, in 2011, the EMA decided to revise its benefit/risk ratio. Besides, in July 2011, the clinical trial PALLAS (conducted on patients with permanent atrial fibrillation) had to be interrupted because of the excess of serious adverse cardiovascular reactions in the treated group respect to the placebo one. Even though dronedarone had not been approved for the indication that was under study by PALLAS, the EMA extended its revision in order to also evaluate the cardiovascular safety and published the results in September 2011, with usage restrictions and safety recommendations.
The periodic analysis of spontaneous reports collected by the AIFA National Network for Pharmacovigilance highlighted a safety signal for renal damage induced by dronedarone. This signal was then examined in depth by the Emilia-Romagna Region Centre for Pharmacovigilance, which published a follow-up in Italian and, together with the Lombardy Region Centre for Pharmacovigilance, an article on the British Journal of Clinical Pharmacology.
The Summery of Product Characteristics for dronedarone lists the increase of creatininemia as the only renal adverse reaction, recommending a check-up both before starting the therapy and 7 days after it and a new dosage in case of increased creatininemia, which should anyway reach a plateau after 7 days of therapy without compromising the renal function.
Even though a study on healthy subjects showed that dronedarone, like amiodarone, partially inhibits the tubular transportation of creatinine causing an increase of its level without reducing the renal function,[7,8] the later study PALLAS reported a higher frequency of renal adverse reactions in the dronedarone group. In December 2011, the EMA decided to wait for the necessary evidences in order to distinguish between cases where increased creatininemia reaches a plateau phase and cases where it continues to increase leading then to renal damage.
The Italian data
On the 31st December 2011, the Italian National Network for Pharmacovigilance listed 55 reports on dronedarone, 9 of them for adverse renal reactions: 4 cases of acute renal failure, 2 of renal failure and 3 of creatininemia increase. All reports came from specialist or hospital practitioners (from different Italian regions) between October 2010 and December 2011. Patients’ age (6 females and 3 males) ranged between 61 and 84 years old. In the majority of cases, the adverse reactions occurred within 13 days (from 6 days to 2 months) since the therapy started. Except for one case, all acute renal failure and renal failure reports required hospitalization or its prolongation.
In 7 cases, dronedarone was the only suspected medicine. In 8 cases other drugs were concurrent with dronedarone, but only for 3 of them the Summary of Product Characteristics listed renal failure as possible adverse reaction.
For all the reports, except for one, a clear improvement was registered after the therapy suspension.
As is known, spontaneous reports analysis can generate alarm signals which, however, must be confirmed by methodologically more complex and reliable studies. In this case, patients’ advanced age, comorbidity and concurrent drugs could have facilitated the renal failure onset. On the other side, in most reports dronedarone was the only suspected medicine and its suspension was followed by the adverse reaction regression, with creatinine values back to normality. In the end, even the number of cases (apparently low) is not negligible if considering the low consumption of this drug (0.1 DDD/ 1,000 population/ day) and its under-reporting in pharmacovigilance. The safety profile of dronedarone is very critical and still evolving. Data from this investigation sum up to the already known cardiovascular, hepatic and pulmonary safety issues and, besides further deluding the expectations for this antiarrhythmic drug, they suggest the necessity of reviewing its risk/benefit ratio again.
In the meantime new evidences are gathered, it would be appropriate to check risk factors1 for any patient starting dronedarone therapy and to pay attention, both by prescribers and users, to the possible onset of renal failure induced by dronedrone.
CreVIF, Regional Centre for Evaluation and Information on Drugs,
Pharmacology Dept. University of Bologna
- Riassunto delle Caratteristiche del Prodotto.
- Reactions Weekly 2011;:14-15. CDI NS
- Arch Intern Med 2012;172:516-7. CDI #fff#
- EMA/CHMP/718819/2011 www.ema.europa.eu
- Segnali di Farmacovigilanza AIFA 2011 www.agenziafarmaco.gov.it
- Brit J Clin Pharmacol 2012;DOI:10.1111/bcp. 12005. CDI #fff#
- Brit J Clin Pharmacol 2007;64:785-91. CDI #nnn#
- Clin Med Insights Cardiol 2011;5:103-19. CDI #fff#
- EMA/905311/2011 www.ema.europa.eu
- Rapporto OsMed 2012.