January 14th, 2011
FDA Warns About Severe Liver Injury Associated with Multaq (Dronedarone)
Larry Husten, PHD
The FDA has released a safety communication about severe liver injury associated with Multaq (dronedarone). The FDA said that information about the risk of liver injury would be added to the dronedarone label. The drug’s manufacturer, Sanofi-Aventis, has also sent a letter to healthcare professionals informing them of the warning.
The FDA is recommending that doctors advise their patients “to contact a healthcare professional immediately if they experience signs and symptoms of hepatic injury or toxicity while taking dronedarone.” In addition, doctors should “consider obtaining periodic hepatic serum enzymes,” but the FDA acknowledged that there is no evidence whether this step will prevent liver injury.
The safety warning is based on several reported cases of liver injury and failure, including two patients who required liver transplants 4.5 and 6 months after starting dronedarone treatment. In both cases no other causes for liver failure were found.
8 Responses to “FDA Warns About Severe Liver Injury Associated with Multaq (Dronedarone)”
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I have significant concerns about the safety, efficacy and tolerability of dronedarone. Although liver toxicity was not anticipated, other safety issues have been apparent even prior to launch. The increased risk of death in heart failure patients represented a particularly concerning finding in pre-approval studies. The drug is substantially less efficacious compared with amiodarone and the GI tolerability is poor. Despite these warning signs, the drug has been aggressively promoted, often through industry-sponsored CME offered by professional medical societies. Over-promotion of a risky drug during its initial launch period has been a historically important harbinger of serious safety concerns. Dronedarone may be headed for trouble.
Fully agree with Dr. Nissen’s insightful comments–Ongoing surveillance and reporting to the FDA is definitely mandatory, as is getting an estimate of frequency of occurrence!
Competing interests pertaining specifically to this post, comment, or both:
None
Considering that dronedarone is being marketed as the safe alternative to amiodarone, I agree that I am a bit concerned about these revelations. We must however acknowledge the reality that all anti-arrhythmic drugs are unsafe and these issues with dromedarone must be taken in that relative context.
The dronedarone example exposes an interesting dilemma in clinical practice.
Does one prescribe medications because they are touted to be safe, even though they might be less efficacious than the alternative?
Or does one prescribe medications that are efficacious as long as they come with an acceptable safety tradeoff?
The safety communication concerning dronedarone comes at the same time that FDA has elected to require a boxed warning concerning acute liver failure on prescription drugs containing acetaminophen, now limited to 325 mg in these combinations. Acetaminophen has been shown to be the most common cause of ALF. Moreover, studies show that 52% of cases with acetaminophen-induced ALF occur without overdose (i.e., within the 4 gram/day limit). While there are various explanations for normal doses causing ALF, one possiblity is that patients on dronedarone or another drug displaying hepatotoxicity may also be taking acetaminophen, either OTC or in another prescription drug. Since the liver effects may be additive,it may be appropriate to warn patients on dronedarone to avoid acetaminophen.
Competing interests pertaining specifically to this post, comment, or both:
None.
The United States Food and Drug Administration (FDA) has issued a warning to healthcare professionals concerning severe liver injury in patients taking dronedarone (Multaq) for maintenance of sinus rhythm in patients with atrial fibrillation. This included two cases of acute liver failure leading to liver transplantation. Between approval in July, 2009 and October, 2010 there were 492,000 prescriptions for dronedarone and 147,000 patients in the United States filled outpatient prescriptions for dronedarone. Additional surveillance and careful choice of patients will be necessary concerning administration of dronedarone. The implications of this finding are not yet clear. It is not clear that dronedarone is the cause of the liver failure, and the incidence does appear to be low. Continued observation will be necessary. Indeed, there have been other pharmaceuticals which have been shown to cause liver damage of varying severity both before and after drug approval. This also shows the importance of post-marketing surveillance. The clinical trials leading up to approval would be unlikely to find an abnormality requiring tens to hundreds of thousands of exposures to the drug. The only way that rare reactions that may be life-threatening can be noticed is by continuing observation after the drug is brought to market. This may occur by means of voluntary reporting, or it may come to light through analysis of observational databases, both clinical and administrative. This is an imperfect method of evaluating drug safety, and undoubtedly there have been cases where drugs have been inaccurately implicated as causing side effects as well as cases where serious side effects have been overlooked.
Competing interests pertaining specifically to this post, comment, or both:
I receive grant support from Sanofi-Aventis
Are we in a situation anything different from that with amiodarone?
I think not. There have been some serious cases of liver injury from amiodarone as well. And we keep it administering to our patients.
Surveillance and reporting is what is to be done, and in the way that provides data of good quality to assess causality otherwise the link between a specific drug and its side effect may not be evident or clear, and the bad data might be misused by both proponents and opponents of the drug. The future will show the safety profile.
For anyone interested in the issue:
1/ A number of case reports can be found in: Meyler’s Side Effects of Cardiovascular Drugs by J. K. Aronson, 2009.
2/ Causality assessment of liver injury after chronic oral amiodarone intake _ at: http://www.ncbi.nlm.nih.gov/pubmed/19165760
Certainly this requires close monitoring. But I am trying to understand how to gauge the importance of low frequency events in patients exposed to drugs. Most likely, these patients were exposed to other drugs and had other confounding factors. Bill Weintraub notes that there are 2 cases out of 492,000 prescriptions. The event rate is so low – on the order of dying in an airplane crash or drowning, and probably less than the expected mortality rate for many elective surgical procedures. When does the event rate become clinically important? Is there a threshold? What are the criteria that the FDA uses? I would like more information on the science of drug surveillance. More knowledge about the science of drug surveillance will help the average practitioner put this into perspective.