New FDA Watch List Has Drug Making Fifth Straight Appearance

July 18, 2011

July 18, 2011 — The US Food and Drug Administration (FDA) has published its latest quarterly list of drugs to monitor after having identified potential signs of serious risks or new safety information, and dronedarone (Multaq, Sanofi-Aventis), appears on it for the fifth straight time.

The new watch list covers the first 3 months of 2011. During this span, the FDA detected potential signs of renal impairment and failure for dronedarone, approved in July 2009 to reduce the risk for cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. The 4 watch lists covering 2010 reported different potential signals of risk, 3 of which preceded related label changes for the drug this year.

The FDA compiles these quarterly lists based on data collected through its Adverse Event Reporting System (AERS). The FDA cautions that a drug's appearance on the list does not mean that the agency has determined that the drug actually poses the health risk reported through AERS. However, it will study these drugs to determine whether there is a causal link. If a link is established, the agency then would consider regulatory action, such as revising the drug's label, requiring a risk evaluation and mitigation strategy, or gathering more data to better characterize the risk.

In the meantime, physicians should not stop prescribing these drugs, nor should patients stop taking them, according to the FDA.

Past Potential Signals Include CHF, Warfarin Interaction, Liver Failure

In the case of dronedarone, reports of several potential signals of risk reported for 2010 were followed by regulatory action.

  • The AERS watch list for the first quarter of 2010 cited potential signals of congestive heart failure for the drug. On February 22, 2011, the FDA revised the warnings and precautions section of dronedarone's label regarding patients with new or worsening heart failure during treatment to state that postmarketing cases of such problems have been reported. The label had originally stated that there were limited data for patients with atrial fibrillation/atrial flutter who develop worsening heart failure during dronedarone therapy, but nevertheless advised clinicians to consider suspending or discontinuing the drug if heart failure commences or worsens.

  • In the second quarter, AERS identified potential signals of torsade de pointes, a rare kind of ventricular tachycardia.

  • The list for the third quarter of 2010 listed a potential signal for an interaction with warfarin that increases its anticoagulant effect. On March 21, 2011, the drug interactions section of dronedarone's label was changed to mention postmarketing cases of higher internal normalized ratio (INR) clotting times with or without bleeding events in patients taking warfarin. Physicians were advised to monitor INR in such individuals. The label had originally stated that in clinical trials, "there was no observed excess risk for bleeding compared to placebo" when dronedarone was coadministered with oral anticoagulants to patients with atrial fibrillation/atrial flutter, and that INR should be monitored according to the warfarin label.

  • Potential signals of liver failure for dronedarone appeared in the watch list for the last 3 months of 2010. On February 11, 2011, the FDA changed the warnings and precautions section of the label to mention postmarketing cases of hepatocellular liver injury and acute liver failure, and the need to promptly discontinue dronedarone if such an injury is suspected. Other parts of the label were revised accordingly.

There were 2 other label changes for dronedarone in 2011 that do not appear to be directly related to potential risk signals detected in 2010. On January 31, 2011, the FDA revised the drug interaction section to state that exposure to dabigatran is higher when it is administered with dronedarone as opposed to alone. In addition, on June 21, 2011, the FDA revised the adverse reaction section to state that postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have surfaced.

Data Still Support "Favorable Benefit Risk Profile," Company Says

The release of the latest AERS watch list comes at a time when dronedarone is undergoing regulatory scrutiny in Europe. As reported last week by Heartwire, the European Medicines Agency will review the cardiovascular risks of dronedarone after the recent decision by Sanofi-Aventis to suspend the phase 3 Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial, which was designed to test the drug in patients with permanent atrial fibrillation, because of an increase in cardiovascular events in those randomly assigned to receive dronedarone.

During phase 3 testing and early postapproval, dronedarone had been viewed by many as potentially less effective, but safer, than amiodarone for treating atrial fibrillation. Medscape Medical News asked Sanofi-Aventis about dronedarone's safety profile in light of its regular appearances on the AERS watch list and the label changes since its approval, and received this response:

"Approximately 400,000 patients have been treated with dronedarone worldwide and post marketing surveillance continues to support the favorable benefit risk profile of Multaq in its approved indication in non-permanent atrial fibrillation."

Asked whether 5 repeat appearances on the AERS watch list is out of the ordinary, an FDA spokesperson responded, saying, "FDA acknowledges that the appearance of Multaq on 5 consecutive 921 reports may appear to be uncommon.... These FDA activities are examples of our continuous safety monitoring for marketed products, and should not be used as a surrogate marker for a product's overall safety profile. The FDA closely looks at new safety signals and conducts further evaluations when new signals arise."

Vivaglobin, on Watch List, Was Taken off Market by Manufacturer

The FDA included 13 other medications in addition to dronedarone in its AERS watch list for the first quarter of 2011. They treat conditions ranging from head lice and rheumatoid arthritis to stent thrombosis and leukemia. One of the drugs, immune globulin subcutaneous (human) 6% liquid (Vivaglobin, CSL Behring), was taken off the market by the manufacturer on April 4.

In May, the FDA updated the label of another drug on the list, azathioprine (Imuran, Prometheus), to include acute febrile neutrophilic dermatosis as an adverse reaction. That condition, also known as Sweet's syndrome, had shown up as a potential risk signal in the first quarter of the year.

Potential Signals of Serious Risks/New Safety Information Identified by AERS, January to March 2011

Product Potential Signal of a Serious Risk/New Safety Information Additional Information (as of May 31, 2011)
Adalimumab (Humira, Abbot Laboratories) Hepatic dysfunction, hepatic failure  
Azathioprine (Imuran, Prometheus) Acute febrile neutrophilic dermatosis (Sweet's syndrome) The label's adverse reactions section was updated in May to include Sweet's syndrome
Cetuximab (Erbitux, Eli Lilly and Bristol-Myers Squibb) Corneal infection, ulcerative keratitis, skin necrosis  
Dabigatran etexilate mesylate (Pradaxa, Boehringer Ingelheim) Labeling for proper storage and handling to preserve potency The FDA issued a safety communication on March 29 reminding users and pharmacies about the correct handling and storage of the drug
Dronedarone HCl (Multaq, Sanofi-Aventis) Renal impairment, renal failure  
Fibrin Sealant (Tisseel VH, Baxter Healthcare; Evicel, Omrix Pharmaceuticals) Graft failure in ophthalmological procedures and lack of efficacy in neurosurgical procedures for repair of dural tears Tisseel VH and Evicel have been used off- label in ophthalmological and neurosurgical procedures as tissue adhesives
Immune Globulin Subcutaneous (Human) 6% Liquid (Vivaglobin, CSL Behring) Thromboembolic adverse events have been reported in association with numerous product lots The product was taken off the market on April 4
Iron sucrose injection (Venofer, Luitpold Pharmaceuticals) Anaphylactic reactions  
Quinolone products Pseudotumor cerebri  
Malathion (Ovide, Taro Pharmaceutical Industries) Burns and burning sensations  
Mercaptopurine (Purinethol, Teva Pharmaceuticals) Hepatosplenic T-cell lymphoma  
Prasugrel HCl (Effient, Eli Lilly) Hypersensitivity reactions  
Rituximab (Rituxan, Roche) Hypogammaglobulinemia  
Ropinirole HCl (Requip, GlaxoSmithKline) Medication errors resulting from similarities in product name and labeling to risperidone  

More information on this list of drugs and their potential safety issues is available on the FDA's Web site. Also available are the AERS-generated watch lists covering earlier time periods.

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