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ISMP QuarterWatchT Report (2010 Quarter 1)
Signals for acetaminophen, dronedarone, and botulinum toxins

From the November 4, 2010 issue

QuarterWatch™ is an ISMP program that monitors all serious, disabling and fatal adverse drug events (ADEs) in the US reported to FDA through the MedWatch reporting program. For the first quarter of 2010, we analyzed computer excerpts from 33,046 reports, which is an 11% increase since the last quarter of 2009 and a 19% increase over the first quarter of 2009. Reports originating from consumers have grown more rapidly than direct reports from healthcare providers. However, drug manufacturers dominate the reporting process, accounting for 82% of all the reports reviewed this quarter.

Fatal Adverse Drug Events
MedWatch data from the first quarter of 2010 revealed that the top three drugs associated with fatalities were ALPRAZolam, HYDROcodone with acetaminophen, and acetaminophen. The apparent spike in deaths associated with ALPRAZolam (473 reports) was caused by duplicate cases submitted to MedWatch. Four companies that manufacture ALPRAZolam had each reported more than 100 of the same cases of fatalities extracted from a 2008 annual report by the American Association of Poison Control Centers (AAPCC) that had recently been published in Clinical Toxicology.1 (Because drug manufacturers are required to monitor the medical literature, adverse events reported in annual reports and other published summaries may be submitted in the quarter when the reports are published, which may not be when the adverse events occurred.) However, ALPRAZolam was the primary suspect drug in only 13 deaths listed in the annual report. In the 96 other cases, ALPRAZolam was a drug taken by an individual who died of a drug overdose, although ALPRAZolam was not listed as the primary cause of death.

Because deaths reported to FDA in the first quarter of 2010 included the entire year’s (2008) data from the AAPCC report cited above,1 we analyzed the AAPCC data independently to guard against duplicate reports in the MedWatch database. We limited our analysis of the poison control data to over-the-counter (OTC) and prescription pharmaceutical products, excluding other substances. As with the MedWatch data, acetaminophen and acetaminophen with HYDROcodone were at the top of the AAPCC list (see Table 1) of primary suspect drugs in overdose deaths, accounting for 26% of all drug overdose fatalities. About 55% of these deaths involved OTC acetaminophen products; the remainder involved prescription acetaminophen-opioid combination products. A large majority (85%) of deaths associated with acetaminophen-containing products were classified as intentional overdoses.

We believe FDA needs to continue its efforts to provide extensive patient education about potentially fatal overdose risks when taking acetaminophen products as well as the importance of seeking immediate medical treatment should an overdose occur. Clear and strong warnings are needed on OTC and prescription product labeling about maximum safe doses, and the labels need to specify that combination products contain acetaminophen. The amount of acetaminophen in each tablet/dose also needs to be clearly stated on the package. The abbreviation APAP, which is unfamiliar to patients, should be avoided. FDA should continue to evaluate the risks and benefits of unbundling acetaminophen-opioid combination products, reducing the individual tablet strength of prescription combination products, and limiting the number of units (e.g., tablets) in a package of OTC acetaminophen, which has been done in the United Kingdom, to reduce the risk of toxicity from an impulsive suicide attempt. 

Other Adverse Drug Event Signals
Dronedarone (MULTAQ). In 2009, FDA approved dronedarone to reduce the risk of cardiovascular hospitalization in patients with a recent episode of paroxysmal or persistent atrial fibrillation or atrial flutter who are now in normal sinus rhythm or will undergo cardioversion. Since then, FDA has received reports that the drug may cause or worsen heart failure, interact with other drugs, trigger potentially lethal arrhythmias, and impair renal function. We identified 387 serious adverse events involving dronedarone, including 24 deaths, 2 cases of disability, and 361 other serious adverse events. Overall, 29% of the reports indicated new or worsening heart failure. Heart rhythm disturbances included 18 cases of bradycardia, 47 cases of atrial tachycardia, and 13 cases of ventricular tachycardia. There were 15 cases of kidney failure or impairment, although computer excerpts did not provide sufficient detail to fully evaluate these cases.

Dronedarone had a troubling safety profile when FDA approved the drug in 2009. Development had been halted in 2005 after a clinical trial in patients with severe heart failure had to be stopped when it was found that the drug doubled their risk of death.2 FDA allowed continuation of a clinical trial in patients without heart failure, which showed a reduction in cardiovascular hospitalizations by 24% and no statistically significant effect on mortality.3 Animal testing also showed the drug to be a carcinogen.4 Dronedarone has also been found to cause serious interactions with other medications commonly prescribed to patients with cardiac disease, including digoxin, warfarin, statins, and beta-blockers.2 The drug prolonged the QT interval and increased serum creatinine, although the manufacturer maintained that the drug did not otherwise reduce kidney function.5 In the only head-to-head trial comparing dronedarone with amiodarone, dronedarone was found to be markedly less effective than amiodarone and did not demonstrate any statistically significant safety advantage.6
Evidence is accumulating that the risks of dronedarone may have been underestimated while its clinical benefits appear to be limited. The drug’s risk of causing or worsening heart failure and arrhythmias, and its interactions with other drugs frequently taken by heart patients raise doubts about its suitability for widespread use.

Botulinum Nerve Toxins (BOTOX, BOTOX COSMETIC, DYSPORT). Botulinum toxin products are approved for a number of conditions, including reduction of wrinkles on the forehead, treatment of cervical dystonia in adult patients, and a recently approved indication for the prophylactic treatment of chronic migraine headaches in adults. In the first quarter of 2010, we identified 6 reported deaths, 18 cases of disability, and 100 other reports of serious injury associated with botulinum toxin products—a markedly higher number of reports than in previous quarters. The adverse event reports were dominated by cases indicating that the nerve toxin was paralyzing muscles distant from the intended sites, causing difficulty swallowing, speaking, breathing, and incontinence. These adverse effects may continue for months. Among the reported cases, 64% involved Botox, 21% involved Botox Cosmetic, and 14% involved Dysport.

These reports raise questions about potentially misleading safety claims. The prescribing information for healthcare practitioners states: No definitive serious adverse event reports of distant spread of toxin effect associated with dermatologic use of Botox/Botox Cosmetic at the labeled dose of 20 units (for glabellar lines)...have been reported… The patient’s Medication Guide states: There has not been a confirmed serious case of spread toxin effect away from the injection site when…Botox Cosmetic has been used at the recommended dose to treat frown lines. These statements might lead doctors and patients to discount safety warnings, including an FDA-required boxed warning, about the spread of the toxin beyond the site of injection that appears elsewhere in the Medication Guide and prescribing information.

FDA should not allow blanket safety claims that no “confirmed” or “definitive” cases of spread of the toxin beyond the site of injection with botulinum toxins have been “reported.” Instead, the agency should require a summarization of the data from valid studies the agency has independently evaluated. In addition, the Medication Guide should be revised so it, too, does not downplay the risks associated with spread of the toxin beyond the site of injection.

Contamination from Wood Preservatives
TYLENOL brand products (acetaminophen and acetaminophen-combination products). FDA received 1,066 reports associated with product purity/quality problems for all drugs in the first quarter of 2010. Approximately 46% (492) of the reports involved OTC Tylenol brand products, primarily in tablet and capsule form. In January 2010, the manufacturer, McNeil Consumer Healthcare, initiated a large recall of Tylenol tablets and other OTC products after possible contamination with the fungicide, 2,4,6-tribromoanisole (TBA), was identified. The TBA source, which had contaminated the air in a manufacturing plant, was discovered on the wood pallets on which empty bottles had been delivered.

FDA reports based on earlier data suggested that no serious injuries had occurred from the contaminated tablets. Upon follow-up, the company told us that analyzed samples of the returned product showed that contaminant quantities were too small to cause human illness; the company instead believes the media surrounding the recall led consumers to blame the drug for gastrointestinal illnesses that were likely the result of other causes. Nevertheless, according to the reports we reviewed, hundreds of consumers believed the contaminated Tylenol made them ill. Reports included 172 cases of hospitalization, 28 deaths, 3 cases of disability, and 3 cases described as life threatening. Eleven of the 28 deaths involved patients who were older (75 to 91 years old) and may have had complicating illnesses. Eight other reported deaths contained very little detail, making it difficult to evaluate whether the contaminated Tylenol played a role in the fatal outcomes. The cause of the remaining 7 fatalities requires further investigation by FDA. Thus, a direct link between these reports of death and the contaminated Tylenol product could not be established or ruled out from these data alone. Unfortunately, just a few weeks ago, the company again announced the recall of Tylenol caplets after consumers reported becoming sick after ingesting the pills and/or smelling a moldy odor in the bottle.

Given such a large product recall, the unusual type of product contamination, and hundreds of adverse event reports claiming injury, we believe FDA should ensure that a complete and objective scientific investigation is conducted regarding the risk of harm from the contamination, including investigation into other explanations for the reported adverse events such as unusual sensitivity to the TBA contaminant and contamination in larger concentrations in some of the recalled tablets. Then, the results of such an investigation should be published.
The full QuarterWatch™ report can be viewed at:

Editor’s note: On October 30, 2010 Pfizer announced a recall of LIPITOR (atorvastatin) after receiving reports of a musty odor consistent with the presence of 2,4,6-tribromoanisole (TBA). This provides further evidence to substantiate the need for FDA to investigate potential harm from TBA, as suggested in the above paragraph.

1) Bronstein AC, Spyker DA, Cantilena LR, et al. 2008 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol. 2009; 47(10):911-1084.
2) Moreschi G, Freidlin V. Clinical Review NDA 21-913 Dronedarone hydrochloride. Silver Spring, MD: Food and Drug Administration; 2006.
3) Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.
4) Karkowsky A. Cross Discipline Team Leader Review Application Number: 22-425. Silver Spring, MD: Food and Drug Administration; 2009.
5) Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007;64(6):785-791.

6) Le Heuzey J, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21(6):597-605.
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