QuarterWatch™ is an ISMP surveillance program that monitors all serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by drug manufacturers and by the public through its MedWatch reporting program. The goal of QuarterWatch™ is to improve patient safety through the identification of signals that may represent important drug safety issues. The term signal means evidence we judge to be substantial enough to warrant publication but which usually requires further investigation to determine its frequency of occurrence and establish a causal relationship to the suspect drug. The latest QuarterWatch™ combines data from the four quarters of 2011 to examine annual reporting totals, trends, and ADE signals.
Annual reporting totals and trends
In 2011, FDA received 179,855 reports of serious, disabling, or fatal ADEs that identified a therapeutic drug as a primary suspect. This was an increase of 15,386 cases (9.4%) from the 2010 total. Reports reached FDA through two mechanisms:
- Spontaneous and voluntary ADE reports from health professionals and consumers submitted to the FDA MedWatch program (21,002), which are referred to as direct reports
- Reports from manufacturers, including expedited reports of serious ADEs for which adequate warnings do not exist, and periodic reports of events for which warnings already exist (158,853).
The growth in reported ADEs is primarily due to increases in expedited reports from manufacturers, driven in large part by marketing activities for newer brand name drugs that cause the industry to learn of more adverse events. However, direct reports from health professionals and consumers, who are concerned enough to report the observed ADE to FDA, provide important insights not available elsewhere. Although these reports can only provide clues to how frequently the ADE is occurring, in a field with a limited research base, health professional and consumer reports remain one of the best resources available to assess drug safety risks.
In a consensus view (supported by limited research), less than 1% of all serious ADEs are reported directly to FDA.1 With 21,002 direct reports submitted to MedWatch in 2011, we estimate that more than 2 million serious injuries, which includes 128,000 patient deaths, occurred in 2011. Including manufacturers’ reports produces a midpoint estimate (if 5% of all ADEs are reported) of 3.6 million serious and fatal injuries, with a range of 1.8 million (10% reporting) to 18 million (1% reporting). Taken together, these data result in a conservative estimate of 2 to 4 million drug-induced serious injuries in 2011. While these estimates are large, the definition of a serious ADE includes events that might not result in hospitalization such as accidents, suicide, depression, hyperglycemia, dyskinesia, or angioedema. Most estimates in the range of 1 to 2 million found in literature are based on hospitalization rates.2-3
Most frequent suspect drugs
The 10 drugs with the largest numbers of direct reports to FDA in 2011 are shown in Table 1 (on page 1 in the PDF version). These are the medications that health professionals and consumers told the FDA were causing serious and fatal side effects during 2011. For reference, the number of manufacturer reports is also shown. The year of approval shows that major drug safety issues are hardly confined to recently approved drugs. Just two of these drugs were approved in the last decade, and only one in the previous year.
ADEs with anticoagulant drugs
Dabigatran and warfarin ranked first and second among all direct reports submitted to FDA in 2011. Both were also prominent in the overall totals that include drug manufacturer reports. Dabigatran surpassed all other regularly monitored drugs in several categories, including overall number of reports (3,781, including manufacturer and direct reports), deaths (542), hemorrhage (2,367), acute renal failure (291), and stroke (644). It was also suspect in 15 cases of liver failure. Warfarin has been prominent in the rankings of direct reports to the FDA for many years. It accounted for 1,106 reported ADEs overall, including 731 reports of hemorrhage and 72 deaths.
Although in the overall count, dabigatran ADEs outnumbered warfarin ADEs (3,781 vs. 1,106), these data alone are insufficient to conclude that dabigatran has a higher risk of bleeding than warfarin. In a large comparative trial, rates of major and minor bleeding were similar for the two drugs, although gastrointestinal hemorrhages were more frequent with dabigatran.4 What is clear, however, is that FDA is receiving a strong signal about this risk. Approximately 79% of dabigatran direct reports come from health professionals (21% from consumers) suggesting that, despite a well-known risk of hemorrhage, the bleeding was unexpected or unusually severe.
Excessive bleeding in older patients, especially those with declining renal function, led to a manufacturer’s recommendation in January 2012 to “assess renal function during therapy as clinically indicated and adjust therapy accordingly.” However, the official prescribing information still only recommends a dose adjustment from 150 mg twice daily to 75 mg twice daily in patients with a creatinine clearance (CrCl) of 15-30 mL/minute. We believe FDA, the medical community, and the manufacturer need to reassess the dose recommendations for dabigatran. Among the possibilities warranting study are making the 110 mg dose (used outside the US) available for older patients, requiring more specific monitoring of kidney function and anticoagulation effect, and identifying patient subgroups where safer alternatives may provide adequate stroke prevention.
Severe side effects and suspect drugs
In the annual data we identified nine suspect drugs most frequently associated with five severe side effects (Table 2 on page 3 in the PDF version) resulting in an estimated 179,000 cases of injury based on an assumption of a 5% reporting rate.
Severe liver injury. The liver has the capacity to recover from moderate injury, a problem reported with many drugs; a few drugs can overwhelm the liver, leading to severe liver injury or liver failure. In 2011, inFLIXimab accounted for 159 reported cases of severe liver injury, and acetaminophen, 139 cases.
Severe cutaneous reactions. When the immune system reacts to a drug, severe skin reactions may occur. In serious cases, this can involve exfoliation of large areas of skin and intensely painful, life-threatening conditions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. In 2011, the two drugs accounting for the most reported cases of severe cutaneous reactions were lamoTRIgine (119) and varenicline (93).
Suicidal/homicidal thoughts. Reports of suicide or attempted suicide may identify a drug that was a means of self injury—an intentional overdose—without the drug itself contributing to the suicidal behavior. For this reason, we monitored drugs reported to be causing thoughts of injury to self or others. The most frequently identified drug in 2011, with 197 reported cases, was QUEtiapine, a drug developed for psychosis but now used for a wide variety of conditions including depression and off label as a sleep aid. Ranked second was varenicline (187 cases).
Pancreatitis. The pancreas can become inflamed in the presence of some drugs. In extreme cases, pancreatic tissue is lost. As newer glucagon-like peptide-1 (GLP-1) agents used to treat Type 2 diabetes spread into wider use, so did reports of acute and chronic pancreatitis. Liraglutide was the most frequent suspect with 413 reported cases, and exenatide ranked second with 404 cases. These two drugs alone accounted for 43% of all reported cases of pancreatitis.
Rhabdomyolysis. The release of large amounts of myoglobin from damaged skeletal muscle cells can lead to renal failure. Awareness has grown that the risk of muscle damage caused by HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitors has been underestimated. In 2011, 516 cases of drug-related rhabdomyolysis were reported. Ranked first with 123 cases was simvastatin; rosuvastatin ranked second with 73 cases.
Among the nine drugs resulting in severe side effects (Table 2 in the PDF version), most carry some form of FDA-approved warnings, often prominent ones. On one hand, this shows that FDA and manufacturer safety surveillance programs have identified these significant safety risks. On the other, it illustrates that placing warnings in product information only begins the process of managing the risks. Numerous tools are available to address these risks. For example, given there are many alternative anticonvulsants, FDA may consider restricting lamoTRIgine to second-line use. We have previously concluded that the smoking cessation drug varenicline, with psychiatric, cardiovascular, and accident risks, is unsuitable for first line use. In other cases, comparative studies are needed to document the safest agents and more clearly identify high-risk groups. For HMG-CoA reductase inhibitors, the emerging information about rhabdomyolysis and diabetes provide an example of a drug class deserving priority attention to identify the optimal dosages, target populations for treatment, and safest drugs within this class of medications.
As QuarterWatch™ concludes its fourth year of publication, we note that the suspect drugs identified in this annual report include some of the most widely used and valuable prescription drugs now available. But, the substantial health benefits achieved only increase the need to do a better job managing their risks.
The full QuarterWatch™ report can be viewed at: www.ismp.org/QuarterWatch.
1) Ahmad SR, Goetsch RA, Marks NS. Spontaneous reporting in the United States. In: Strom BL, ed. Pharmacoepidemiology, 4th ed. New York: John Wiley & Sons; 2005:135-159.
2) Einarson TR. Drug-related hospital admissions. Ann Pharmacother. 1993;27:832–840.
3) Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–1205.
4) Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.