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ISMP QuarterWatchT Report (2010 Quarter 2) Adverse drug event signals warrant action

From the January 27, 2011 issue

QuarterWatch™ is an ISMP program that monitors all serious, disabling and fatal adverse drug events (ADEs) in the US reported to the FDA by drug manufacturers and through its MedWatch reporting program. The primary goal of the program is to improve patient safety through the identification of signals that may represent serious safety issues with medications. The term signal means evidence of sufficient weight to:-----Warrant additional investigation to establish a causal relationship between the safety issue and the drug, and determine its incidence -----Justify an alert to the public and scientific community.
Reporting totals and trends
For the second quarter (Q2) of 2010, we analyzed computer excerpts from 33,068 reports. Overall, the steady increase in reports continued, up 12% compared to the same quarter (Q2) in 2009. While reports to FDA from manufacturers increased by 24%, reports directly to FDA from consumers and health professionals were 25% fewer than the same quarter in 2009, and a downward trend has now extended across the last four quarters (Q3 and Q4 in 2009, and Q1 and Q2 in 2010).
Limited physician reporting. Despite more than 800,000 active physicians in the United States, FDA received only 425 reports of serious adverse events directly from physicians in Q2 2010. Physicians were much more likely to report adverse events through drug company channels, which accounted for 28% of all the expedited reports submitted to FDA from drug manufacturers. Physician reports to drug manufacturers make a valuable contribution to drug safety, as the manufacturers, in turn, report the events to FDA. However, the physician is clearly in a better position to describe how the drug affected the patient and to provide important clinical details about the patient’s condition to FDA than drug company staff. Given the new era of information systems, it should be possible to make physician reporting simple, accurate, and timely.
Frequent adverse drug events

Table 1 provides five specific drug safety issues that were reported frequently in numbers disproportionate to all reported events for each drug, making them unlikely to have occurred by chance. In the table, the Proportional Reporting Ratio (PRR) measures the extent to which the reports of the adverse event for that drug exceed what might be expected through chance and background noise.1,2
FentaNYL (DURAGESIC) maladministrations. Maladministrations with fentaNYL patches were one of the most frequently reported (447 cases) drug safety issues in Q2 2010. These problems were reported 12.6 times more frequently than expected, given the total number of reports for the drug. For comparison, only 10 reports were received indicating maladministration of nicotine products—also widely used in patch form. Specific problems included adherence issues in which the patch fell off, improper placement on the body which affected drug absorption, and application at the wrong time. With a potent opioid, these problems can lead to potentially lethal overdoses or opioid withdrawal symptoms.
QUEtiapine (SEROQUEL)and diabetes. Reports identifying QUEtiapine as suspect in inducing diabetes greatly outnumber reports for all other newer antipsychotic drugs that also carry a warning about diabetes risk. While QUEtiapine is one of the most widely used drugs in its class, reports regarding diabetes were received 16.5 times more often than expected, given the total number of reports for the drug. Glucose monitoring is recommended for patients who take this and other drugs in this class.
InFLIXimab (REMICADE)and skin cancer. A cluster of 154 new reports of non-melanoma skin cancers were reported with this drug. Many drugs that immobilize important components of the immune system carry an increased risk of infection and certain cancers. This new cluster of reports, approximately 101.3 times more than expected, suggests the possibility of a broader cancer risk and a need to monitor patients’ skin carefully.
Alendronate (FOSAMAX) and lower limb fractures. In March 2010, scattered reports began to appear suggesting a new safety issue for alendronate and other bisphosphonate drugs used to treat osteoporosis. The new reports suggested that while bone density was preserved, bones might become more brittle over time and fracture easily—notably at the hip and femur. From April to June 2010 (Q2 2010), FDA received 126 reports of lower limb fractures associated with alendronate—50.4 times more frequently than expected given all reports for this drug—together with additional but fewer reports for other bisphosphonate drugs. Merck believes the increase in reports may be due in part to media attention to the issue. In October 2010, FDA announced it was going to require a warning ( regarding the possibility of atypical fractures for all bisphosphonates used to treat osteoporosis; however, label changes had yet to be implemented by January 2011. A Medication Guide will also be required to be given to patients when they pick up their prescription.
Exenatide (BYETTA) and pancreas inflammation. In 2007, FDA issued a public health alert about 30 reported cases of an inflamed pancreas associated with exenatide, urging discontinuation of the drug if the problem occurred. FDA updated this warning in August 2008, identifying six more cases of hemorrhagic or necrotizing pancreatitis, leading to two patient deaths. In Q2 2010, we identified 118 new reported cases of this medical disorder, reported 32.5 times more frequently than expected. Eli Lilly and Amylin Pharmaceuticals told us they observed an increase in the cases reported following the two FDA alerts ( We also identified the signal for a second serious adverse effect: 31 cases of renal failure or impairment, also the subject of a previous FDA public health alert in November 2009 ( We believe these signals are of sufficient concern to require a more systematic study on the incidence of this drug’s adverse effects on the pancreas and kidneys.
Other adverse drug event signals
Varenicline (CHANTIX) update. Despite a prominent boxed warning, a mandatory Medication Guide for every patient, and declining use, the smoking-cessation drug varenicline continued to account for a large number of reported serious psychiatric side effects. In Q2 2010, reports were received for 130 possible cases of clinical depression, 112 cases of hostility-aggression, and 70 cases of psychosis or losing touch with reality. The drug was suspect in more possible cases of hostility-aggression, depression, and psychosis than any other monitored drug.  FDA has deployed most of its regulatory tools short of product withdrawal—issuing two public health advisories, requiring a Risk Evaluation and Mitigation Strategy (REMS), which includes a patient Medication Guide, and requiring boxed warnings. We have seen possible improvement for one psychiatric side effect—suicidal and self-injurious behavior. The 45 possible cases of suicidal behaviors were fewer than other categories of harm and did not outnumber all other monitored drugs. This may reflect some benefit of the FDA warnings, which focused primarily on this adverse effect. Nevertheless, a large volume of serious adverse event reports for varenicline continues despite a decline in dispensed prescriptions. Thus, a major reassessment of this drug is needed. 
Levofloxacin (LEVAQUIN) and muscle, ligament, and tendon injuries. Levofloxacin was suspect in more reports (246) of serious injury than any other antibiotic. Most cases involved tendon rupture and other muscle, tendon, and ligament injuries. Case reports of this problem substantially outnumbered those for two chemically similar drugs—ciprofloxacin and moxifloxacin. These data raise the question of why tendon disorders and joint problems are reported more frequently for levofloxacin, particularly since moxifloxacin (1.5 million prescriptions/Q2) is dispensed almost as often as levofloxacin (2.1 million prescriptions/Q2), and ciprofloxacin (5.3 million prescriptions/Q2) has a much higher dispensing volume than levofloxacin (2.1 million prescriptions/Q2). While the FDA requires identically worded warnings about this risk in the labeling for all three of these drugs, no information is provided about how frequently such events might occur. Studies are required to further document whether one or more of the fluoroquinolones has significant safety advantages or higher risks.
Dronedarone (MULTAQ)update. Safety concerns continued for this relatively new antiarrhythmic. For Q2 2010, we identified 134 reported cases of serious injury, including new or worsened heart failure, potentially lethal arrhythmias, and renal impairment and failure. In mid-January 2011, sanofi-aventis notified physicians and regulatory agencies of a new serious reported side effect: severe and potentially life-threatening injury to the liver, including two cases requiring liver transplant. Additional evidence of serious injuries was associated with medication errors. Since approval of the drug, we identified 39 cases (including 4 deaths) in which patients received another antiarrhythmic in addition to dronedarone, a practice explicitly contraindicated, 12 cases of drug interactions, and 15 reports of dosing or administration errors. 

Johnson & Johnson OTC recalls. More than a year after Johnson & Johnson’s McNeil Consumer Healthcare began a long series of drug recalls of its over-the-counter (OTC) products, reports of serious injuries associated with the recalls continued to dominate all new case reports of product problems. Cases from Q2 2010 primarily involved McNeil ibuprofen and acetaminophen products for infants and children that were recalled starting in May 2010. Evidence available was insufficient either to establish or rule out a direct connection between more than 700 reported injuries and any identifiable form of product contamination or other defect. The full QuarterWatch™ report can be viewed at: 1) Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10(6):483-486.2) Moore TJ, Glenmullen J, Furberg CD. Prescription drugs associated with reports of violence towards others. PLoS ONE. 2010;5(12):e15337.
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