QuarterWatch monitors domestic, serious adverse drug events reported to the FDA. We identify trends in drug safety, report signals for specific drugs, and seek to improve the system.

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January 2015
Perspectives in This Issue
A Critique of a Key Drug Safety Reporting System 

QuarterWatch 2014 Q1 The U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS)—based on MedWatch reports–is the government’s primary safety surveillance system designed to identify harms from therapeutic drugs. For the last six years these vital data have formed the core of ISMP’s QuarterWatch™ drug safety reports. In this issue we decided to look closely at the system itself. Our conclusion: it seems clear that this drug safety monitoring system is in need of modernization. It suffers from a flood of low quality reports from drug manufacturers and has not yet been updated for the changing environment in which drugs are marketed to health professionals and consumers. We discuss key problems below and offer some recommendations as an organization that relies heavily on data collected through FAERS.

This issue of QuarterWatch includes two recently released calendar quarters of FAERS data, from 2013 Q4, and 2014 Q1. To provide a broader perspective, the main analysis focuses on the 12 months ending with 2014 Q1, and includes all adverse event reports received by the FDA in that one-year period. Previous issues of QuarterWatch have focused on a subset of these case reports, those with a serious outcome and reported by patients in the United States.

Key Findings

  • Incomplete Manufacturer Reports
  • Was the Drug Responsible?
  • Gaps in System Coverage
  • Outdated FDA Regulations
  • Strengths of the System

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September 2014
Perspectives in This Issue
Dimethyl fumarate (TECFIDERA): tolerability problems with a new multiple sclerosis drug
Varenicline (CHANTIX): reports of suicidal/homicidal thoughts surpass all other drugs
Sodium oxybate (XYREM): a restricted drug with severe side effects
Fingolimod (GILENYA): cardiac, vision, and pregnancy risks

QuarterWatch 2013 Quarters 3-4  In this issue we analyze severe gastrointestinal toxicity and hypersensitivity reactions reported for the new oral drug for multiple sclerosis (MS), dimethyl fumarate (TECFIDERA). The risks of serious psychiatric side effects are highlighted in a new analysis of varenicline (CHANTIX), an aid to smoking cessation. We also examine the frequent and broad spectrum of serious adverse effects on the brain of sodium oxybate (XYREM), an orphan drug for narcolepsy. Cardiac, ocular, infection, and pregnancy risks are reviewed for a second newer MS drug, fingolimod (GILENYA).

Because the FDA has corrected its previously delayed quarterly releases of serious adverse event reports, this issue of QuarterWatch includes data from two calendar quarters of 2013, Q2 and Q3. Totals from the two quarters reveal that after many years of a steady increase in reported fatal, disabling and serious adverse drug events, reports have hit a plateau in 2013. The Q3 total of 47,864 was almost unchanged (+108) from the preceding quarter Q2, and was 8.7% lower than Q3 of the preceding year.

An Evolving Adverse Event World

This report focuses on three drugs (dimethyl fumarate, sodium oxybate, fingolimod) that share several characteristics with substantial effects on the total number of adverse event reports submitted. All three are expensive medications (more than $50,000 per patient-year) for small patient populations (10,000-25,000 patient-years). The high costs and small patient populations lead to marketing and safety surveillance plans that place the manufacturer in contact with every new patient. In the case of sodium oxybate, the central pharmacy calls every patient every month before shipping a refill. For all three drugs, manufacturers have extensive contact with practically all patients as treatment is initiated to assist in navigating insurance coverage for these high-cost specialty drugs. This leads to a different adverse event reporting environment compared with traditional brand name drugs where patient contacts by the manufacturer are limited, but contacts with physicians are more extensive. Nevertheless, the exact same reporting regulations apply to both quite different settings.

These high-patient-contact settings provide a new opportunity to achieve unprecedented and high-quality postmarket surveillance. It would be especially valuable for orphan drugs with clinical trials for efficacy in patient populations of just 100-200 subjects on the active drugs. Given that patient contact is already occurring for commercial and safety reasons, additional costs would be minimal. But to achieve these benefits, the FDA, manufacturers and stakeholders need to develop regulations, guidances and contact protocols to cover a steadily growing number of drugs.

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May 2014
perspective on drug hypersensitivity
Allergic reactions second most frequently reported serious event
Hypersensitivity signals for omalizumab (XOLAIR) and telaprevir (INCIVEK)
Update on anticoagulants, rivaroxaban (XARELTO) and dabigatran (PRADAXA)

QuarterWatch 2013 Q1 This issue focuses on serious hypersensitivity reactions reported to the US Food and Drug Administration (FDA) for therapeutic drugs using data from the most recent 12 months available. It also surveys the newly released case reports for 2013, Quarter 1, and provides an update on the continuing drug safety issues surrounding anticoagulant drugs.

The FDA received 56,165 domestic reports of serious adverse drug events in the calendar quarter ending March 30, 2013. This was an apparent drop of 685 cases (-1.2%) from the previous quarter and a decline of 5,305 reports (-8.6%) from the same quarter in 2012. The total included 12,899 patient deaths and 2,653 cases indicating a possible medication error. The apparent decline is likely exaggerated. Historical records show the new quarter totals are artificially low since the agency typically releases additional reports for the quarter at a later date.
Hypersensitivity Highlights

Cases of reported drug hypersensitivity (mostly drug allergies) were identified using a standardized set of medical terms created by the pharmaceutical industry to classify possible cases of adverse drug events occurring in clinical trials or identified through postmarket surveillance. To identify suspect drugs, we screened 147,318 selected cases of serious adverse drug events from March 2012 through March 2013.

  • Hypersensitivity was very common, accounting for 13,042 cases (8.9%), and more than any other among 91 adverse reaction categories except non-specific gastrointestinal symptoms. We classified 4,045 of these cases as severe, involving death, disability, or a medical emergency.
  • A large and diverse selection of drugs was implicated, with 234 drugs having 10 or more hypersensitivity reports in one year. However, only 87 drugs fell into the subset of the 4,045 most severe cases.
  • A sample of prescribing information for health professionals for 20 drugs with 10 or more reported cases of severe hypersensitivity showed all 20 provided information about these reactions, and 14/20 (70%) had prominent warnings.
  • To highlight drugs with the most frequently reported severe hypersensitivity reactions, cases were divided into four categories: anaphylactic shock, a rapid onset systemic immune reaction; severe cutaneous, widespread skin eruptions that can be life-threatening; angioedema, a localized swelling of lips, tongue, eyelids, or other body parts; and other severe forms of hypersensitivity. The 10 most frequently reported drugs in each category are identified in the report, constituting useful clinical alert lists


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January 2014
Psychiatric side effects prominent in 10 of 15 most frequently reported drugs
Ibuprofen associated with severe hypersensitivity
Few reports for antibiotics and albuterol

QuarterWatch 2014  This report analyzes15 drugs that accounted for 41% of recent serious adverse events in children reported to the U.S. Food and Drug Administration (FDA) over the five years 2008-2012. In addition, we examine reporting trends from the same period for all domestic reports to the agency that identified adverse events in children under age 18.


Our study identified 45,610 adverse drug events reported in children less than 18 years of age. Of these, 64% (29,298) indicated a serious injury. Reports in children grew substantially over time--from 6,320 in 2008 to 11,401 in 2012, increasing at the same rate as for adult patients. Examined by year of age in children, the reports formed a U-shaped curve. The number was greatest in the first year of life, then declined and leveled off until adolescence, when cases again rose rapidly. There were insufficient data to evaluate 70% of the 741 drugs with reported serious adverse events in children because of fewer than 2 reports per year.

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October 2013
Leading Drug Safety Issues of 2012
Anticoagulants leading drug safety problem reported directly to FDA
Three anti-TNF agents dominate manufacturer reports of new, serious injuries
Fentanyl patches (DURAGESIC) prominent in product problems and medication errors Lower limb fractures when taking alendronate (FOSAMAX) a major reported adverse event

QuarterWatch 2012 Quarter 4  In this report we examine the leading drug safety problems reported to the US Food and Drug Administration (FDA) for the calendar year 2012. Our ranking of the year’s major issues in drug safety comes from four different perspectives on tens of thousands of serious and fatal adverse drug events.

  1. Reports that consumers and health professionals submitted directly to the FDA identified two anticoagulants, dabigatran (PRADAXA) and warfarin (COUMADIN), as the most frequent suspect drugs for the year.
  2. Cases from drug manufacturers about new, serious adverse events without adequate current warnings in the prescribing information flagged three anti-tumor necrosis factor (anti-TNF) products, etanercept (ENBREL), adalimumab (HUMIRA), and infliximab (REMICADE).
  3. The potent synthetic opioid fentanyl (DURAGESIC) in patch form was prominent in two different kinds of drug safety issues, product quality complaints and reported medication errors.
  4. Lower limb fractures and other bone disorders associated with alendronate (FOSAMAX) for osteoporosis were key results from our statistical tests to link suspect drugs with specific side effects.

In 2012, the FDA received a total of 210,648 domestic reports of serious, disabling, or fatal adverse events associated with therapeutic drugs, an increase of 16% from the previous year. Reports that consumers and health professionals made directly to the FDA declined from 21,000 to 20,310 (-3.3%) while reports originated by manufacturers increased by 18.5%, from 160,598 to 190,338

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April 2013
Varying signals for pancreatitis, hypersensitivity, and cancer

Three oral versus two injectable agents compared

Link to human and animal studies of the pancreas

QuarterWatch 2012 Quarter 3 This issue focuses on five widely used drug treatments for Type 2 diabetes, exenatide (BYETTA), liraglutide (VICTOZA), sitagliptin (JANUVIA), saxagliptin (ONGLYZA), and linagliptin (TRADJENTA). These drugs are known as glucagon-like peptide-1 (GLP-1) agents because they mimic or increase the availability of GLP-1 in regulating blood sugar levels. Given emerging safety concerns about this increasingly prescribed class of drugs, we examined their safety profiles over 12 months of adverse drug event data.

The U.S. Food and Drug Administration (FDA) is changing the internal computer system that manages its adverse event report database, now called FAERS (FDA Adverse Event Reporting System). The agency released for public use reports from a partial quarter extending from July 1, 2012, through August 27, 2012. The partial-quarter data totaled 136,225 reports of all kinds, including 29,186 domestic, fatal, disabling, or serious events meeting the QuarterWatch criteria. Adjusted for partial reporting, it appears a full quarter total will be similar to recent previous quarters. Because examining a partial quarter of data has significant limitations, this issue will rely on the 12 months ending June 30, 2012.

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January 2013
Perspectives in This Issue
Finasteride (PROPECIA, PROSCAR) and possibly persistent sexual side effects
Methylphenidate patch (DAYTRANA) and product problems
Update on anticoagulants dabigatran (PRADAXA) and rivaroxaban (XARELTO)

QuarterWatch 2012 Quarter 2 In this report we analyze a signal for persistent sexual side effects reported by men who have taken finasteride (PROPECIA) for male pattern baldness or for an enlarged prostate (PROSCAR). We also review product problems with the DAYTRANA methylphenidate patch used in young children to treat ADHD. In addition, we update our coverage of anticoagulant drugs with new perspectives on adverse events reported for dabigatran (PRADAXA) and rivaroxaban (XARELTO).

In the newly released quarterly data, we examined 50,289 reports of fatal, disabling, or other serious injury received by the U.S. Food and Drug Administration for events in the United States during the second quarter of 2012. The total represented a 17.7% decline from the previous quarter, but an increase of 13.1% compared to the second quarter of the previous year. We investigated the substantial quarter-to-quarter decline and found it was primarily the result of a regulation that permits companies marketing older drugs to submit many of its adverse event reports on an annual basis. Comparing totals to the same quarter one year previously adjusts for this anomaly, making the 13.1% growth a better indicator of reporting trends. Additional details appear in the full report.

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October 2012
Why Reports of Serious Adverse Drug Events Continue to Grow
QuarterWatch 2012 Quarter 1  The last four years have seen a 90% increase in the number of serious adverse drug event reports received by the Food and Drug Administration (FDA). Investigating the reasons for the four-year trend, we concluded that they could be divided into three groups. Reports for new drugs not widely used in 2008 accounted for 23% of the growth; increasing reports for drugs seen in all four years accounted for 40%. The substantial remainder (37%) was due to special circumstances involving a few suspect drugs that resulted in greatly increased numbers of reports. We examine the reasons for the increase in detail in the full report.

In this report we also analyze signals for duloxetine (CYMBALTA) and serious withdrawal symptoms; pioglitazone (ACTOS) and reported bladder cancer; aliskiren (TEKTURNA) and angioedema, and rivaroxaban (XARELTO) and thromboembolic events.

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May 2012
Anticoagulants the Leading Reported Drug Risk in 2011

QuarterWatch 2011 Quarters 3-4  For the calendar year of 2011 an estimated 2 to 4 million persons suffered serious, disabling, or fatal injury associated with prescription drug therapy, based on our analysis of a full year of reports to the U.S. Food and Drug Administration. The most frequently identified suspect drugs in direct reports to the FDA were the anticoagulants dabigatran (PRADAXA) and warfarin (COUMADIN), showing that inhibiting clotting ranks among the highest risk of all drug treatments. In addition, we identified nine other drugs associated most frequently with five clinically relevant, drug-related injuries, and show the drugs most frequently the target of lawsuits.

In 2011 the FDA received 179,855 reports of serious, disabling, and fatal adverse drug events in the United States. This was an increase of 15,386 cases, or 9.4% from 2010. We made a minor technical change in our selection criteria that increased the quarterly totals of serious adverse drug event reports, but all historical comparisons use recalculated data. In the same period an estimated 48% of the population was taking a prescription drug in any given month, and an estimated 3.6 billion outpatient prescriptions were dispensed, according to data from IMS Health, a total unchanged from 2010.

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April 2012
Signals for Fingolimod (GILENYA) and Infliximab (REMICADE)

QuarterWatch 2011 Quarter 2  In this issue we analyze signals for severe side effects associated with two different but important drugs that suppress elements of the human immune system, fingolimod (GILENYA) for multiple sclerosis, and infliximab (REMICADE) for ulcerative colitis, rheumatoid arthritis, and other autoimmune disorders. We also update our findings for dabigatran (PRADAXA) and metoclopramide (REGLAN). 

In the second quarter of 2011 the Food and Drug Administration (FDA) received 40,222 reports of domestic, serious adverse events, including reports of 6,617 patient deaths. The total was similar to the previous quarter (an increase of just 32 cases) and 20% higher than the same quarter in the previous year. The trend continued of increasing numbers of reports from drug manufacturers, with a more rapid increase in reports from consumers, compared with health professionals. In the same period, IMS Health data showed that total dispensed outpatient prescriptions totaled 911 million, a decline of 2.8% from the previous quarter, and an increase of 0.8% from the same quarter of 2010.

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