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ISMP
QuarterWatch™ Annual Report Issue
Trends and changes in 2015 that impact medication safety
June 30, 2016

ISMP’s QuarterWatch™ (see box below) provides an overview of drug safety issues reflected in adverse drug events reported to the US Food and Drug Administration (FDA) during 2015. Based on these data, along with outpatient prescription volume data from IMS Health, this annual report identifies both positive and negative changes in 2015 with significant implications for patient safety, including:

  • A dangerous health gamble with the rapid uptake of a new class of type 2 diabetes drugs, sodium-glucose cotransporter-2 (SGLT2) inhibitors
  • Nearly 3,000 deaths and 16,000 hemorrhages reported with oral anticoagulants
  • An overall drop in the use of HYDROcodone and acetaminophen, but growing use of oxyCODONE products
  • A decline in outpatient prescriptions for zolpidem, a drug with public health concerns related to nonadherence to safety recommendations
  • Rivaroxaban, adalimumab, fluoroquinolone antibiotics, and pioglitazone, as the drugs associated with the most reports in four monitoring categories—domestic serious events, direct manufacturer reports to FDA, persistent adverse effects, and legal claims, respectively   

 Reporting totals

In 2015, FDA received 1.2 million adverse drug event reports, including 94,220 deaths. This represents a 32.9% increase in total reports over the previous year and nearly five times the total received 10 years ago. Most of the increase between 2014 and 2015 (73.2%) occurred with non-serious reports and was largely the result of reporting system technology improvements. However, a 9.9% increase in reported serious injuries between 2014 and 2015, and a near doubling of reported serious injuries since 2010, provide an approximate measure of either increased reporting or the upward trend in harm caused by the growing use of prescription drugs.

Dangerous gamble with new SGLT2 inhibitors

A new class of oral diabetes drugs, SGLT2 inhibitors, has gained rapid acceptance into clinical practice, despite only short-term evidence about its effect on a biomarker, and uncertainty about long-term clinical benefits. QuarterWatch™ first reported safety concerns with INVOKANA (canagliflozin) in May 2015, when the first substantial group of adverse event reports became available. With still more adverse event data for 2015, we expanded our analysis in January 2016. Since then, we observed new signals as well as ample reporting indicating that multiple safety problems have emerged since approval of the three current SGLT2 inhibitors on the market, Invokana (canagliflozin), FARXIGA (dapagliflozin), and JARDIANCE (empagliflozin), as well as combination products that contain these medications, INVOKAMET (canagliflozin and metFORMIN), SYNJARDY (empagliflozin and metFORMIN), and XIGDUO XR (dapagliflozin and metFORMIN extended-release). By the end of 2015, the three single-entity drugs and the three metFORMIN combination products accounted for 2 million outpatient prescriptions, according to IMS Health, representing a nearly six-fold increase since early 2014. (One new combination, GLYXAMBI [empagliflozin and linagliptin] was not evaluated).

Adverse drug events and emerging clinical trial data provide growing evidence of the adverse events associated with SGLT2 inhibitors, as well as positive findings for empagliflozin in a cardiovascular trial in high-risk patients. Since May 2015, FDA has issued five drug safety communications about serious adverse events, including life-threatening ketoacidosis, severe electrolyte imbalances, acute kidney injury, possible increased risk of limb amputation, and higher risk of bone fracture, sepsis, urogenital infections, and urosepsis. The adverse event data support these communications and show that most adverse effects first reported with canagliflozin are also associated with dapagliflozin and empagliflozin. Table 1, for example, shows that ketoacidosis and infection cases for the three drugs are roughly similar in proportion to total reports for the drug and patient exposure. Furthermore, there are emerging signals for several other adverse effects, including pancreatitis (n=120) and hypersensitivity (n=877). We conclude that current data provide insufficient evidence that the benefits of SGLT2 inhibitor drugs outweigh their risks. The FDA should re-evaluate its decision to allow unrestricted long-term use of these of drugs.

Good news, bad news on opioid use

The White House, FDA, CDC, and Congress have proposed an array of new policies to prevent abuse, dependence, and overdose deaths with opioid drugs. The President proposed measures to increase treatment options for dependence. The CDC sought to change clinical practice with new, more restrictive guidelines for physician prescribing of opioids for chronic pain. The FDA announced an action plan that included promoting abuse-deterrent formulations, increased warnings, and improved access to naloxone. Currently, Congress is debating actions to improve opioid addiction treatment and how to pay for it. Some states have also taken steps in an attempt to curb opioid dependency.

Trends measured between early 2014 and the fourth quarter of 2015 confirm the positive news that, overall, opioid use, measured by dispensed outpatient prescriptions, has declined by about 8% over the 2 years. However, the decline was driven almost entirely by a drop in the leading mid-potency opioid, HYDROcodone and acetaminophen. Placing increased restrictions on prescribing of this drug product in 2014 had the effect of reducing dispensed outpatient prescriptions by 21%, or 6.6 million fewer prescriptions during the 2-year period. This is one of the largest known changes in drug utilization, affecting what once was the most widely prescribed therapeutic drug. However, the trend was not favorable for the higher potency oxyCODONE and the oxyCODONE with acetaminophen combinations. Over the same 8 calendar quarters, outpatient prescriptions dispensed for oxyCODONE increased by 10.9%, reaching 15.8 million. Unfortunately, current policy changes, or restrictions that may come in the future, fail to address the central medical dilemma: For moderate to severe pain, there are insufficient viable pharmaceutical alternatives without the safety problems of tolerance, withdrawal symptoms, dependence, abuse, and overdose.

Oral anticoagulant use and injuries increase

In 2015, FDA received 34,765 adverse drug event reports for oral anticoagulants, including 2,997 patient deaths and 9,523 adverse events severe enough to require hospitalization. The major problem reported was hemorrhage (n=16,222; 47%), with the most frequent bleeding sites being gastrointestinal (n=4,828), and the brain and central nervous system (n=3,711). These totals include foreign reports. The median age of patients in the reports was 73 years, with one-quarter of patients 81 years or older, underscoring that anticoagulants are among the highest risk outpatient drug treatments in older adults. The actual numbers of deaths and injuries associated with anticoagulant therapy are unknown, but thought to be 10 to 100 times higher than those reported. 

In 2015, important changes could also be seen in the utilization of oral anticoagulants, particularly with the newer, novel oral anticoagulants. There are now four novel oral anticoagulants on the market: PRADAXA (dabigatran, approved in 2010), XARELTO (rivaroxaban, approved in 2011), ELIQUIS (apixaban, approved in 2012), and SAVAYSA (edoxaban, approved in 2015). Dispensed prescriptions for novel oral anticoagulants rose 73.6% from early 2014 through the end of 2015, while warfarin use decreased by 10.9% during the same time period.

Novel oral anticoagulants were developed to be easier-to-use alternatives to warfarin, rather than for improved safety or efficacy. While warfarin requires biweekly testing when beginning therapy, and regular dose adjustments to keep inhibition of blood clotting within the optimal range, novel oral anticoagulants are prescribed in only one or two dose regimens, with no therapeutic monitoring required or generally available. However, the best that can be concluded from clinical trial data and post-market surveillance is that the novel oral anticoagulants are about the same as warfarin in terms of benefits and risks in most settings. The clinical trials comparing warfarin to the new agents had numerous flaws. For example, dabigatran clinical testing results were partially corrected after re-analysis revealed unreported cases of major bleeding and acute myocardial infarction. In a rivaroxaban trial, the warfarin comparison group was flawed because the point-of-care devices underestimated warfarin anticoagulation effects. The apixaban claim of a mortality benefit is not supported if excluding the results of a clinical site in China after an FDA inspection disclosed fabricated data. In an edoxaban trial, FDA reviewers were concerned with weak results in nonvalvular atrial fibrillation patients with normal renal function, resulting in a major limitation to avoid use in this large patient group. These problems raise questions about superiority claims for the newer agents. In fact, warfarin retains the advantage of widely available laboratory tests to assess and manage bleeding risks.

Zolpidem prescriptions decline

An estimated 1 in 4 adults has chronic sleep problems, and medication is frequently the therapeutic approach chosen. The most widely used sleep medication, zolpidem, has led to a public health concern because the majority of use does not adhere to the manufacturers’ and FDA safety recommendations. Our previous study showed that 68% of zolpidem patients used it over the long term rather than for a few weeks as recommended; another 22.3% combined zolpidem with opioids, increasing the risk of fatal depression of the central nervous system; a third group combined two drugs active on the same target receptors, also increasing the risk of overdose and next-day impairment. Only 5% of women and 10% of older persons were then taking the newly recommended lower dose of 5 mg (or 6.25 mg extended release). While it seemed a positive safety development to observe that dispensed outpatient prescriptions for zolpidem declined by 9.4% since early 2014, the use of this drug remains very substantial with 8.9 million dispensed outpatient prescriptions just in the last quarter of 2015. 

Leading drugs in four monitoring categories

For the 2015 annual report, QuarterWatch™ also examined the drugs accounting for the most reports of injury in four different safety monitoring categories.

Domestic, serious events. Xarelto (rivaroxaban) accounted for the largest number of reported cases of domestic, serious injury among the regularly monitored drugs, with a total of 10,674 reports, including 1,121 patient deaths and 4,508 injuries requiring hospitalization. The most frequent side effect with rivaroxaban was hemorrhage, accounting for 8,643 cases.

Direct reports to FDA. HUMIRA (adalimumab) was the leading suspect drug in reports submitted directly to the FDA, rather than through drug manufacturers. We regard direct reports as a key indicator of risks because these voluntary reports are not increased due to manufacturers’ contacting consumers and subsequently learning about adverse drug effects. In 2015, adalimumab accounted for 1,581 direct reports to the FDA, but overall, the drug accounted for a total of 7,300 domestic serious reports, 34,035 non-serious reports, and 8,592 foreign reports. Notable were reports of infection and injection site reactions.

Persistent adverse effects. Fluoroquinolone antibiotics accounted for the largest number of reports of persistent adverse effects (n=855) that became long-term health issues. The total included 489 (57.2%) reports for levoFLOXacin and 366 (42.8%) for ciprofloxacin. The persistent adverse effects described most often were painful joint, muscle, and tendon disorders. In 65% of the cases the person affected was reported to be disabled by the event. Ciprofloxacin and levoFLOXacin are the two most widely used fluoroquinolones, accounting for 5.9 million and 3.5 million outpatient prescriptions, respectively, in the last quarter of 2015. These data suggest that persistent injuries from fluoroquinolones could be much larger than indicated by these case totals (see Sidebar below).

Legal claims. ACTOS (pioglitazone) was the most frequent suspect drug in cases explicitly identified as legal cases, accounting for 3,041 reports. Drug problems that spur thousands of legal claims often signal a notable safety issue, although observing a large number of legal claims does not prove the drug was responsible. For pioglitazone the issue was bladder cancer. After five of the first eight cases tried in federal court resulted in verdicts against the company, Takeda Pharmaceuticals, the manufacturer, settled the remaining 9,000 cases for $2.4 billion. Pioglitazone illustrates the significant challenges inherent in assessing cancer risks. An unfavorable signal in lifetime animal studies raises questions whether the findings are applicable to humans, and clinical trials are typically too short to provide an adequate period of surveillance. The latest company-sponsored epidemiological study claimed to see no association of the drug with bladder cancer.

The full report with references can be found at: www.ismp.org/sc?id=1702.

 

What is QuarterWatch™?

QuarterWatch™ is an independent ISMP surveillance program that monitors adverse drug events reported to FDA by manufacturers, health professionals, and the public. The agency releases excerpts of all reports it receives into its adverse event reporting system (FAERS) for research and data analysis. The goal is to identify signals that may represent important drug safety issues. The term signal means evidence judged to be substantial enough to warrant publication but which requires further investigation to determine its frequency and establish a causal relationship to the suspect drug.

 

Sidebar: More on harm from fluoroquinolones

ISMP’s QuarterWatch™ report notes that fluoroquinolone antibiotics accounted for the largest number of reports of persistent, long-term adverse effects. Last month, the US Food and Drug Administration (FDA) published a drug safety communication stating that fluoroquinolones used systemically (i.e., tablets, capsules, injectable) are associated with disabling and potentially permanent serious side effects that can occur together (www.ismp.org/sc?id=1755). These adverse effects can involve the tendons, muscles, joints, nerves, and also the central nervous system, and again, they can be permanent! FDA further stated that these adverse effects generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options. Fluoroquinolones in patients with these conditions should be reserved for those without alternative treatment options. At greater risk are patients with organ transplants, renal impairment, recent exposure to topical or systemic corticosteroid therapy, and the elderly (Bidell MR, Lodise TP. Fluoroquinolone-associated tendinopathy: does levofloxacin pose the greatest risk? Pharmacotherapy. 2016;36 (6):679-93). Therapy should be stopped if a patient reports serious side effects, and the patient should be switched to a non-fluoroquinolone antibacterial drug to complete the treatment course. Safe and judicious use of fluoroquinolones should be part of every hospital’s antibiotic stewardship program.

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