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QuarterWatch™ (includes new data from Quarter 2, 2019) Methotrexate Errors, Trends Among Addictive Drugs, and Underreporting of Serious Events

The latest issue of ISMP’s QuarterWatch™ describes findings that focus on:

  • Confusion about daily-vs-weekly doses of oral methotrexate that has led to patient harm and death

  • Growth in adult use of prescribed amphetamine-like stimulants while exposure declines for use of therapeutic opioids

  • Underreporting of serious adverse drug events to the US Food and Drug Administration (FDA)

The following is a summary of the full QuarterWatch™ report, which can be found with references by clicking here. A description of QuarterWatch™ is also provided.

Preventable Oral Methotrexate Errors

Methotrexate is a high-alert medication with a narrow therapeutic index and an exceptionally wide range of doses and duration of treatment. It has a Boxed Warning listing 11 different risks, all serious and many fatal. Examples include bone marrow suppression, renal impairment, hepatotoxicity, tumor lysis syndrome, opportunistic infections, and severe toxic reactions. It was first approved in 1953 to treat advanced cancers. However, oral use has grown rapidly, primarily as a treatment for rheumatoid arthritis and psoriasis. From 2013 to 2017, we estimate that the number of people exposed to methotrexate nearly doubled, from 561,000 to 1 million patients.

For non-oncologic uses, it is essential that methotrexate be taken only on a weekly basis rather than daily. The consequences of daily administration are dire. Even 1 week of daily administration can result in many painful and severe adverse effects, including death. There are few oral medication errors with more immediate and severe consequences.

We analyzed 14 reported cases of mistaken daily administration of methotrexate reported to FDA in the 18 months ending with June 30, 2019. All occurred in patients age 65 years or older. In 5 cases, the patients died; the other 9 patients required hospitalization. In some cases, death and injury were the result of daily administration for 1 week or less.

In 6 of these cases, the error was made by the patient. An older population is likely to take multiple daily medications and have trouble reading the instructions on medication labels; thus, it is not surprising some patients became confused. The risk of confusion is worsened if the “weekly” dose is ordered in 3 smaller divided doses taken 12 hours apart. Patients have also been confused by directions for escalating doses. For example, instructions on a methotrexate (2.5 mg) prescription vial to “Take 3 tablets by mouth 1 day a week for 2 weeks then increase to 4 tablets by mouth 1 day thereafter” led to taking 3 tablets daily. Within 5 days, the patient was hospitalized with septic shock, pancytopenia, and hypotension. Even the FDA-approved Patient Information section of the prescribing information fails to prominently highlight the detrimental consequences of daily oral methotrexate dosing for rheumatoid arthritis and psoriasis. Notably, the warning against daily administration is buried about halfway through the Patient Information in a general paragraph about dosing and thus fails to effectively communicate the potentially fatal consequences of non-adherence to weekly administration.

In the other 8 cases, the oral methotrexate was ordered, labeled, or dispensed incorrectly. In one case, a community pharmacy dispensed a 3-month supply of methotrexate with instructions to take six 2.5 mg tablets daily instead of weekly. The patient survived after a long hospitalization.

Other adverse events consistent with some form of an overdose (but without information about how the injury occurred) were among the 1,810 domestic reports of methotrexate injuries received by FDA in the 12 months ending on June 30, 2019. Most notable were suppression of bone marrow (n = 117), mucosal inflammation (n = 54), lung fibrosis and other damage (n = 130), and infections (n = 267).

A recently published FDA-sponsored study demonstrated the extent of daily rather than weekly administration of oral methotrexate (Herrinton LJ, Woodworth TS, Eworuke E, et al. Development of an algorithm to detect methotrexate wrong frequency error using computerized health care data. Pharmacoepidemiol Drug Saf. 2019;28[10]:1361-8). The investigation found 3 confirmed cases of dose frequency errors requiring treatment among just 722 patients receiving their initial methotrexate prescription, a rate of 4 per thousand. (No confirmed errors were found with refills.) This incidence rate suggests the number of methotrexate dose frequency errors could be far greater than the 14 cases we investigated that were reported to FDA over 18 months.

Conclusion. Given that this oral medication can cause potentially fatal errors affecting up to 1 million people, we should ensure that adequate safety precautions are in place to protect patients. Unfortunately, we estimate that the risk for error is growing rather than declining. Patient use has nearly doubled between 2013 and 2017, and as explained later (Extent of Underreporting), the adverse event reporting rates for many older drugs (like methotrexate) are likely less than 1%. This means that we not only have inadequate precautions in place, but we also have a post-market surveillance system that is unable to measure the extent of this risk or assess whether we are making progress or losing ground.

We believe FDA should require manufacturers of oral methotrexate used for non-oncologic indications to take the following steps to deal with wholly preventable but often fatal errors:

  • Provide oral methotrexate tablets for non-oncologic use in calendar packaging (as with alendronate [FOSAMAX]) to discourage daily use, and include on the package a warning that emphasizes weekly use only (e.g., “For use ONLY one day per week,” “For weekly use ONLY”)

  • Simplify dosing schedules to take methotrexate just once a week rather than in several divided doses 12 hours apart

  • Improve the Patient Information section of the prescribing information to prominently state the importance of the weekly dose regimen for the appropriate indications and the consequences of non-adherence

For decades, ISMP has highlighted for healthcare providers harmful and fatal oral methotrexate errors and how to prevent them. In fact, the ISMP Medication Safety Alert! has warned healthcare providers about this risk on more than 60 occasions. For years, we have recommended defaulting to a weekly dosage regimen when entering electronic orders or prescriptions for all oral methotrexate, requiring an appropriate oncologic indication for all daily methotrexate orders, and provision of patient and family education. While these are included in our Targeted Medication Safety Best Practices for Hospitals (Best Practice #2), compliance has been voluntary and partial. These Best Practices should be considered mandatory guidelines for all healthcare providers. Additionally, no more than a 30-day supply should be dispensed by community pharmacies.

Prescription Opioid Exposure Declines

The opioid crisis has triggered one of the largest and most intense public health campaigns in recent years. Among the many federal initiatives have been stricter prescribing guidelines and documentation requirements, abuse-deterrent formulations, and outreach programs for disposal of unused opioids. Nevertheless, between 2013 and 2017, reported overdose deaths associated with therapeutic or illicit use of prescription opioids have increased by 18%. However, hidden in the reports of opioid overdose deaths is a mostly favorable trend in exposure to prescription opioids: Since 2013, the therapeutic use of prescription opioids has declined steadily, and a large majority of use has been short-term (30 days or less). Changes between 2013 and 2017 (measured in reported outpatient opioid prescriptions) include the following:

  • The trend. Overall, reported use of prescription opioids declined by 25%, from 49 million persons in 2013 to 37 million persons in 2017. Nevertheless, more than 1 in 10 Americans reported taking opioids in 2017.

  • FentaNYL. Reported use of prescription fentaNYL products declined by 55%; however, the death toll from overdoses of illicit fentaNYL is increasing.

  • HYDROcodone and acetaminophen (e.g., LORCET, NORCO, VICODIN). The most widely used opioid for many decades, this combination product declined in use by 40% between 2013 and 2017, a reduction of 8 million persons. However, a new abuse-deterrent formulation of HYDROcodone, HYSINGLA ER, acquired 2.6 million users in 2017. 

  • Lower-potency opioids. TraMADol use declined by 19%, and codeine products by 40%. (FDA published warnings to restrict the use of codeine and traMADol in children, which may have contributed to the overall decline.)

  • OxyCODONE. This opioid, frequently implicated in illicit use and overdose deaths, was an exception to the downward trend in use. Overall, 4.2 million persons reported using oxyCODONE products in 2017, largely unchanged from 2013.

Conclusion. The 25% reduction in prescription opioid utilization demonstrates the result of multiple public health campaigns aimed at reducing deaths from opioid overdoses. A steady stream of media publicity also has likely reduced public willingness to take opioids even for short-term pain relief. However, the reported death rates from prescription opioids have continued to increase slowly, and illicit opioid overdose deaths have grown rapidly. This suggests the need for more research into the pathways that lead to dependence and addiction to identify the most effective point for intervention. For example, short-term dispensing limited to a few days’ supply might provide needed pain relief without substantial risks.

Prescribed Amphetamine and Methylphenidate Use Expands

While therapeutic opioid use declined between 2013 and 2017, we observed a substantial increase in prescriptions for amphetamine and methylphenidate products, the other major Schedule II drugs. These potent stimulants of the central nervous system (CNS) increase the release of multiple neurotransmitters, including dopamine and norepinephrine. Despite well documented risks of dependence and addiction, an estimated 7.8 million persons, about 2.4% of the US population, reported taking amphetamine products in 2017.

Overall, reported use of amphetamine and methylphenidate products increased by 37% from 2013 to 2017, with the most rapid growth among adults (66% increase) rather than children (14% increase). The changes in exposure are shown in Table 1.

Table 1. US population exposure to amphetamine and methylphenidate products, 2013-2017

Table 1. US population exposure to amphetamine and methylphenidate products, 2013-2017

Source: Medical Expenditure Panel Survey

The factors driving this rapid increase have not been studied; however, likely contributing factors include pharmaceutical promotion of some of the brand name drugs for adult indications (attention-deficit hyperactivity disorder [ADHD] and binge eating), off-label use by persons seeking increased alertness, continued use in adults who were initially prescribed amphetamines as children, and use in combination therapy with other psychoactive drugs.

Conclusion. The substantial growth of amphetamine and methylphenidate stimulants has gone largely unnoticed and reverses safety efforts of earlier decades to control the number of persons exposed to these drugs. While the risk of overdose with amphetamines is somewhat lower than with opioids, amphetamine and methylphenidate products have a long history of misuse. The FDA and public health community need to monitor and evaluate the rapidly increasing use in the adult population and investigate the extent to which the increase is due to promotion by manufacturers granted approved indications for adult use.

Extent of Underreporting to FDA

In the past year, more than 400,000 domestic reports of serious injury and death involving the therapeutic use of drugs were submitted to the FDA Adverse Event Reporting System (FAERS). But since this surveillance system is voluntary for consumers and health professionals, we wondered how many adverse drug events might go unreported.

To dig deeper into this question, we conducted 5 in-depth studies of specific drugs with higher rates of adverse effects and higher-quality scientific evidence about incidence—meloxicam, celecoxib, risperiDONE, apixaban, and adalimumab. We were limited to these case studies in part because of severe limitations in the underlying research about most adverse drug events. The examples selected have well documented but mostly high incidence rates over 1 full year of exposure: The FDA estimates that at least 2% of those treated with meloxicam or celecoxib will experience severe gastrointestinal (GI) events; studies show 9% of those treated with risperiDONE will develop movement disorders and 18% of those treated with apixaban will develop bleeds. Tuberculosis in patients taking adalimumab occurred much more rarely, in 2 per thousand patients. We focused on data from 2017 because it is the most recent survey available on overall patient exposure to therapeutic drugs. See the full QuarterWatch™ report for the specific methodology used to estimate the actual number of adverse events and reporting rate. Key results are shown in Table 2.

Table 2. Estimated annual adverse events and FAERS reports in 2017

 Table 2. Estimated annual adverse events and FAERS reports in 2017

1No generic available in 2017

Overall, we found that only about 1% of the serious adverse events with our 5 primary suspect drugs had been reported to FAERS. However, variability in the reporting rate was large, ranging from less than 1 in 1,000 for severe GI harm from meloxicam, to 7.6% of cases of tuberculosis linked to the newer drug adalimumab. These cases showed that brand name drugs had much higher reporting rates than older generics. While reporting is voluntary for consumers and health professionals, FDA requires drug manufacturers to report all cases they learn about in the ordinary course of business. In promoting their brand name drugs, drug manufacturers are much more likely to learn about adverse events through interactions with consumers and health professionals. Also, a rare and mostly unexpected event such as tuberculosis is more likely to be reported than more common medical problems with many possible causes.  

Conclusion. We estimate that approximately 1% or fewer of serious adverse drug events that are likely occurring are subsequently reported to FAERS. In addition, the large variation in reporting rates means the number of cases reported to FAERS is not a uniform and reliable indication of how many events may be occurring in treated patients. Note that only 31 cases of severe GI disorders associated with meloxicam were reported to FAERS, even though we estimate more than 45,000 cases likely occurred in 2017. These 5 case studies do not provide enough data to support an estimate of the overall number of persons who experience serious drug-induced injuries in 1 years’ time. But with more than 400,000 serious and fatal adverse events in the US reported to FAERS annually, it is clear that the extent of injury and death from the therapeutic use of drugs must be measured in the millions.

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