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We’ve now done multiple columns on errors
with methotrexate therapy. The basic problem is that methotrexate is used in
different doses and different regimens when used for oncological indications or
immunomodulating indications for conditions like rheumatoid arthritis,
psoriasis, and inflammatory bowel disease.
For the latter conditions, low dose methotrexate is used, typically
administered in once-a-week doses.
Nimkar et al. (Nimkar 2022) recently described a case of an
unintentional overdose of methotrexate in a patient with psoriasis, resulting
in severe myelosuppression and mucositis. The patient was a 65-year-old woman with a past medical history
of psoriasis for 10 years. She was taken to the emergency department by her family
with a complaint of increased skin lesions, bleeding from the lesions, and painful
mouth ulcers for the last 15 days. She also had high-grade fever and shivering
for the last three days and black-colored stools for the last two days. She had
stopped taking food due to painful ulcerations in her mouth.
Exam
showed multiple ulcerated and necrotic psoriatic plaques with redness and
tenderness on various parts of the body, with signs of active bleeding from the
skin lesions. There was also blood in the stool. Her hemoglobin was 7.7,
leukocyte count 100/mm3, and platelets 48,000/mm3. She
continued to deteriorate in the hospital and, despite
multiple medical interventions, she died.
The
patient had a long history of psoriasis and had been taking methotrexate 7.5 mg
once a week and folic acid 5 mg once a day for 10 years. However, for the last
15 days, a relative had accidentally gave her methotrexate 7.5 mg once daily
and folic acid 5 mg once a week, after which signs of toxicity appeared.
Obviously,
in this case, the family relative transposed the dosing frequency of
methotrexate and folate. But it raises a key question we have raised with other
medication issues, particularly IV infusions. That question is “Why would
you ever allow a potentially lethal dose of a medication to be given if it were
to be given over a much shorter time frame than intended?” We’ve raised
that question in cases where IV infusions of 5-Fluorouracil (5-FU), intended to
be infused over several days, instead get infused over several hours. But the
concept here is similar – why should a patient have a supply of methotrexate
large enough to be lethal if taken daily by accident? The monthly supply of
methotrexate for these patients should only be 4-5 tablets. We don’t know
details of how the methotrexate was prescribed or dispensed in the current
case. Perhaps the patient was given a 90-day supply, which could have allowed
for the 15 daily doses she received.
In
the study highlighted in our June 21,
2016 Patient Safety Tip of the Week “Methotrexate Errors in Australia” Cairns
et al. (Cairns 2016) noted that folate and methotrexate were
both small yellow tablets, likely increasing the chance the two might be mixed
up. We wonder whether that might have been a factor in the current case (such
detail was not provided in the current case).
In
2018, ISMP issued a “Call to Action” to prevent accidental daily methotrexate
dosing (ISMP 2018), noting that harmful or fatal errors with
daily oral methotrexate for nononcologic use had been reported to ISMP and
published in more than 60 ISMP Medication Safety Alert! Newsletters since early
1996.
The
fundamental problem is that relatively few medications are dosed weekly. So, it
is not surprising that accidental daily dosing of oral methotrexate might
occur. ISMP notes that this type of wrong frequency error has originated in all
stages of the medication use process, from prescribing to self-administration.
IMSP
notes that titrated methotrexate doses or divided weekly doses have often
caused confusion. Patients may misunderstand complex regimens. ISMP (ISMP 2018) gave such an example. An 8-week supply of
2.5 mg tablets (30 tablets) had been dispensed with label instructions that
said, “Take 3 tablets by mouth one day for 2 weeks then increase to 4 tablets
by mouth 1 day per week thereafter.” Despite counseling, the patient was
confused by the label instructions and took 3 tablets (7.5 mg) daily for 5 days
before serious symptoms led his doctor to identify the error.
ISMP
also notes that computer order entry systems may contribute to this type of
incorrect dosing. They noted that some systems present common orders for oral
methotrexate in both daily and weekly dosing frequencies. A clinician may pick
the first choice that matches the desired dose, without noticing that the
frequency of administration listed is daily, not weekly. Methotrexate today is
far more often used for non-oncologic conditions, so it makes sense that CPOE or
ePrescribing systems should default to weekly dosing
rather than daily dosing.
ISMP
has the following recommendations:
·
Defaulting to a weekly dosing schedule in
prescriber and pharmacy order entry systems
·
Requiring verification and entry of an appropriate
oncologic indication in order entry systems for daily orders
·
Educating patients and providing them with
verbal and written instructions that specify the weekly dosing schedule and
emphasize the danger with taking daily or extra doses
·
Asking patients to repeat back the instructions
for taking oral methotrexate to validate understanding
·
Verifying the dose and frequency of all
medication lists and discharge instructions
·
Limiting the prescription quantity to a
30-day supply (e.g., dispensing just eight 2.5 mg tablets for a 5 mg weekly
dose would reduce the risk of a serious overdose)
ISMP
also encourages the FDA to require manufacturers to package oral methotrexate
for nononcologic use in patient dose packs that direct consumers to the
correct weekly dosing. They note that, in Spain, blister packs of oral
methotrexate limit the quantity of tablets available to patients. The outer
carton and blister packs include the nononcologic indications and a specific
warning that the dose is once a week for these approved indications.
ISMP’s
2022-2023 ISMP Targeted Medication Safety Best Practices for Hospitals (ISMP 2022) includes BEST PRACTICE 2:
a)
Use a weekly dosage regimen default for oral
methotrexate in electronic systems when medication orders are entered.
b)
Require a hard stop verification of an
appropriate oncologic indication for all daily oral methotrexate orders.
i) For
manual systems and electronic order entry systems that cannot provide a hard
stop, clarify all daily orders for methotrexate if the patient does not have a
documented appropriate oncologic diagnosis.
ii) Hospitals
need to work with their software vendors and information technology departments
to ensure that this hard stop is available. Software vendors need to ensure that
their order entry systems are capable of this hard stop as an important patient
safety component of their systems.
c)
Provide specific patient and/or family education
for all oral methotrexate discharge orders.
i) Double-check
all printed medication lists and discharge instructions to ensure that they indicate
the correct dosage regimen for oral methotrexate prior to providing them to the
patient.
ii) Ensure
that the process for providing discharge instructions for oral methotrexate includes
clear written instructions AND clear verbal instructions that specifically
review the dosing schedule, emphasize the danger with taking extra doses, and
specify that the medication should not be taken “as needed” for symptom
control.
iii) Require
the patient to repeat back the instructions to validate that the patient understands
the dosing schedule and toxicities of the medication if taken more frequently
than prescribed.
iv) Provide
all patients with a copy of the free ISMP high-alert medication consumer leaflet on
oral methotrexate.
Our June 21, 2016 Patient Safety Tip of the
Week “Methotrexate Errors in Australia” highlighted
a study by Cairns and colleagues (Cairns
2016) on methotrexate-related adverse events.
Unintended daily dosing was the predominant contributing factor. Mistaking
methotrexate for another medication (most often folic acid or prednisone) was
another common contributing factor. Several cases were due to error by a
caregiver or nursing home. Other reasons noted were newly prescribed
methotrexate, dosette packing errors by pharmacists,
misunderstood instructions, prescribing error, dispensing/labeling error, and
one case where the patient believed it would improve efficacy.
That
study emphasized that taking methotrexate daily for even 3 consecutive days
could be fatal but noted wide variability in the duration of daily dosing
before toxic effects occurred. Possible contributory factors cited included
increasing patient age, renal function and hydration
status. Since first-time users and older patients appear to be at greater risk,
they emphasized the importance of taking time to counsel these patients. The
authors also note that in addition to physiologic changes that might alter
methotrexate metabolism and excretion, the elderly may have other problems like
confusion, memory impairment, visual decline, and others that could put them at
increased risk of dosing errors.
ISMP’s
QuarterWatch™ (ISMP 2019) noted that even 1 week of daily
administration of methotrexate can result in many painful and severe adverse
effects, including death. They reviewed 14 cases of methotrexate overdoses, all
of which occurred in patients age 65 and older. In 6
of the cases, the error was made by the patient. They note that 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. That’s especially the case 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. In the other 8 cases, the
oral methotrexate was ordered, labeled, or dispensed incorrectly.
That QuarterWatch™ notes that the warning against daily
administration is buried about halfway through the Patient Information label
and fails to effectively communicate the potentially fatal consequences of
non-adherence to weekly administration. ISMP’s high-alert medication consumer leaflet on
oral methotrexate is a much better tool for conveying to
patients the risks of methotrexate.
An
article by ISMP’s Matthew Grissinger (Grissinger 2018), based on an ISMP Canada Safety Bulletin (ISMP Canada 2015) discusses most of the points made in the
above resources, but also reminds us that computer systems should include a
robust drug–drug and drug–disease interaction module for methotrexate, with
links to laboratory results where possible, so prescribers and pharmacists can
effectively evaluate the potential for toxic effects. He also suggests that, if
folate has not been prescribed, the pharmacist should follow up with the
prescriber to suggest initiation of this supplement.
In our What's New in the Patient Safety World
columns for July 2011 “More Problems With Methotrexate”
and February 2016 “Avoiding
Methotrexate Errors” we
noted that the patient in a long-term
care facility may be especially vulnerable. In such cases, the original
order for methotrexate is usually written by a specialist. It’s especially
likely to occur when an LTC patient gets admitted to a hospital and then gets
transferred back to the LTC unit. The patient is then followed in the LTC
facility typically by a primary care physician who may be less knowledgeable
about the particular use of methotrexate for that condition. Also, the LTC
patient may not be seen by a physician for periods as long as
a month. And many LTC patients have cognitive impairments that might prevent
them from understanding issues about their medications. So, if a medication
reconciliation error has occurred and a patient intended for once weekly dosing
is now on daily dosing, the opportunity for toxicity is greatly increased. So
LTC facilities should take steps to ensure that any of their residents taking methotrexate
get the same level of supervision and protections that non-LTC patients would
get.
We’ve
often harped on the need to include the indication when we order or
prescribe a medication. In our August 2019 What's New in the Patient Safety
World column “Including
Indications for Medications: We Are Failing” we gave a methotrexate example. We said if
a pharmacist saw an order for daily methotrexate and the indication was
“rheumatoid arthritis” (or other non-oncologic indication), the pharmacist
might recognize the dosing error.
One
recommendation that appeared in some of the older studies but seems to have
disappeared was to tell the patient to take the methotrexate on a specific day
of the week (but avoid “every Monday”, since that may be confused with “every
morning”) in order to emphasize that the medication is
to be taken weekly rather than daily. We’ve always liked that recommendation.
The
twist in the current case is what a relative did. That relative probably never
received any education or counselling about methotrexate dosing. Of all the
actions and interventions we’ve talked about in this
and our previous columns, probably the only one that might have prevented this
catastrophe would have been limiting the number of methotrexate tablets
available to the patient. Perhaps that is the most important lesson here. With
more than 1 million patients currently taking methotrexate in the US (ISMP 2019), the risks of this type of accidental
overdose remain substantial.
Our
prior columns related to methotrexate issues:
References:
Nimkar SV, Yelne P, Gaidhane SA, et al. Fatal Manifestations of Methotrexate
Overdose in Case of Psoriasis Due to Dosing Error. Cureus
2022; 14(10): e30041
Cairns R, Brown JA, Lynch A-M, et al. A
decade of Australian methotrexate dosing errors. Med J Aust 2016; 204(10): 384
https://www.mja.com.au/system/files/issues/204_10/10.5694mja15.01242.pdf
ISMP (Institute for Safe Medication
Practices). Call to Action: Longstanding Strategies to Prevent Accidental Daily
Methotrexate Dosing Must Be Implemented. ISMP Medication Safety Alert! Acute
Care Edition 2018; 23(16): August 9, 2018
Institute for Safe Medication Practices
(ISMP). 2022-2023 ISMP Targeted Medication Safety Best Practices for Hospitals.
ISMP 2022
https://www.ismp.org/system/files/resources/2022-02/2022-2023%20TMSBP%20final.pdf
ISMP high-alert medication consumer leaflet
on oral methotrexate. Accessed October 9, 2022
https://www.ismp.org/sites/default/files/attachments/2018-11/Methotrexatefinal.pdf
ISMP (Institute for Safe Medication
Practices). QuarterWatch™ (includes new data from
Quarter 2, 2019) Methotrexate Errors, Trends Among Addictive Drugs, and
Underreporting of Serious Events. ISMP Medication Safety Alert! Acute Care
Edition 2019; December 5, 2019
Grissinger M.
Severe Harm and Death Associated With Errors and Drug
Interactions Involving Low-Dose Methotrexate. P&T 2018; 43(4): 191-248
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871236/
ISMP Canada. Severe harm and deaths
associated with incidents involving low-dose methotrexate. ISMP Canada Safety
Bulletin 2015; 15(9): 1-5
https://ismpcanada.ca/wp-content/uploads/ISMPCSB2015-09_Methotrexate.pdf
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