August 9, 2018 Volume 23 Issue 16

Call to action: Longstanding strategies to prevent

accidental daily methotrexate dosing must be implemented Eligard label improvements needed.
Methotrexate is a folic acid antagonist that was originally approved to ELIGARD (leuprolide acetate for injectable
treat a variety of cancers. Used for oncologic indications, methotrexate suspension) is a gonadotropin-releasing
is administered in cyclical frequencies and in variable doses based on hormone (GnRH) agonist indicated for the
body surface area and the type of cancer being treated—for example, palliative treatment of advanced prostate
12 g/m2 per dose when treating osteosarcoma. The labeled indications cancer. The drug is given subcutaneously,
for methotrexate later expanded to include the treatment of nononcologic which provides continuous release of le-
conditions, including psoriasis (approved in 1971) and rheumatoid arthritis uprolide acetate over a 1-, 3-, 4-, or 6-month
(approved in 1988). Other nononcologic off-label uses include the treatment of Crohn’s treatment period based on one of four avail-
disease, multiple sclerosis, inflammatory myositis, reactive arthritis (Reiter’s syndrome), able dosage strengths (see below).
graft-versus-host disease, Takayasu arteritis, uveitis, and ectopic pregnancy. For most
nononcologic indications, a low dose of methotrexate is administered just once or Dosage Recommendation
twice weekly—for example, 7.5 mg per week when treating rheumatoid arthritis. 7.5 mg 1 injection every month
22.5 mg 1 injection every 3 months
Relatively few medications are dosed weekly; thus, accidental daily dosing of oral
methotrexate has occurred all too frequently. This type of wrong frequency error 30 mg 1 injection every 4 months
has originated in all stages of the medication use process, from prescribing to self- 45 mg 1 injection every 6 months
administration. These errors have resulted in serious methotrexate overdoses that
led to vomiting, mouth sores, stomatitis, serious skin lesions, liver failure, renal The Eligard carton contains two syringes in
failure, severe myelosuppression, gastrointestinal bleeding, life-threatening pulmonary separate overwraps that must be mixed to-
symptoms, and, in some cases, death. gether prior to injection. Syringe A is prefilled
with ATRIGEL, a polymeric (non-gelatin con-
Since early 1996, harmful or fatal errors with daily oral methotrexate for nononcologic taining) delivery system. Syringe B is pre-
use have been reported to ISMP and published in more than 60 of our ISMP Medica- filled with leuprolide acetate powder. How-
tion Safety Alert! newsletters. Thus, oral methotrexate for nononcologic use has ever, it is easy to miss the wording on the
been included on the ISMP List of High-Alert Medications (www.ismp.org/ front of the carton, “Must be constituted
node/103) since the inception of the list in 2003. Although the risk of errors with oral before use,” and a full description of the
methotrexate for nononcologic use has been known for a long time, harmful and syringe contents is only mentioned in small
fatal errors are still occurring today. Descriptions of recently reported events follow. print on the back of the carton (Figure 1).
Also, the Atrigel overwrap emphasizes the
Methotrexate Errors name Eligard, not the Atrigel delivery system.
Medication reconciliation and transition-in-care error
The most recent event involved an error that was caught during hospitalization but
continued upon discharge when an incorrect entry for daily methotrexate on a pa-
tient’s home medication list was not corrected. An elderly man with rheumatoid
arthritis was admitted to a hospital with renal failure. At home, he had been taking
oral methotrexate 2.5 mg twice weekly (Mondays and Wednesdays). The admitting
nurse began creating a list of the patient’s home medications.The admitting physician
noticed that methotrexate was missing from the home medication list in the patient’s
electronic health record and added it. However, he mistakenly documented that the
patient had been taking 2.5 mg of oral methotrexate twice daily instead of twice
weekly. He then made this an active order during the patient’s hospitalization.

Noticing the daily order for methotrexate, a pharmacist in the central pharmacy
contacted the physician to let him know that he must prescribe daily methotrexate
on a hospital-mandated chemotherapy order template. However, the pharmacist Figure 1. Eligard outer carton front panel does not
did not verify that the patient had an appropriate oncologic indication for the order. clearly indicate the contents of the two syringes.
continued on page 2—Methotrexate > continued on page 2—SAFETY briefs >
 August 9, 2018 Volume 23 Issue 16 Page 2

> Methotrexate—continued from page 1 cont’d from page 1

The physician simply complied with the pharmacist’s request and prescribed the ISMP has received two complaints about
daily methotrexate via a chemotherapy order template. Fortunately, an oncology the overwraps looking identical, with both
pharmacist identified the error after talking to the patient and corrected the active labeled primarily as Eligard (Figure 2). In
order, changing the dose from twice daily to twice weekly. However, it never crossed one case, a hospital pharmacist found only
his mind to correct the methotrexate entry on the patient’s home medication list. one syringe in an Eligard carton stored in
the refrigerator and dispensed that for a
The patient received the correct dose—one 2.5 mg tablet—of methotrexate on Wednes- patient. The dispensed syringe contained
day during his 5-day hospital stay before being transferred to a skilled nursing facility only the Atrigel delivery system. Fortunately,
(SNF). Upon discharge, the physician reconciled the patient’s list of home medications the patient’s nurse was aware that two sy-
for continuation upon discharge. In doing so, he pulled the erroneous methotrexate ringes were needed for dose preparation
entry over to the list of medications to continue upon discharge, thus prescribing and intercepted the dispensing error before
oral methotrexate 2.5 mg twice daily for the patient while at the SNF. The patient re- administration. However, when the med-
ceived twice daily methotrexate for more than a week before he was rehospitalized ication was returned to the pharmacy, the
with a change in mental status, severe neutropenia, and mucositis. Sadly, he never
recovered and died in the hospital about a week later.

Misunderstood instructions
Another recent error involved a correctly filled outpatient prescription for weekly
methotrexate with an escalating dose change 2 weeks later. Unfortunately, the
patient misunderstood the instructions on the label and took the medication daily.
An 8-week supply of 2.5 mg tablets (30 tablets) had been dispensed with label in-
structions 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.

Overall complexity with titrated methotrexate doses or divided weekly doses have
previously caused confusion. For example, in 2017, a patient with rheumatoid arthritis
was hospitalized after mistakenly taking methotrexate 3 tablets twice a day for 4 days
instead of 3 tablets in the morning and 3 tablets in the evening once a week. The pre- Figure 2. Overwraps for Eligard powder and the
Atrigel delivery system are both prominently
scription label said, “Take 6 tablets by mouth weekly. Take 3 tablets in AM and 3 tablets labeled as containing Eligard.
in PM.” In the labeling for methotrexate, single oral doses of 7.5 mg once weekly are
recommended for initial treatment of rheumatoid arthritis. However, divided oral doses second syringe was not found. This led
of 2.5 mg at 12 hour intervals for 3 doses, given as a course once weekly, are also rec- pharmacy staff to suspect that, previously,
ommended. It appears that the use of divided doses has added to patient confusion. someone may have dispensed only the sy-
ringe containing leuprolide powder.
Look-alike, sound-alike issues
Some of the recently reported errors have also involved accidentally selecting This product has difficult mixing instructions
methotrexate instead of the intended diuretic metOLazone. Both drug names start that require attaching the syringes to one
with “m-e-t” and have overlapping tablet strengths of 2.5, 5, and 10 mg. In one case, another, shifting the Atrigel directly into the
a pharmacy technician who was entering a telephone prescription for oral metOL- leuprolide, and then mixing back and forth
azone 2.5 mg daily accidentally selected methotrexate 2.5 mg daily. She had searched between the two syringes. The product must
for metOLazone using the first three letters of the drug name and the strength and then be administered within 30 minutes or
selected methotrexate 2.5 mg by mistake since it met both criteria. The computer discarded, which may require nurses in cer-
system did not flag the methotrexate order to require verification of an appropriate tain settings to mix the products together
oncologic indication since the dosing frequency was daily. The medication was dis- immediately before use. Preparation and
pensed without the pharmacist noticing the error. The patient’s husband picked up handling errors may lead to lack of efficacy.
the medication and was asked if he had any questions. When he had no questions,
counseling was not provided. The patient took methotrexate 2.5 mg daily as directed We have contacted the manufacturer, Tol-
on the label and died less than a month later. Mix-ups between these two medications mar Pharmaceuticals, to suggest label im-
have been previously reported in this newsletter. provements: the Atrigel delivery system
overwrap should prominently be labeled as
Assessment of Best Practices such, with Eligard deemphasized; and the
To prevent accidental daily dosing of oral methotrexate, ISMP has long recommended front panel of the carton should list the con-
defaulting computer order entry systems to a weekly dosing regimen, requiring tents of the two syringes and clarify that
pharmacist verification of an appropriate oncologic indication for daily dosing of they need to be mixed before administration.
continued on page 3—Methotrexate > continued on page 3—SAFETY briefs >

© 2018 ISMP. Reproduction of the newsletter or its content for use outside your facility, including republication of articles/excerpts
or posting on a public-access website, is prohibited without written permission from ISMP.
 August 9, 2018 Volume 23 Issue 16 Page 3

> Methotrexate—continued from page 2 cont’d from page 2

methotrexate, and educating patients about the weekly dosing regimen. These best Import of potassium chloride injection.
practices have also been on the national to-do list with the ISMP Targeted Medica- Because of the severe shortage of potas-
tion Safety Best Practices for Hospitals since 2014 (see best practice #2 [a, b, c] sium chloride injection, the US Food and
at: www.ismp.org/node/160). Drug Administration (FDA) has approved
importation by Athenex Pharmaceuticals
Although implementation of these best practices has been rising since 2014 of 20 mEq/10 mL ampules (2 mEq/mL) of
(www.ismp.org/ext/69), the most recent data (Table 1) from the ISMP Medication the product, which is manufactured and
Safety Self Assessment® for High-Alert Medications demonstrate opportunities marketed in Italy by Galenica Senese.
to improve implementation of these and other best practices that could prevent Complete information, including product
errors with methotrexate in many hospitals. In the recent self assessment, methotrex- access, photographs of the carton and
ate for nononcologic use scored lowest among the 11 high-alert medications included ampule label, and comparison to the US
in the assessment. For the 501 US hospitals that submitted data to ISMP for this product, is on the FDA drug shortages
medication, a mean percent score of only 50% was achieved. Participating hospitals website at: www.ismp.org/ext/71.
scored particularly low on defaulting to a weekly dosing regimen with computer
order entry systems, requiring verification of an appropriate oncologic indication It is important to recognize that the ampule
for daily dosing of methotrexate, educating patients about the weekly dosing regimen, label expresses the potassium chloride
prescribing the medication in quantities that do not exceed a 30-day supply, and concentration as 2 mEq/mL, with 20 mEq/
verifying that all lists and instructions provide the correct dosing instructions. 10 mL in parentheses (Figure 1), which is
the opposite of how the concentration is
One of the barriers to defaulting to a weekly dosing regimen with computer order expressed on the US vial label per USP
entry systems appears to be that some systems present common orders for oral <7>. Also, a barcode is not on the label,
methotrexate in both daily and weekly dosing frequencies, without an option to edit so alternate procedures are needed to
the display of these orders. When searching for the intended drug, a clinician may verify product identification. Finally, this
pick the first choice that matches the desired dose, without noticing that the frequency product is in an ampule rather than a vial
of administration listed is daily, not weekly.
continued on page 4—Methotrexate >
Table 1. Implementation of best practices associated with methotrexate (nononcologic use), n = 501 US hospitals
Implementation†
Best Practice
None Partial Full
Computer order entry systems default to a weekly rather 19% 18% 63%
than daily dosage regimen.*
Computer order entry systems require a hard stop veri-
fication and mandatory entry of an appropriate oncologic
indication in order to override the weekly dosage regimen 44% 21% 35%
and select a daily schedule for a defined number of Figure 1. Concentration on imported potassium
doses or days.* chloride injection is prominently expressed per mL
OR as 2 mEq/mL, followed by the amount per total
Pharmacists clarify daily orders for methotrexate if the volume in parentheses (20 mEq/10 mL), the opposite
patient does not have a documented oncologic diagnosis 14% 25% 61% of concentration expression on US labels.
to ensure the frequency and duration is appropriate and
safe.*
and does not have a black band or series
Patients who are discharged on methotrexate receive of black bands above the ampule neck
verbal and written instructions that specify the weekly constriction, as would a US product.
17% 38% 45%
dosing schedule and emphasize the danger with taking
extra doses.*
If these products are purchased, we highly
Patients discharged on methotrexate repeat back the recommend storing and utilizing these am-
instructions to validate understanding of the weekly dos- pules only within the pharmacy.
30% 40% 30%
ing schedule and toxicities if taken more frequently than
prescribed.*
Kudos to PA Patient Safety Authority
Prescriptions for nononcologic methotrexate only include for requiring patient weights. With ap-
the number of tablets or other dosage forms needed for 47% 22% 31% proval of the Pennsylvania (PA) Depart-
weekly dosing, not to exceed a 4-week (30-day) supply.
ment of Health, the PA Patient Safety Au-
A healthcare professional verifies all printed medication thority issued draft recommendations on
lists and discharge instructions to ensure they indicate July 14, 2018, to licensed acute care facil-
10% 32% 58%
the correct dosage regimen prior to providing them to
the patient. ities in PA to ensure accurate patient
weights (www.ismp.org/ext/70). The Au-
†
Implementation: None = A & B scores; Partial = C & D scores; Full = E scores continued on page 4—SAFETY briefs >
*This best practice has been included in the Targeted Medication Safety Best Practices for Hospitals since 2014
 August 9, 2018 Volume 23 Issue 16 Page 4

> Methotrexate—continued from page 3 cont’d from page 3

thority is recommending that acute care
Recommendations facilities in PA have processes in place to
Ongoing errors with oral methotrexate for nononcologic use suggest that more weigh each patient as soon as possible
needs to be done to reduce the risk of patient harm. Most of the wrong frequency on admission, when a patient experiences
and wrong drug errors with methotrexate could be prevented by fully implementing a change in condition that may lead to sig-
the Targeted Medication Safety Best Practice associated with methotrexate nificant weight changes, and during each
and other related risk-reduction strategies in the ISMP Medication Safety Self appropriate outpatient or emergency de-
Assessment® for High-Alert Medications, including: partment encounter (except in critical sit-
uations). The use of an estimated, histori-
Defaulting to a weekly dosing schedule in prescriber and pharmacy order entry cal, or stated weight should be avoided.
systems This includes all encounters in which the
Requiring verification and entry of an appropriate oncologic indication in order patient is being seen by a licensed inde-
entry systems for daily orders pendent practitioner, excluding life-threat-
Educating patients and providing them with verbal and written instructions ening situations where the delay in weigh-
that specify the weekly dosing schedule and emphasize the danger with taking ing the patient could lead to serious harm
daily or extra doses (for example, major trauma). It excludes
Asking patients to repeat back the instructions for taking oral methotrexate to laboratory and other services where med-
validate understanding ications are not prescribed or administered.
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 Also, organizations must have a process
eight 2.5 mg tablets for a 5 mg weekly dose would reduce the risk of a serious in place to measure and document a pa-
overdose) tient’s weight in metric units (for example,
grams or kilograms) only. This would in-
Other important risk-reduction strategies for clinicians, technology/drug information clude documentation in computer infor-
vendors, and the US Food and Drug Administration (FDA) are provided below. mation systems, infusion pumps and other
medication devices, and printouts and
Clinicians: Medication reconciliation preprinted order forms that prompt users
Update and edit the patient’s home medication list as needed throughout the to record patient weight.
patient’s hospitalization so it can accurately guide medication reconciliation.
Create a daily list of active orders and discharge prescriptions for oral The draft recommendations have a 30-
methotrexate generated from the order entry system, and require a pharmacist day comment period. Once finalized, the
to review the orders and prescriptions to verify the dose and frequency based Authority is responsible for issuing guide-
on the patient’s diagnosis. lines to acute care facilities in PA.

Clinicians: Prescribing Contrived drug names wreak havoc.

Provide clear directions on oral methotrexate prescriptions. Avoid “take as di- An emergency department physician ver-
rected” instructions, include the strength and dose in mg, provide clear in- bally requested “Neostick” from a bedside
structions for weekly dosing, and limit the number of tablets to a 4-week (30- clinical pharmacist. However, the pharma-
day) supply. cist misheard the request as “neostig” and
retrieved neostigmine when the provider
Clinicians: Dispensing wanted phenylephrine (NEOSYNEPHRINE,
Provide clear instructions on pharmacy labels for weekly dosing, and specify a former US brand of phenylephrine). We
the day of the week (written in full, not abbreviated) the medication should be were surprised by how many hits we re-
taken. Affix an auxiliary warning label (preferably preprinted) to remind patients ceived when we searched “Neostick” on
that the dose should be taken weekly. Google. Apparently, it’s a very popular
When available and covered by the patient’s insurance, dispense oral methotrex- slang term. ISMP has occasionally re-
ate for nononcologic use in outpatient settings in a dose pack that helps guide ceived medication error reports in which
patients to take the proper dose weekly. Dispensing loose tablets of methotrex- other contrived drug names were an is-
ate for nononcologic use in prescription vials is highly discouraged in outpatient sue, such as “Ketofol” (ketamine and
pharmacies if methotrexate dose packs are available and covered by the pa- propofol combined in a syringe), “levo”
tient’s insurance. (LEVOPHED [norepinephrine], levothyrox-
ine, or levoFLOXacin [LEVAQUIN]), and
Clinicians: Patient education “nitro” (nitroglycerin or nitroprusside).
Provide all patients with a copy of the free ISMP high-alert medication consumer The hospital that reported use of the con-
leaflet on oral methotrexate (found at: www.ismp.org/ext/68). trived name, Neostick, has discouraged
When possible, provide the patient with a visual calendar to clarify the weekly further use of any made-up drug names
dosing schedule. and abbreviations.
continued on page 5—Methotrexate >
 August 9, 2018 Volume 23 Issue 16 Page 5

> Methotrexate—continued from page 4

If folic acid is prescribed along with methotrexate, educate patients about the dif-
ferences between the medications and their respective administration schedules.1
Educate patients about the key symptoms of methotrexate toxicity and to
whom to report the symptoms. Free webinar on global medication
safety issues
Clinicians: Patient monitoring Join ISMP on September 26 for a FREE
If a methotrexate dosing error is discovered, ensure the patient receives im- webinar, Working Together to Address
mediate medical attention.2,3 Global Drug Safety Issues with Packaging
and Labeling. Speakers will discuss drug
Technology/drug information vendors product issues that contribute to medica-
Build computer order entry systems to ensure clinicians have access to the tion errors around the world, and success-
functionality needed to prevent methotrexate errors (e.g., default to weekly ful changes that some countries have
dosing, hard stop for verification of indication with daily orders). made to reduce the risk of errors. High-
lights from a recent international summit
FDA (which is currently evaluating the need for regulatory action) held by global regulators and the Interna-
Change and limit the approved dosing regimen to once weekly as a single tional Medication Safety Network (IMSN)
dose (not divided doses 12 hours apart or twice weekly), if appropriate. will be presented. Practitioners outside the
Encourage manufacturers to package oral methotrexate for nononcologic US are encouraged to attend. For details,
use in patient dose packs that direct consumers to the correct weekly dosing. visit: www.ismp.org/node/1113.
Require prominent warnings on the packaging of oral methotrexate for nononco-
logic use about weekly administration, as is done in other countries (Figure 1). Revised ADC guidelines open for public
comment
References ISMP is seeking public comment from cli-
1) Harrison A, Jones P. Safer prescribing of nicians, vendors, regulators, and profes-
high-risk medicines – methotrexate: potentially sional organizations on its revised Guide-
fatal in overdose. Best Practice Advocacy Cen- lines for the Safe Use of Automated
tre New Zealand. Best Practice Journal.
2014;64:48-52. www.ismp.org/ext/72 Dispensing Cabinets (ADCs) through Au-
gust 31, 2018. The guidelines, originally
2) Howard SC, McCormick J, Pui C, Budding- published in 2009, have been updated to
ton RK, Harvey RD. Preventing and managing
toxicities of high-dose methotrexate. Oncolo- reflect current safe ADC practices. To sub-
gist. 2016;21(12):1471-82. mit your comments, visit: www.ismp.org/
node/1107.
Figure 1. In Spain, blister packs of oral methotrexate limit the 3) Bidakil R, Kian M, Owliaey H, Babaei Zarch
quantity of tablets available to patients. The outer carton and M, Feysal M. Accidental chronic poisoning
blister packs include the nononcologic indications and a spe- with methotrexate; report of two cases. Emer- Survey on IV push medications
cific warning that the dose is once a week for these approved gency. 2017;5(1):e67. If you are a practitioner who administers
indications (red text). intravenous (Iv) push medications to
ADULTS, please take our survey on Iv push
New ISMP white paper helps support the role of the medication practices by August 31 by vis-
medication safety officer iting: www.ismp.org/ext/49.

Accepting Cheers Awards nominations

W H I T E PA P ER

A recently released ISMP white paper, The Case for Medication Safety
Officers (MSO), stresses the need for an MSO to be included as an integral Nominations for this year’s Cheers Awards
part of the healthcare team. The white paper provides detailed information will be accepted through September 7,
for hospital leadership on the value of creating a dedicated position directly 2018. Outside and self-nominations are ac-
responsible for and empowered to lead medication safety strategy and im- cepted. The awards spotlight efforts to im-
plementation initiatives. It also describes key roles MSOs can play in optimiz- prove medication safety from all health-
ing safety, and comparable positions in other safety industries that can serve care disciplines. To submit a nomination,
as models.The white paper can be downloaded at: www.ismp.org/node/1132. visit: www.ismp.org/cheers-awards.

If you would like to subscribe to this newsletter, visit: www.ismp.org/node/10

ISMP Medication Safety Alert! Acute Care (ISSN 1550-6312) © 2018 Institute for Safe Medication Practices (ISMP). Subscribers are granted per-
mission to redistribute the newsletter or reproduce its contents within their practice site or facility only. Other reproduction, including posting on a public-
access website, is prohibited without written permission from ISMP. This is a peer reviewed publication.
Report medication and vaccine errors to ISMP: Please call 1-800-FAIL-SAF(E), or visit our website at: www.ismp.org/MERP or www.ismp.org/VERP.
ISMP guarantees the confidentiality of information received and respects the reporters’ wishes regarding the level of detail included in publications.
Editors: Judy Smetzer, BSN, RN, FISMP; Michael Cohen, RPh, MS, ScD (hon), DPS (hon); Ann Shastay, MSN, RN, AOCN; Russell Jenkins, MD; Ronald S. Litman, DO. ISMP,
200 Lakeside Drive, Suite 200, Horsham, PA 19044. Email: [email protected]; Tel: 215-947-7797; Fax: 215-914-1492.

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