F RO M T H E DATA B A S E Data Snapshot: Errors Involving Methotrexate Methotrexate is a folate antimetabolite used in oncology for a variety of leukemias, DRUG INFORMATION FOR lymphomas, and other types of cancers.1,2 Since the drug’s introduction, its labeled METHOTREXATE indications have expanded to include non-oncology uses. It is now used to treat a vari- ety of immune disorders, including psoriasis, severe rheumatoid arthritis, lupus, and Oncology uses: A variety of leuke- multiple sclerosis. Other uses include treatment of Crohn’s disease, ectopic pregnancy, mias, lymphomas, and other types of cancers. inflammatory myositis, myasthenia gravis, Takayasu arteritis, and asthma. For oncology uses, normal doses of methotrexate are based on body surface area and Non-oncology uses: A variety of immune disorders, including pso- vary depending on the specific type of cancer being treated.1,2 The drug is typically riasis, severe rheumatoid arthritis, given one or two days per chemotherapy cycle (i.e., seven days apart, or days one and lupus, and multiple sclerosis; Crohn’s eight) every three to four weeks. For non-oncology uses, a low dose is administered disease; ectopic pregnancy; inflam- once or twice weekly; it is uncommon for a drug to be dosed in this way, and this matory myositis; myasthenia gravis; dosing may lead to confusion, as a once-daily dosing regimen is most familiar to both Takayasu arteritis; and asthma. patients and clinicians. Inadvertently high dosing of methotrexate, such as daily dosing Elimination half-life: 3 to 10 hours when weekly dosing is intended, can result in toxicity affecting multiple organ systems, at low doses; 8 to 15 hours at high which can quickly lead to death. Large cumulative doses and prolonged exposure doses. has been associated with acute and chronic hepatotoxicity as well as myelosuppres- sion. Patients receiving large doses of methotrexate may also present with pulmonary Absorption, oral: Dose depen- symptoms, mouth sores, stomatitis, or skin lesions.1,3-5 (For more specifics about metho- dent. The drug is well absorbed at trexate, see “Drug Information for Methotrexate.”) low doses, but after higher doses, absorption is incomplete. The literature contains a number of articles that describe errors involving methotrex- ate.5-7 For example, Moore et al. analyzed all of the adverse-event reports submitted to Distribution: Occurs slowly. The drug is retained in the liver and kid- the U.S. Food and Drug Administration’s Adverse Event Reporting System between ney at sustained concentrations. November 1997 and December 2001 that indicated potential medication errors involv- ing methotrexate.6 They identified 106 medication errors associated with methotrexate. Toxicity: Renal failure, hepatotoxicity, Roughly 24% of the errors (25 of 106) resulted in patient death, while another 45% immunosuppression, myelosuppres- (48 of 106) resulted in serious adverse effects. The authors found that the most com- sion, mucositis. mon types of errors were confusion about the once-weekly dosing of methotrexate Sources and other dosage errors. The Institute for Safe Medication Practices issued a special Lexi-Comp Online. Methotrexate [online]. alert in 2002 warning practitioners about the risk of inadvertent administration of 2010 [cited 2010 Aug 24]. Available from methotrexate daily rather than weekly.8 In one case, a 79-year-old patient died after the Internet: http://online.lexi.com/crlsql/ physician prescribed methotrexate 15 mg daily rather than weekly. The patient received servlet/crlonline. nine doses before the error was discovered. More recently, as reported in the news, an Roxane Laboratories, Inc. Methotrex- 82-year-old woman suffered bleeding and eventually died after receiving methotrex- ate [full prescribing information online]. ate 12.5 mg daily instead of weekly.9 During a hospitalization, the patient’s dosing 2008 May [cited 2010 Oct 28]. Available was incorrectly recorded as daily. Tragically, the mistake was not discovered when the from Internet: http://bidocs.boehringer- ingelheim.com/BIWebAccess/ViewServlet. patient was discharged to a specialty care facility, and she received a number of daily ser?docBase=renetnt&folderPath=/ doses of methotrexate. Prescribing%20Information/PIs/Roxane/ Pennsylvania facilities have reported events involving methotrexate to the Pennsylvania Methotrexate/Methotrexate%20Tablets%20 USP%202.5mg.pdf. Patient Safety Authority. Ongoing individual case review and analysis indicated that dosing errors similar to those cited in the literature5-8 have been occurring in Pennsyl- vania. Authority analysts reviewed all methotrexate-related reports submitted to the Authority to identify what is going wrong. DATA OVERVIEW Analysts examined all medication error reports submitted to the Authority from June 2004 through July 2010 that included mention of methotrexate (n = 253) in the medication prescribed, medication administered, or event detail data fields. Review of the events found that 204 indicated that some type of error occurred involving metho- trexate. (In the remaining 49 event reports, methotrexate was mentioned in the error Vol. 8, No. 2—June 2011 Pennsylvania Patient Safety Advisory Page 77 ©2011 Pennsylvania Patient Safety Authority F RO M T H E DATA B A S E description, but the drug was not used Table 1. Top Five Event Types Involving Methotrexate, June 2004 through in error.) July 2010 (N = 204) Analysis of the events filtered by reported ERROR TYPE NUMBER OF EVENTS level of harm showed that nearly half the Wrong dose/overdosage 42 (20.6%) errors involving methotrexate (100 of 204) reached the patient. Roughly 3% of the Wrong dose/underdosage 22 (10.8%) reports (7 of 204) indicated that some Wrong time 21 (10.3%) level of patient harm, including death, Dose omission 21 (10.3%) occurred. Patients required either moni- toring to confirm that no harm occurred Wrong drug 16 (7.8%) or intervention to prevent harm in another 15% of the events (31 of 204). patient. The harm scores associated with days. Patient developed neutropenia Wrong-dose events were the most com- these 33 reports can be found in Table 2. and was transferred to ICU [inten- mon type of events (64 of 204) (see Table Analysts examined these 33 events to sive care unit]. Patient recovered 1). Of wrong-dose events, 65.6% (42 determine where in the medication-use completely without further sequelae, of 64) resulted in an overdosage. Of all process the event originated. Analysis has no permanent harm, and was methotrexate-related events, 20.6% (42 of revealed that 84.8% of the problems (28 discharged to home. 204) were wrong-dose/overdosage errors. of 33) began with the prescriber’s order. The physician wrote [an order] for MIX-UPS OF DAILY VERSUS Despite opportunities in the dispens- methotrexate daily 10 mg. The WEEKLY DOSING ing and administration phases of the pharmacist entered the dose and the medication-use process to intercept these patient received 5 days of the drug When looking just at reports of wrong- errors, 42.9% of these prescribing errors before the error was caught. The dose/overdosage events, analysts found reached the patient, with five events records from the facility where the that 59.5% (25 of 42) indicated that the resulting in patient harm. Order-entry patient came from showed that the patient was to receive methotrexate once errors accounted for 9.1% of the mix-ups patient was taking a total of or twice a week but was ordered and/or (3 of 33). 10 mg weekly. The patient experi- administered the drug daily. This finding enced stomatitis, pancytopenia, and prompted a review of all methotrexate- Selected events reported to the Authority include the following: was transferred to the ICU. related reports for occurrences of mix-ups between weekly and daily dosing. Analysis Patient has past medical history of CONCLUSION of the narratives of all event types uncov- rheumatoid arthritis. Patient taking ered 8 additional reports, for a total of 33 methotrexate 10 mg po once weekly Roughly 20% of reported events involving reports that described situations in which on Mondays and [this prescription methotrexate were identified as wrong an inappropriately high dose was ordered was] correctly listed on medication doses/overdosages. A total of 33 events or administered because of a mix-up reconciliation form. Physician writes (16.2% of all methotrexate-related events) between daily and weekly dosing sched- order for methotrexate 5 mg po BID were directly related to mix-ups in which ules. These 33 reports account for 16.2% daily. Order transcribed on Kardex the patient was to receive methotrexate of all methotrexate-related events. Further and entered by pharmacist as daily once or twice a week but was ordered analysis of these 33 reports found that 11 versus weekly. One erroneous dose of and/or administered the drug daily. The patients received at least one erroneous 5 mg of drug was given. Intercepted risk of this type of mix-up is likely higher dose before the error was detected, while by pharmacy staff the next day. for methotrexate than for most other 20 patients had not received the drug. For drugs, as relatively few other medications Patient admitted due to severe compli- are dosed once or twice a week. Nearly the two remaining reports, analysts were cations of rheumatoid arthritis. Prior unable to verify that the patient received a 85% of the daily-versus-weekly dosing to admission, patient was taking events (28 of 33) began with the prescrib- dose because there was insufficient detail methotrexate 10 mg twice per week. included in the reports’ event descrip- er’s order. Just over 15% of these events On admission, physician wrote order (5 of 33) resulted in patient harm, with tions. However, based on the harm scores, for methotrexate twice per day and it appears that the errors reached the two resulting in patient death. medication was administered for five Page 78 Pennsylvania Patient Safety Advisory Vol. 8, No. 2—June 2011 ©2011 Pennsylvania Patient Safety Authority Table 2. Harm Scores* of All Events Identified as Involving Inadvertent Daily Dosing of Methotrexate Rather Than Once or Twice Weekly, Reported June 2004 through July 2010 HARM SCORE NUMBER OF EVENTS No Harm (n = 28) A. Circumstances that could cause adverse events 1 (3.0%) B1. An event occurred, but it did not reach the individual because of chance alone 1 (3.0%) B2. An event occurred, but it did not reach the individual because of active recovery efforts by caregivers 16 (48.5%) C. An event occurred that reached the individual but did not cause harm and did not require increased monitoring 6 (18.2%) D. An event occurred that required monitoring to confirm that it resulted in no harm and/or required intervention to prevent harm 4 (12.1%) Harm (n = 5) E. An event occurred that contributed to or resulted in temporary harm and required treatment or intervention 1 (3.0%) F. An event occurred that contributed to or resulted in temporary harm and required initial or prolonged hospitalization 1 (3.0%) G. An event occurred that contributed to or resulted in permanent harm 0 (0%) H. An event occurred that resulted in a near-death event (e.g., patient required ICU [intensive care unit] care or other intervention necessary to sustain life) 1 (3.0%) I. An event occurred that contributed to or resulted in death 2 (6.1%)) Total 33 * Adapted from: National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). NCC MERP index for categorizing medication errors [online]. 2001 [cited 2010 Sep 17]. Available from Internet: http://www.nccmerp.org/medErrorCatIndex.html. NOTES 1. Lexi-Comp Online. Methotrexate psoriasis. Am J Health Syst Pharm 2008 Nov 7. Weingart SN, Toro J, Spencer J, et al. [online]. 2010 [cited 2010 Oct 28]. Avail- 15;65(22):2117-21. Medication errors involving oral able from Internet: http://online.lexi. 4. Sinicina I, Mayr B, Mall G, et al. Deaths chemotherapy. Cancer 2010 May com/crlsql/servlet/crlonline. following methotrexate overdoses by 15;116(10):2455-64. 2. Roxane Laboratories, Inc. Methotrexate medical staff. J Rheumatol 2005 Oct; 8. Institute for Safe Medication Practices. [full prescribing information online]. 2008 32(10):2009-11. Special alert: Methotrexate overdose May [cited 2010 Oct 28]. Available from 5. Blinova E, Volling J, Koczmara C, et al. due to inadvertent administration daily Internet: http://bidocs.boehringer-ingel- Oral methotrexate: preventing inadver- instead of weekly [online]. ISMP Med heim.com/BIWebAccess/ViewServlet. tent daily administration. Can J Hosp Saf Alert 2002 Dec 3 [cited 2011 Feb 5]. ser?docBase=renetnt&folderPath=/ Pharm 2008 Jul-Aug;61(4):275-7. Available from Internet: http://www. Prescribing%20Information/PIs/Roxane/ 6. Moore TJ, Walsh CS, Cohen MR. ismp.org/hazardalerts/ha.pdf. Methotrexate/Methotrexate%20Tablets% 9. Family files lawsuit against UPMC Pas- Reported medication errors associated 20USP%202.5mg.pdf. with methotrexate. Am J Health Syst Pharm savant [online]. Pittsburgh Post-Gazette 3. Bookstave PB, Norris L, Rudisill C, 2004 Jul 1;61(13):1380-4. 2010 Jun 11 [cited 2011 Feb 1]. Available et al. Multiple toxic effects of low-dose from Internet: http://www.post-gazette. methotrexate in a patient treated for com/pg/10162/1064827-54.stm. Vol. 8, No. 2—June 2011 Pennsylvania Patient Safety Advisory Page 79 ©2011 Pennsylvania Patient Safety Authority PENNSYLVANIA PATIENT SAFETY ADVISORY This article is reprinted from the Pennsylvania Patient Safety Advisory, Vol. 8, No. 2—June 2011. The Advisory is a publication of the Pennsylvania Patient Safety Authority, produced by ECRI Institute and ISMP under contract to the Authority. Copyright 2011 by the Pennsylvania Patient Safety Authority. This publication may be reprinted and distributed without restriction, provided it is printed or distributed in its entirety and without alteration. Individual articles may be reprinted in their entirety and without alteration provided the source is clearly attributed. This publication is disseminated via e-mail. To subscribe, go to http://visitor.constantcontact.com/ d.jsp?m=1103390819542&p=oi. To see other articles or issues of the Advisory, visit our website at http://www.patientsafetyauthority.org. Click on “Patient Safety Advisories” in the left-hand menu bar. THE PENNSYLVANIA PATIENT SAFETY AUTHORITY AND ITS CONTRACTORS The Pennsylvania Patient Safety Authority is an independent state agency created by Act 13 of 2002, the Medical Care Availability and Reduction of Error (“Mcare”) Act. Consistent with Act 13, ECRI Institute, as contractor for the Authority, is issuing this publication to advise medical facilities of immediate changes that can be instituted to reduce Serious Events and Incidents. For more information about the Pennsylvania Patient Safety Authority, see the Authority’s An Independent Agency of the Commonwealth of Pennsylvania website at http://www.patientsafetyauthority.org. ECRI Institute, a nonprofit organization, dedicates itself to bringing the discipline of applied scientific research in healthcare to uncover the best approaches to improving patient care. As pioneers in this science for nearly 40 years, ECRI Institute marries experience and independence with the objectivity of evidence-based research. More than 5,000 healthcare organizations worldwide rely on ECRI Institute’s expertise in patient safety improvement, risk and quality management, and healthcare processes, devices, procedures and drug technology. The Institute for Safe Medication Practices (ISMP) is an independent, nonprofit organization dedicated solely to medication error prevention and safe medication use. ISMP provides recommendations for the safe use of medications to the healthcare community including healthcare professionals, government agencies, accrediting organizations, and consumers. ISMP’s efforts are built on a nonpunitive approach and systems-based solutions.