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Hospital Admission Due to High-Dose Methotrexate Drug Interaction

Lydia C. Siegel, MD; Tejal K. Gandhi, MD, MPH | January 1, 2009
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The Case

A 40-year-old woman with osteosarcoma in her left leg received neoadjuvant high-dose methotrexate, doxorubicin, and cisplatin (MAP) prior to left leg resection and reconstruction. She continued to receive MAP in the outpatient oncology center after surgery. Four months after leg reconstruction, the patient developed left lower extremity erythema and was admitted to the plastic surgery service for presumed cellulitis. The wound was debrided, and the patient received antibiotic therapy. Four days after admission, she was discharged home to complete a 14-day course of intravenous vancomycin and oral ciprofloxacin.

On the 10th day of antibiotics, she went to the outpatient oncology center for high-dose methotrexate in accordance with the MAP cycle. She returned the following day to the oncology center for routine leucovorin "rescue" and IV hydration. She reported extreme fatigue and was found to have transaminitis (aspartate aminotransferase [AST] 668 IU/L, alanine aminotransferase [ALT] 822 IU/L) in the presence of an elevated methotrexate blood level. After her readmission to the hospital for leucovorin rescue and aggressive hydration, she received a diagnosis of methotrexate toxicity due to a presumed interaction with ciprofloxacin.

The Commentary

Significant progress has been made in reducing adverse drug events (ADEs) in cancer chemotherapy with the advent of controlled-dose pumps, protocols, checklists, multiple reviews, and the introduction of pharmacists into chemotherapy infusion centers. These and other inventions represent important first steps for improving the safety of treatment in both inpatient and outpatient settings.(1) However, this case illustrates the ways in which chemotherapy risks extend beyond the infusion center, and how safety considerations must now adapt to a broader environment with multiple transitions of care, many prescribers, and increasingly frequent outpatient treatment.

As with most ADEs, this case involves numerous contributing factors, including several transitions of care, lack of coordination, and, in this case, a rare interaction. Care fragmentation seems to have created an opportunity for this ADE to occur: it appears that an oncology consult service did not follow the patient during her hospitalization or consult with her treating team upon hospital discharge, such that her ongoing chemotherapy did not receive adequate attention.

Electronic medical records (EMRs) with computerized prescriber order entry have been promoted as the best method to alert clinicians about potential drug–drug interactions. However, the cyclic nature of outpatient chemotherapy creates a unique safety challenge that may not be detected by many EMRs. In this case, even if an EMR had been available in the inpatient setting, such a system may not have been linked to the patient's outpatient medication list. Even when such lists are available, an integrated EMR with a complex decision support feature is required, one that can alert inpatient physicians about an interaction with an intermittent outpatient medication. And finally, an EMR is not always the complete solution, since alerts can be voluntarily overridden by a prescriber unfamiliar with a specific interaction.(2)

Another best practice is to require pharmacist review of medications at discharge to identify potential problems such as drug interactions. In one study, a pharmacist intervention to review medications with patients at discharge and screen for likely nonadherence, combined with a follow-up call 3-5 days postdischarge, led to fewer medication discrepancies and fewer preventable ADEs.(3) It is not known whether a similar review occurred in this case. However, even if there had been final pharmacy review, the pharmacist may not have had access to the patient's home medications or chemotherapy regimen, particularly if the patient's care took place at separate institutions.

The patient's outpatient pharmacy likely cannot access her complete medication list either, another missed opportunity for postdischarge alerts. Finally, and most importantly, prior to her next cycle of methotrexate in the ambulatory oncology clinic, there appears to have been no formal review of any new medications added to her regimen since her last dose. This could have allowed her oncologist to delay chemotherapy until the ciprofloxacin was cleared, avoiding the methotrexate toxicity and its sequelae.

Patients undergoing chemotherapy face potential ADE risks even without hospital admissions. Many also take over-the-counter medications and often complementary or alternative agents as well, and they see other prescribers who may not be familiar with the numerous possible interactions. Moreover, methotrexate toxicity can occur with several common over-the-counter medications, such as nonsteroidal antiinflammatory drugs (NSAIDs), as well as prescription antibiotics such as trimethoprim and penicillin. Therefore, medication histories must include questions about over-the-counter and complementary, alternative, and herbal medications to generate as comprehensive a list as possible. These histories should be taken at every visit.

Preventing Ambulatory Medication Errors

As more complex forms of care shift to the outpatient setting, avoiding medication errors in ambulatory care settings is an increasingly important challenge.(4,5) Transitions of care, particularly at hospital discharge, are a common source of preventable and ameliorable ADEs, including drug–drug interactions.(6) Indeed, a new mandate by the Joint Commission requires medication reconciliation in both inpatient and outpatient settings to ensure careful review of the entire medication list and reconciliation of newly prescribed medications with home regimens.

Electronic comparison of preadmission medication lists at hospital admission and discharge has also been shown to be an effective method of reducing avoidable postdischarge ADEs. A preadmission medication list that can be compared with a discharge list (7) and reviewed with patients prior to discharge for changes that were made in the hospital is an important step to ensure patient understanding, lack of duplication, and lack of critical interactions. Adapting these inpatient models to the outpatient oncology setting can systematize the medication reconciliation process and help avoid future ADEs.(8)

For example, the oncology team must maintain updated medication lists, ideally within an EMR, and perform medication reconciliation at every outpatient visit. This approach has the potential for reducing discrepancies, as shown in one recent study at an outpatient cancer center.(9) In addition to medication reconciliation prior to the administration of chemotherapy, patients should leave every ambulatory oncology visit with an updated medication list, which is essential for use at visits at other sites of care.

In addition to improved medication reconciliation, strong communication underlies patient safety: a member of the oncology team needs to be aware of new prescriptions or non-oncology medication dose changes. In a recent study of outpatient chemotherapy administration errors, improved communication was rated as the most likely intervention to reduce adverse events, enabling adjustments for renal function or other clinical factors prior to administration of a planned dose of chemotherapy.(10) Automated alerts for critical drug interactions may also help, in both the inpatient and outpatient settings, along with clinical decision support to guide safe antibiotic choices. Finally, pharmacist review of all medication orders should be required for potential interactions and dose adjustments, and pharmacists should be part of the medication reconciliation process.

Take-Home Points

  • A detailed medication history with reconciliation of newly prescribed medications should occur at every inpatient and outpatient visit and must include not only daily prescription medications but also ongoing treatments, over-the-counter medications, herbal supplements, and complementary, alternative, and traditional remedies, as any of these can contribute to serious ADEs. This medication history is particularly critical at care transitions, such as after hospital discharge.
  • It is crucial to consider drug–drug interactions when prescribing commonly used medications to patients receiving chemotherapy in any clinical setting. Pharmacist involvement on inpatient and ambulatory oncology teams can reduce avoidable ADEs.
  • A team-based approach, led by oncologists but with essential participation from pharmacists, is required for safe outpatient chemotherapy treatment. There must be continuity of care across inpatient and outpatient settings, particularly when no common EMR is available, or when patients receive care in a nonaffiliated hospital or clinic. In such instances, effective communication and timely access to records are essential.

Lydia C. Siegel, MD

Fellow in General Internal Medicine

VA Boston Healthcare System

Brigham and Women's Hospital

Tejal K. Gandhi, MD, MPH

Executive Director of Quality and Safety

Brigham and Women's Hospital

Assistant Professor of Medicine

Harvard Medical School


1. Gandhi TK, Bartel SB, Shulman LN, et al. Medication safety in the ambulatory chemotherapy setting. Cancer. 2005;104:2477-2483. [go to PubMed]

2. Weingart SN, Toth M, Sands DZ, Aronson MD, Davis RB, Phillips RS. Physicians' decisions to override computerized drug alerts in primary care. Arch Intern Med. 2003;163:2625-2631. [go to PubMed]

3. Schnipper JL, Kirwin JL, Cotugno MC, et al. Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med. 2006;166:565-567. [go to PubMed]

4. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003;348:1556-1564. [go to PubMed]

5. Thomsen LA, Winterstein AG, Søndergaard B, Haugbølle LS, Melander A. Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care. Ann Pharmacother. 2007;41:1411-1426. [go to PubMed]

6. Forster AJ, Murff HJ, Peterson JF, Gandhi TK, Bates DW. Adverse drug events occurring following hospital discharge. J Gen Intern Med. 2005;20:317-323. [go to PubMed]

7. Turchin A, Hamann C, Schnipper JL, et al. Evaluation of an inpatient computerized medication reconciliation system. J Am Med Inform Assoc. 2008;15:449-452. [go to PubMed]

8. Schnipper JL, Hamann C, Ndumele CD, et al. Effect of an electronic medication reconciliation application and process redesign on potential adverse drug events: a cluster-randomized trial. Arch Intern Med. 2009;169:771-780. [go to PubMed]

9. Weingart SN, Cleary A, Seger A, et al. Medication reconciliation in ambulatory oncology. Jt Comm J Qual Patient Saf. 2007;33:750-757. [go to PubMed]

10. Walsh KE, Dodd KS, Seetharaman K, et al. Medication errors among adults and children with cancer in the outpatient setting. J Clin Oncol. 2009;27:891-896. [go to PubMed]

This project was funded under contract number 75Q80119C00004 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services. The authors are solely responsible for this report’s contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report. View AHRQ Disclaimers
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