Clinical Pharmacology

"Adverse Drug Event of the month"

A patient with accidental methotrexate overdose - a case of medication error, a preventable adverse event.

Case report:

A 57-year-old male patient who visited the dermatology outpatient dept in February 2005 was diagnosed to have psoriasis vulgaris. The patient had lesions all over body except face since November 1994. He was prescribed tablet methotrexate 7.5mg (3 tablets of 2.5mg each) stat on Wednesday every week along with folic acid 5mg and white soft paraffin for local application on the lesions. Stat is derived from the Latin word statim meaning with "no delay" or "at once". Both the patient and the pharmacist mistook it for "start".

Thus, the patient inadvertently started taking 7.5 mg methotrexate daily starting from Wednesday for a total of 6 days. After taking total of 16 tablets (total 40mg) the patient presented with erythema and tenderness and "burning" of existing lesions which started on Day 3 of treatment which gradually worsened. Earlier the lesions were never painful. Patient also developed gastritis, two episodes of vomiting and shivering intermittently during this treatment. Patient stopped taking methotrexate on 7th day after consuming 16 tablets. After stopping the treatment patient recovered within a week. He was then prescribed folic acid 10mg. His blood was collected for estimation of plasma methotrexate levels before starting folic acid (10mg). At the same time his blood was collected for complete blood cell count.

Methotrexate levels in plasma were estimated by High Performance Liquid Chromatography (HPLC). Sensitivity of the assay was 0.02mg/ml. Method was precise with interday and intraday variation at 0.02mg/ml of MTX being 7.92% and 7.93% The assay was linear over the range of 0.02 mg/ml -1.0mg/ml with a correlation coefficient of r = 0.999.

Methotrexate was not measurable in his plasma. It is likely that since blood was collected two days after he stopped treatment, methotrexate could not be detected (terminal half life for low dose methotrexate is 3-10 hours and for high dose it is 8-15 hours).

After complete recovery patient was again put on weekly methotrexate (15mg once weekly) and now takes the medication correctly.

Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses) (2). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematological and gastrointestinal reaction for example, leucopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported (1).

Apart from hepatic, hematological, neurological and renal adverse effects severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases (1).

Painful erosion of psoriatic plaques is a less common sign of methotrexate toxicity that may precede evidence of bone marrow suppression. A case report describing a 43-year-old white man developing a shallow erosion of a psoriatic plaque after chronic administration of methotrexate was published as early as 1988 (3). Another case report described two patients in whom painful erosions of their psoriasis developed as the presenting sign of methotrexate toxic (4).

In case of this patient the adverse event was due to medication error, the patient took methotrexate daily instead of weekly schedule.

What is a medication error?

"A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use"(5).

Medication errors, which are iatrogenic injuries, are a well-known, worldwide phenomenon and are common, costly and important (6,7). Approximately, 28% of adverse dug events are associated with medication errors and therefore judged preventable (8).

In a study published in 2004, all adverse-event reports submitted to US FDA between November 1997 and December 2001 indicating potential medication errors involving methotrexate were analyzed to determine the indication for use, the type of error, and the point in the medication-use process where the error occurred. A total of 106 cases of reported medication errors associated with methotrexate were identified, including errors resulting in 25 deaths (24%) and 48 other serious outcomes (45%). The most common types of errors involved confusion about the once-weekly dosage schedule (30%) and other dosage errors (22%). The most frequently involved indications for use were rheumatoid arthritis (42%) and psoriasis (12%). Of the errors, 39 (37%) were attributable to the prescribers, 21 (20%) to the patient, 20 (19%) to dispensing, and 18 (17%) to administration by a health care professional (9).

Methotrexate is associated with significant preventable medication errors that warrant careful measures to improve patient safety. While some of the errors could happen for any drug and be hazardous, the distinctive weekly or cyclical dosage scheme and low therapeutic index constitute the most clearly identifiable risks of methotrexate and accounted for the largest number of preventable serious injuries and deaths (9).

Dispensing methotrexate in the weekly dosage pack and communicating effectively with patients about unusual dosage regimens can reduce adverse events. Clinicians should encourage feedback to ensure that the patient understands the weekly dosage schedule and that the medication should not be used "as needed" for symptom control. Patients should be given clear written instructions that name a specific day of the week for taking the drug, that emphasize the weekly-not daily-dosage schedule, and that explain the possible outcomes of a dosage error (9).

To reduce the medication errors patients may be given a treatment diary to monitor their methotrexate treatment. Pharmaceutical companies should develop new packaging (once weekly package) (10). Another problem with methotrexate is similarity between 2.5mg and 10 mg tablets. Having different colour, size and shape for two different strengths can prevent potential confusion.

References:

1. Methotrexate Sodium. Mosby's Drug Consult. Online available at http://home.mdconsult.com/das/drug/view/45056197-2/1/1770/top?sid=343805115. Accessed on 25/02/2005.
2. Karch AM, Karch FE, A weekly dosage taken daily. Am J Nurs 2003;103:64.
3. Kaplan DL, Olsen EA. Erosion of psoriatic plaques after chronic methotrexate administration. Int J Dermatol 1988;27:59-62
4. Pearce HP, Wilson BB. Erosion of psoriatic plaques: an early sign of methotrexate toxicity. Am Acad Dermatol 1996;35:835-8
5. What is a Medication Error? National Coordinating Council for Medication Error Reporting and Prevention. Online available at http://www.nccmerp.org/aboutMedErrors.html. Accessed on 11/02/2005.
6. Lesar TS, Lomaestro BM, Pohl H. Medication prescribing errors in a teaching hospital: a 9 years experience. Arch Int Med 1997;157:1569-76.
7. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients: excess length of stay, excess cost, and attributable mortality. JAMA 1997;277:301-6.
8. Bates DW, Cullen D, Laird N et al. Identifying adverse drug events and potential adverse events: implications for prevention. JAMA 1995;274:29:34.
9. Moore TJ, Walsh CS, Cohen MR. Reported medication errors associated with methotrexate. Am J Health Syst Pharm 2004;61(13):1380-4.
10. Susan Mayor. UK introduces measures to reduce errors with methotrexate. BMJ 2003;327(7406):70.

Photographs of the patient showing erythema and ulceration of the lesions

Fig. 1	Fig. 2