Methotrexate Toxicity Results in Patient Complications

Case Summary

This case involves a female patient who was prescribed methotrexate for rheumatoid arthritis. Her physician initially prescribed a dosage of two 2.5 mg tablets once weekly. She was reportedly doing well with this protocol. Upon her transfer to another practice, the records from the previous practitioner were incorrectly transcribed and consequently, the methotrexate prescription was erroneously recorded as being two 2.5 mg tab tablets by mouth once daily.

The error increased her weekly dosage from 5 mg to 35 mg and the prescription was repeatedly filled by the same pharmacy. This resulted in the patient taking this higher dosage for approximately two months. The patient was then admitted to the hospital with complications including pneumonia, dehydration, and weakness. The prescribed methotrexate dosage continued throughout the hospital admission and the patient was discharged on the same high dosage.

Several days post-discharge, she suffered a bloody emesis. She was taken to the Emergency Department and transferred to a higher level of care where she was diagnosed with methotrexate toxicity. Upon discharge, the patient suffered several methotrexate complications due to the prescription error and overdose.

Case Theory

In this case, both the pharmacist and the rheumatologist were negligent. The pharmacist and treating physician failed to recognize and address the inappropriate dosage. The second treating rheumatology healthcare team also failed to recognize and report the patient’s symptoms of methotrexate toxicity to the prescribing physician.

Proper methotrexate adult dosage is based on body size and must be determined by the treating physician. 20 milligrams per meter squared of body size once a week is a normal starting dose that is adjusted as needed and tolerated. In adult RA patients this initial dose normally amounts to an average of 7.5 milligrams once a week. Studies show a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression at doses greater than 20 mg per week.

In high doses, methotrexate poisoning symptoms include vomiting, diarrhea, and gastrointestinal bleeding, as well as severe bone marrow suppression and liver function disturbance. Long-term liver injury accompanied by blood level elevations of ALT and AST can result in hepatic fibrosis.

Methotrexate can cause reversible neurotoxicity in the form of white matter injury. Treatments are available for use in the early detection of these changes that provide a readily available, rapid, noninvasive reversal for methotrexate toxicity. In this case, had the physician been aware, or made aware of the mistake, there were three antidotes used for methotrexate toxicity including leucovorin, thymidine, and glucarpidase. Leucovorin is the reduced and active form of folic acid. It selectively rescues normal cells from toxic effects caused by methotrexate inhibition of reduced folate production. These effective treatments could have reduced the complications of toxicity and the likelihood of permanent sequelae resulting in an improved outcome for this patient.

Expert Witness Specialties

Pharmacy Toxicologist

An expert in Pharmacotoxicity can opine on the appropriate dosage of Methotrexate to avoid toxicity and the need for diligence in conveying dosage errors and risk.

Rheumatology

An expert in Rheumatology can speak to the standard of care when treating Rheumatoid Arthritis with Methotrexate, and the appropriate dosage for a similar patient.

Questions for the Expert Witnesses

• What is the appropriate dose of methotrexate for the treatment of rheumatoid arthritis?
• What are some potential long-term complications of methotrexate toxicity?
• What is the responsibility of a pharmacist when repeatedly filling an abnormally high dosage of methotrexate?
• How can a delay in the diagnosis of methotrexate toxicity affect a patient’s outcome?
• Should the physician have been alerted to symptoms of toxicity upon hospitalization?
• Is methotrexate toxicity a known complication in treatment?

Expert Witness Involvement

Here is what an expert in Rheumatology had to say about this case:

Expert Witness Response E-294961

I am a board-certified rheumatologist and I care for patients on methotrexate every day. The appropriate dose of methotrexate for treating rheumatoid arthritis is 25mg to 30mg, but the tablets should have been given weekly, not daily. Since the patient was taking the tablets on a regular basis, she should have been monitored during those months and not have gone unchecked. The impact of delaying a diagnosis of methotrexate toxicity depends on which organs were affected. If it is a case of GI toxicity it could take a few weeks for a patient to feel like themselves again, but if it is liver toxicity it could result in liver failure, death, or the need for a transplant.