Toxicity from methotrexate mix-up due to medication error: Stevens–Johnson syndrome

INTRODUCTION

Methotrexate (MTX) is an antimetabolite drug used for a vast number of conditions. It is an analogue of folic acid and inhibits dihydrofolate reductase and thus the synthesis of de novo purine, which is essential for DNA synthesis. Because of its anti-inflammatory property, MTX is used in autoinflammatory conditions such as rheumatoid arthritis (RA) and psoriasis. MTX remains an anchor disease-modifying antirheumatic drug (DMARD) for the treatment of RA.

CASE REPORT

A 50-year-old female patient presented with an ulcerated lesion over the right foot, face including the forehead, both cheeks, medial surface of both forearms, buccal mucosa, and gingiva, developing over a period of 4–5 days. It started as brown discoloration and darkening of skin over the right foot, associated with itching and pain; later, excoriation of skin started resulting in ulcerations. The patient is a known case of RA for 10 years; she was prescribed Tab. MTX 10 mg/week and Tab. leflunomide 20 mg twice a day. On May 31, 2022, due to complaints of increased joint pain, the patient was started on treatment with Inj. MTX 20 mg/week for 4 months (June-September 2022), and after control of pain on October 04, 2022, the patient was shifted on Tablet MTX 10 mg/week and Tab. leflunomide 20 mg twice daily. For about 2½ weeks patient followed the prescribed schedule. On October 22, 2022, the patient developed cough and cold; she was prescribed Tab. Azithromycin 500 mg once a day, Tab. Levocetirizine 5 mg and Tab. Paracetamol 500 mg twice daily for 5 days.

Due to the increased burden of drugs and the similar appearance of formulations, from October 23, 2022, to November 06, 2022, the patient had mistakenly taken Tab. MTX twice daily instead of Tab. leflunomide. After 7 days, on 30^th October, the patient started developing skin first on the right foot. The patient developed itching, brown pigmentation, and darkening with lesions over the right foot. Within 2–3 days on 1^st–2^nd November, itching increased and skin excoriation started to develop. On around 4^th–5^th November 2022, pain increased with oval-shaped ulcers, well-defined raised edges with accumulation of pus. Within 2–3 days of the development of foot ulcers, other areas, such as skin of face, hands, limbs, and mucosal surface of the mouth, were also involved in the form of itching and redness and ulcer [Figures 1 and 2]. On November 07, 2022, the patient reported to his treating physician at private hospital, the condition was identified as drug-induced and Tab. MTX was stopped, with hematological and biochemical investigations. Treatment for skin ulcers like clotrimazole cream and antibiotics for infection was initiated. The patient was referred to Medical College Hospital as ulcers worsened.

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Figure 1:

Patient reaction on hand at the time of admission to the civil hospital, Rajkot.

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Figure 2:

Patient reaction on the face at the time of admission to civil hospital, Rajkot.

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DISCUSSION

RA is a chronic condition that mainly affects the joints but can also involve other parts of the body such as the skin, blood vessels, muscles, heart, and lungs.^[1] In 1988, the Food and Drug Administration (FDA) approved MTX to treat RA.^[2] MTX works by affecting adenosine receptors on immune cells, which helps to reduce inflammation.^[3,4] For RA treatment, MTX is usually taken orally or by injection, with doses ranging from 7.5 mg to 25 mg once a week.^[4] It typically starts to show effects within 3–6 weeks and is generally well tolerated, though its side effects can be dose-dependent.^[5] In the index case, the patient had accidentally taken oral MTX at a dose of 20 mg daily for 15 days. This higher dose caused severe toxicity. MTX toxicity affects rapidly dividing cells like those in the bone marrow, leading to low blood cell counts (pancytopenia).^[6] There are several factors associated with the toxicity of MTX such as age, drug interaction, and comorbidity but the most common is accidentally taken daily doses of MTX instead of weekly doses which may lead to severe acute toxicity, including the presence of oral mucositis, cutaneous ulcerations, and pancytopenia (as drug inhibits rapid cell turnover), followed by sepsis.^[7] All these features were present in the index case. For hematological toxicity, it can be managed by stopping the drug and giving adequate hydration, intravenous leucovorin, recombinant growth factors, transfusion of blood and its components, antibiotic and antifungal coverage due to high risk of infection.^[8] In the index case, two drugs, MTX and leflunomide, had similar appearance, with a prominent manufacturer name, which led to look-alike sound-alike (LASA) medication error [Figures 3 and 4]. Medication names in packaging are visually similar, medication is identified as look-alike medications, and medication names that sound similar are identified as sound-alike medications (LASA).^[9] LASA drugs can cause serious medication mistakes that might harm patients. Brand names that look alike are a big reason for these errors. This could lead to unnecessary drug effects, side effects, or even worsen untreated diseases due to the wrong medication. In countries like India with lower income, uneducated people, pharmacists without adequate training make LASA drugs, a big health risk.^[10] Here, the condition was a result of a combination of lack of understanding of drug names, uneducated patient, multiple drugs, and same manufacturer name displayed prominently for both the drug formulations. A prominent manufacture name may have contributed to the accidental ingestion of Tab. MTX instead of Tab. leflunomide.

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Figure 3:

Strips of drug – methotrexate.

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Figure 4:

Strips of drug – leflunomide.

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CONCLUSION

MTX is used as a DMARD for RA. A similar-looking drug package may have contributed to a medication error and led to serious life-threatening consequences. Hence, it is important for physicians and pharmacists to interact with patients and explain about the drugs and their adverse effects.