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An event is serious (based on the ICH definition) when the patient outcome is:
* death
* life-threatening
* hospitalisation
* disability
* congenital anomaly
* other medically important event
* Drug interaction
A 19-year-old woman developed toxic hepatitis secondary to drug-induced hepatotoxicity following concomitant administration of favipiravir and methotrexate [routes not stated].
The woman was diagnosed with classical type osteosarcoma. She received neoadjuvant chemotherapy with cisplatin and doxorubicin with partial response. Thereafter, she underwent surgery and knee prosthesis was applied. Following the surgery, cisplatin and etoposide were given as adjuvant therapy. However, 3 months after completion of adjuvant therapy, local recurrence and lung metastases were noted. Therefore, she started receiving high-dose methotrexate 8 g/m 2 twice a week as the first-line treatment for metastatic disease. Meanwhile, she received hydration and urine alkalisation as inpatient before each treatment cycle. Folinic acid was also initiated based on her blood methotrexate levels. Two methotrexate cycles were completed without any complication. After 12 hours of the end of the third cycle of high-dose methotrexate therapy, she was admitted with a fever. She also developed shortness of breath and cough in addition to fever; thus, she was tested for SARS-CoV2 PCR. Nevertheless, on 22 January 2021, favipiravir (a loading dose of 2 × 1600mg on the first day of treatment and dose of 2 × 600mg on the second day) treatment was started for suspected COVID-19 infection. However, her SARS-CoV2 PCR test resulted negative. Her liver enzymes started to increase 12 hours after the favipiravir treatment, and at 36 hour, levels were measured as AST of 203 U/L, ALT of 250 U/L and total bilirubin level of 2.26 mg/dL.
The woman's treatment with favipiravir was discontinued on day 2 of the treatment due to the serious increase in liver enzymes, and SARS-CoV2 PCR result was negative. The total bilirubin level increased up to 6.2 mg/dL and the direct bilirubin level to 3.4 mg/dL. While AST and ALT levels increased approximately 10 folds, there was no significant change in ALP and GGT levels. As her liver enzymes increased 12 hours after the initiation of favipiravir, a diagnosis of toxic hepatitis secondary to drug-induced hepatotoxicity caused by interaction between favipiravir and methotrexate (reduced methotrexate elimination by inhibition of aldehyde oxidase) was made. Therefore, she was treated with methylprednisolone. The serum methotrexate level trended down to 0.01 mmol/L within 24 hours of the methylprednisolone therapy. After 72 hours from discontinuation of favipiravir, her total bilirubin level trended down to 3 mg/dL. She was discharged from hospital on oral prednisolone treatment. Five days after discharge, her repeat blood tests showed complete resolution of liver function test abnormality. The Drug Interaction Probability Scale was used to evaluate possible drug interactions and the result was calculated as 5 points (probable).