(054) Incidence Rates of Severe Acute Liver Injury Associated with Hepatotoxic Medication Combinations: Approach to Inform Future Drug-Drug Interaction Studies

Background: Real-world data could be used to identify concomitantly-administered medications associated with elevated rates of hospitalization for severe acute liver injury (SALI).

Objectives: To measure rates of hospitalization for SALI among users of combinations of potentially hepatotoxic medications.

Methods: We first created 195 separate cohorts of new outpatient initiators of suspected hepatotoxic medications (≥4 reported cases of drug-induced liver injury in the US National Institutes of Health LiverTox website) within the US Department of Veterans Affairs electronic health records between 2000-2021. The primary outcome was incident hospitalization for SALI, defined by a composite endpoint of either inpatient: 1) alanine aminotransferase >120 U/L + total bilirubin >2.0 mg/dL, or 2) international normalized ratio 1.5 + total bilirubin >2.0 mg/dL, recorded within the first two days of admission. Patients were excluded if they had a history of liver/biliary disease or were prescribed an oral anticoagulant, to increase likelihood that SALI was associated with the medication. We classified medications with incidence rates (IR) of hospitalization for SALI ≥5.0 events/10,000 person-years (PY) as the most hepatotoxic. Among initiators of the most hepatotoxic medications, we estimated age- and sex-adjusted IRs and 95% confidence intervals (CI) for SALI across the most common combinations for patients dispensed ≥1 concurrent hepatotoxic medications.

Results: Among 17 cohorts of initiators of the most hepatotoxic medications, prevalence of ≥1 hepatotoxic medication dispensed within 90 days prior ranged between 8.9-46.7%. Among users of hepatotoxic medication combinations, 18 had a rate of SALI >5 times higher than initiators without concurrent hepatotoxic medication. The most commonly dispensed medications included clavulanate (n=1,117,686; SALI IR: 6.7 events/10,000 PY [95% CI: 4.5-10.1]), ciprofloxacin (n=926,618; SALI IR: 6.4 events/10,000 PY [95% CI: 4.1-10.0]), and sulfamethoxazole (n=876,779; SALI IR: 6.9 events/10,000 PY [95% CI: 4.6-10.3]). Rates of SALI were >5 times higher in users of these medications with the following combinations: clavulanate with fluconazole (IR: 68.8 events/10,000 PY [95% CI: 22.2-213.4]), ciprofloxacin with prochlorperazine (IR: 87.7 events/10,000 PY [95% CI: 21.9-350.6]), and sulfamethoxazole with lenalidomide (IR: 352.0 events/10,000 PY [95% CI: 132.1-937.9]).

Conclusions: Evaluating rates of SALI among users of concomitant of hepatotoxic medications can identify combinations that warrant further evaluation in self-controlled or cohort analyses of drug-drug interactions for the evaluation of hepatic safety.