Type of liver injury Time of onset of the event Time from drug intake until reaction onset Time

from drug withdrawal until reaction onset Risk factors

CIOMS/RUCAM scale Hepatocellular first exposure

Cholestatic/mixed

Points

second exposure first exposure

second exposure +2 +1 +1 +1 +1 +3 +2 +1 +0 -1

5 to 90 days 1 to 15 days <5 or >90 days >15 days 15 days 15 days

5 to 90 days 1 to 90 days <5 or >90 days >90 days 30 days 30 days

Alcohol Alcohol or pregnancy Age 55 years Age 55 years >50% improvement 8 days >50% improvement 30 days >50% improvement 180 days <50% improvement 180 days Course of the reaction Lack of information or no Lack of information or no improvement improvement Worsening or <50% improvement 30 days Concomitant therapy: o Time to onset incompatible: +0 o Time to onset compatible but with unknown reaction: -1 o Time to onset compatible but known reaction: -2 o Role proved in this case: -3 o None or information not available: +0 Exclusion of non drug-related causes: o Rule out: +2 o Possible to not investigated: -2 to +1 o Probable: -3 Previous information on hepatotoxicity: o Reaction unknown: +0 o Reaction published but unlabeled: +1 o Reaction labeled in the product's characteristics: +2

Response to re-administration: o Positive: +3 o Compatible: +1 o Negative: -2 o Not available or not interpretable: +0 o or plasma concentration of drug known as toxic: +3 o or validated laboratory test with high specificity, sensitivity, and predictive values: Positive: +3 Negative: -3 Not interpretable or not available: +0

Score analysis

0 or lower: relationship with the drug excluded 1-2: unlikely 3-5: possible 6-8: probable >8: highly probable