1. “FDA-approved drug labeling for the study of
drug-induced liver injury”
Chen M, Vijay V, Shi Q, et al.
Drug Discovery Today. May 2011
SUMMARY
By Florentina Eller
2. Study Objective
• The authors (from the National Center for Toxicological
Research of Food and Drug Administration) used FDA-
approved labels for prescription drugs to develop a
classification scheme for assessing and categorizing the drug-
induced liver injury (DILI) potential of a drug.
• The classification scheme can be used for retrospective
analysis of drugs to improving drug safety and development
Chen M, Vijay V, Shi Q, et al. FDA-approved drug labeling for the study of drug-induced liver
injury. Drug Discovery Today. (2011), doi:10.1016/j.drudis.2011.05.007
3. Study Method
• DILI potential classification based 3 FDA-approved labels:
– “boxed warning” (BW)
– “warnings and precautions” ( WP, for older labels)
– “adverse reactions” (AR)
• Daily Med database was used for drug labels
• Drugs must have been on the market for minimum 10 years
Chen M, et al. Drug Discovery Today. 2011.
4. Study Method - Laying the Foundation
DILI risk assessment is based on 3 characteristics:
• Causality – is liver injury caused by a drug or other causes?
• Incidence – how many cases are deemed significant?
• Severity – how severe an injury is considered a clinically
relevant DILI (e.g. elevated alanine transaminase (ALT),
disability and hospitalization, liver failure, liver transplantation
or death)
Chen M, et al. Drug Discovery Today. 2011.
5. Study Method - Laying the Foundation
What is Needed to Correctly Assess Hepatotoxic Risk?
• Reliable figures on the incidence of hepatic injury
• Accurate definitions of the characteristics and severity of liver
injury
However,
• Difficult obtaining exact figures on DILI incidence due to
serious under-reporting of adverse events
• DILI hepatotoxic risk is limited to a small sets of drugs and
incidents
Chen M, et al. Drug Discovery Today. 2011.
6. FDA Drugs Labels vs. Literature Reviews
FDA Labels:
• Balance information about:
– causality
– incidence
– severity
• Information in the label is based on:
– data from controlled trials
– published literature reports
– spontaneous reports to AERS (adverse event reporting systems)
• Are regularly updated and provide safety information
Literature Reviews
• Studies based on case reports or expert consensus
– Limited to a subset of marketed drugs
Chen M, et al. Drug Discovery Today. 2011.
9. Study Method: Determining DILI Potential
• 8-level system grouped into 3 categories:
– SEVERE DILI - contained levels 6, 7, 8
– MODERATE DILI - contained levels 4, 5
– MILD DILI - contained levels 1, 2, 3
• Severe DILI
– 80% of drugs with BW
– 35% of drugs with WP
– 15% of drugs with AR
Chen M, et al. Drug Discovery Today. 2011.
11. Study Method: Determination of DILI potential
• DILI drugs requirements:
– Causality is relatively established
• Not just : “ associated with”
• Not just : “ related to”
– The liver injury is severe
• DILI drug potential based on
1. FDA-label ( BW, WP, AR)
2. Severity level ( severe, moderate, mild - from the 8 level system)
Chen M, et al. Drug Discovery Today. 2011.
12. Results: Drugs with BW for DILI (including 2014)
Generic Name Brand Name Therapeutic Category DILI Severity
Level
Acitretin Soriatane Antiarrhythmics 5
Amiodarone Cordarone Antipsoriatics 8
Bosentan Tracleer Antihypertensives 7
Cytarabine Alexan Antineoplastic agents 3
Dacarbazine DTIC-Dome Antineoplastic agents 6
Danazol Danocrine Sex hormone modulators 8
Dantrolene Dantrium Muscle relaxants 8
Deferasirox Exjade Chelating agents 7
Didanosine Videx Antivirals 8
Docetaxel Taxotere Antineoplastic agents 8
Eltrompopag Promacta Antihemorrhagics 6
Chen M, et al. Drug Discovery Today. 2011
13. Results: Drugs with BW for DILI (Cont.)
Chen M, et al. Drug Discovery Today. 2011.
Generic Name Brand Name Therapeutic Category DILI Severity
Level
Emtricitabine Emtriva Antineoplastic agents -
Felbamate Felbatol Antiepileptics 7
Flutamide Eulexin Antineoplastic agents 8
Gemtuzumab Mylotarg Antineoplastic agents 8
Isoniazid Nydrazid Antimycobacterials 8
Ketoconazole Nizoral Antifungals 8
lamiVUDine Epivir Antivirals 8
Lapatinib Tykerb Antineoplastic agents 8
Leflunomide Arava Immunosuppressants 8
Maraviroc Selzentry Antivirals 3
Methotrexate Trexall Antineoplastic agents 3
Naltrexone Revia Alcohol Deterrents 3
Nefazodone Serzone Antidepressants 8
Neviripine Viramune Antivirals 8
