“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

SUMMARYBy Florentina Eller

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

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.

Chen M, et al. Drug Discovery Today. 2011.

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.

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

injuryHowever, • 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.

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

Study Method: Flowchart Based on FDA labels

Chen M, et al. Drug Discovery Today. 2011.

Chen M, et al. Drug Discovery Today. 2011.

DILI Severity Categories Based on FDA Labels

Chen M, et al. Drug Discovery Today. 2011.

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

Study Method: Distribution of DILI Based on FDA labels

Chen M, et al. Drug Discovery Today. 2011.

Chen M, et al. Drug Discovery Today. 2011.

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 on1. FDA-label ( BW, WP, AR)2. Severity level ( severe, moderate, mild - from the 8 level system)

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

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

Results: Drugs with BW for DILI (Cont.)Generic Name Brand Name Therapeutic Category DILI Severity

Level

Oxandrolone Anavar Anabolic steroids 8

Oxymetholone Adroyd Anabolic steroids 8

Pazopanib Votrient Antineoplastic agents 8

Propylthiouracil Proracyl Antithyroid agents 8

Stavudine Zerit Antivirals 8

Streptozocin Zanosar Antineoplastic agents 3

Sunitinib Sutent Antineoplastic agents 8

Telbivudine Tyzeka Antivirals

Tenofovir Viread Antivirals 8

Tipranavir Aptivus Antivirals 8

Tolcapone Tasmar Dopaminergics 8

Valproic Acid Depakene Antiepileptics 8

Zalcitabine Hivid Antivirals 8

Zidovudine Retrovir Antivirals 8