TABLE 2.

Several drugs and their evaluation in relation to marketing authorization and their potential to induce DILI

Drug name	Indication	DILI‐risks described in literature	Marketing authorization
Diclofenac	Anti‐inflammatory pain medication	Livertox37: ‐ 1‐5 cases/100 000 prescriptions ‐ Likelihood score A Björnsson et al.: Review of Swedish cases from 1966–200277: ‐ out of the 4687 DILI reports, 103 cases were fatal. ‐ 3.8% caused by diclofenac De Valle et al.: Retrospective study in Sweden from 1995–200514: ‐ 1164 liver disease cases; 77 due to DILI ‐ 18.2% caused by diclofenac.	Authorized Widely used painkiller, although many same‐class drugs are available.
Tolvaptan	Long‐term intermittent treatment for autosomal dominant polycystic kidney disease	TEMPO 3:4 registration trial; 961 participating patients41: ‐ 1.5% discontinued due to liver dysfunction ‐ 4.5% showed a clinically significant increase in aminotransferases ‐ 0.9% showed an increase in bilirubin levels ‐ 0% of acute liver failure All cases showed resolution in LFTs after tolvaptan discontinuation Postmarketing studies42, 43: ‐ b1 case of acute liver failure, requiring transplantation	Authorized with restrictions: Risk evaluation and mitigation strategy with frequent LFT: ‐ 2 and 4 weeks after start ‐ monthly in first 18 months ‐ thereafter every 3 months
Sitaxentan	Endothelin receptor antagonist that had been authorized in the European Union for the treatment of PAH PAH is incurable; therapy is aimed at slowing the progression or improve symptoms	Regulatory bodies, after registration trials47, 48, 50: ‐ known DILI risk; therefore, additional safety LFTs were performed during treatment Postmarketing, 2000 treated patients49: ‐ 4 cases of fatal liver injury ‐ 1 case of liver transplantation Cases are thought to be causally related to sitaxentan and did not resolve after discontinuation	Authorized by regulatory bodies Withdrawn by pharmaceutical manufacturer
Ulipristal	Selective progesterone receptor modulator for treatment of uterine fibroids Sole pharmaceutical treatment for long‐term intermittent use	Registration trials; PEARL I‐IV19, 20, 23, 30: ‐ no hepatic toxicity was identified Postmarketing, 900 000 prescriptions: ‐ 91 possible adverse effects in the hepatic disorder spectrum ‐ including 8 reported cases of severe liver injury 5 resulted in liver transplantation 1 fatal outcome	Ulipristal 5 mg tablets are suspended from marketing authorization until a final decision is made by the European Commission.

DILI: drug‐induced liver injury; LFT: liver function test; PAH, pulmonary arterial hypertension.