Olumiant® ▼ (baricitinib): Evaluation of Hepatic Function and Analyte Changes in the Atopic Dermatitis Clinical Trial Program

Baricitinib Label Information Related to Hepatic Transaminases

Warnings and Precautions

Dose dependent increases in blood alanine transaminase (ALT) and aspartate transaminase (AST) activity were reported in patients treated with baricitinib compared to placebo. Increases in ALT and AST to ≥ 5 and ≥ 10 x upper limit of normal (ULN) were reported in less than 1 % of patients in clinical trials. In rheumatoid arthritis clinical studies in treatment-naïve patients, combination with methotrexate resulted in increased frequency of hepatic transaminase elevations compared with baricitinib monotherapy.¹

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, baricitinib should be temporarily interrupted until this diagnosis is excluded.¹

Adverse Drug Reactions

Frequency for ALT elevations ≥ 3 x ULN as common adverse drug reaction (≥ 1/100 to < 1/10) is based on the pooled rheumatoid arthritis and atopic dermatitis clinical trials. In patients treated with baricitinib in the atopic dermatitis clinical trials, the frequency of this event was uncommon (≥ 1/1,000 to < 1/100).

In atopic dermatitis controlled studies, for up to 16 weeks, ALT and AST elevations ≥ 3 x ULN were uncommonly observed in 0.2 % and 0.5 % of patients treated with baricitinib 4 mg, compared to 0.8 % and 0.8 % respectively of patients treated with placebo.¹

Across indications, dose dependent increases in blood ALT and AST activity were also reported in studies extended over week 16. Most cases of hepatic transaminase elevations were asymptomatic and transient. The pattern and incidence of elevation in ALT/AST remained stable over time including in the long-term extension study.¹

Exclusion Criteria Related to Hepatic Function

In the phase 3 atopic dermatitis clinical development program, eligibility criteria related to hepatic function excluded patients who had

• history or presence of hepatic disorder that would constitute an unacceptable risk to participate

• an AST or ALT ≥2X ULN or total bilirubin ≥1.5X ULN upon screening

• active hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, or

• chronic alcohol abuse, intravenous drug abuse, or other illicit drug abuse within the 2 years prior to study entry.²

Integrated Safety Datasets Used to Evaluate Safety

The integrated datasets used to evaluate safety in the AD clinical trials are described in detail in Table 4.

Mean Analyte Changes

Table 1 provide the group mean values in the integrated safety datasets for

• ALT

• AST

• ALP, and

• total bilirubin.²

The majority of hepatic analyte mean values decreased or remained the same for BARI treatment groups through 16 weeks. Mean increases in ALT and total bilirubin were observed with BARI 4 mg treatment.²

Table 1. Mean Change of Hepatic Analytes in Atopic Dermatitis Clinical Trials²

Abbreviations: AD = atopic dermatitis; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BARI = baricitinib; LSMD = least squares mean difference; T. Bili = total bilirubin.

^a From last measure during baseline to last observation post baseline.

^b p <.05 vs placebo.

^c p<.001 vs placebo.

^d p<.01 vs placebo.

^e p<.05 vs BARI 2 mg.

^f p<.01 vs BARI 2 mg.

Increased Hepatic Analytes

Treatment-emergent increased hepatic analytes for all integrated safety datasets are provided in Table 2.

Placebo-Controlled Period

Through 16 weeks, there was no difference between BARI 2 mg, BARI 4 mg, or placebo treatment groups in the proportion of patients with a TEAE of

• ALT ≥3 X ULN

• AST ≥3 X ULN

• ALP ≥3 X ULN, or

• total bilirubin ≥2 X ULN (see Table 2).²

All Baricitinib-Treated Patients With Extended Data

Of the 2531 BARI-treated patients with a total of 2247.4 PYE

• 1 (0.0%) had an ALT ≥10 X ULN

• 3 (0.1%) had an AST ≥10 X ULN

• 10 (0.4%) had a ALP ≥1.5 X ULN, and

• 10 (0.4%) total bilirubin ≥2 X ULN.²

Table 2. Incidence of Treatment-Emergent Increased Hepatic Analytes²

Abbreviations: AD = atopic dermatitis; adj % = adjusted percentage; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BARI = baricitinib; T. Bili = total bilirubin.

^a For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

^b Unless otherwise specified.

^c N observed = 872 was used as denominator.

^d N observed = 709 was used as denominator.

^e N observed = 730 was used as denominator.

^f N observed = 488 was used as denominator.

^g Data through 16-week placebo-controlled period.

^h N observed = 570 was used as denominator.

ⁱ N observed = 2498 was used as denominator.

Adverse Events Related to Hepatic Function

Treatment-emergent adverse events are presented from MedDRA SMQs for hepatic disorders and do not include infectious hepatitis or hepatic neoplasia. Infectious hepatitis and malignancies of all types are covered in separate responses.²

In the clinical trial, most hepatic-related TEAEs were abnormalities in hepatic laboratory tests. There was no evidence that treatment with BARI was associated with an increased risk of hepatic-related TEAEs that

• were considered serious

• led to temporary interruption, or

• led to permanent discontinuation of study drug.²

See Table 3 for incidence by safety dataset and treatment arm.²

Table 3. Hepatic-Related Treatment Emergent Adverse Events²

Abbreviations: AD = atopic dermatitis; adj % = adjusted percentage; AE = adverse events; BARI = baricitinib; ext = extended; IR = incidence rate; perm D/C = permanent discontinuation; TEAE = treatment emergent adverse event; temp int = temporary interruption.

^a Data through the 16-week placebo-controlled period.

^b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the AEs to provide appropriate direct comparisons between treatment groups. 

^c p≤.01 vs BARI 2 mg.