Olumiant® ▼ (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Olumiant Summary of Product Characteristics (SmPC)

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

Baricitinib treatment is associated with small dose dependent increases in ALT and AST, however, most elevations are asymptomatic and transient.

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

LSMDa (SE) [95% CI]

ALT U/L

AST U/L

ALP U/L

T. Bili μmol/L

BARI 2 mg Placebo-Controlled through 16 weeks

Placebo, n=889

-1.4 (.49) [-2.3, -.39]

-1.6 (.42) [-2.4, -.74]

-0.4 (.48) [-1.4, .55]

-0.3 (.13) [-.58, -.07]

BARI 2 mg, n=721

-1.0 (.53) [-2.0, .06]

-0.3 (.45) [-1.1, .62]b

-3.5 (.52) [-4.6, -2.5]c

0.0 (.14) [-.31, .24]

BARI 4 mg Placebo-Controlled through 16 weeks

Placebo, n=743

-1.4 (.52) [-2.4, -.39]

-1.5 (.35) [-2.1, -.76]

-0.4 (.50) [-1.4, -.57]

-0.2 (.16) [-.52, .11]

BARI 4 mg, n=489

0.3 [.59) [-.90, 1.4]b

-0.1 (.40) [-.88, .70]d

-5.5 (.57) [-6.6, -4.4]c

0.5 (.18) [.16, .87]c

BARI 2 vs 4 mg through 16 weeks

BARI 2 mg, n=576

-0.7 (.59) [-1.9, .41]

-0.2 (.49) [-1.2, -.73]

-3.9 (.56) [-5.0, -2.8]

0.0 (.18) [-.32, .37]

BARI 4 mg, n=489

0.2 (.62) [-1.0, 1.4]

-0.3 (.51) [-1.3, .75]

-5.5 (.59) [-6.6, -4.3]e

0.5 (.19) [.11, .84]

BARI 2 mg vs 4 mg extended

BARI 2 mg, n=576

-0.2 (.72) [-1.7, 1.2]

0.0 (.57) [-1.1, 1.2]

-4.2 (.59) [-5.4, -3.0]

-0.2 (.18) [-.58, .12]

BARI 4 mg, n=489

2.6 (.76) [1.1, 4.1]f

1.4 (.60) [.20, 2.6]

-5.0 (.62) [-6.3, -3.8]

0.1 (.19) [-.31, .43]

All BARI AD

All doses, N=2531

0.9 (.45) [-.01, 1.8]

1.0 (.31) [.35, 1.6]

-4.0 (.31) [-4.6, -3.4]

-0.2 (.09) [-.38, -.01]

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

n (adj %) ab

ALT ≥3 x ULN

ALT ≥5 x ULN

ALT ≥10 x ULN

AST ≥3 x ULN

AST ≥5 x ULN

AST ≥10 x ULN

T. Bili ≥2 x ULN

ALP ≥1.5 x ULN

BARI 2 mg Placebo-Controlled

Placebo, n=889c

9 (1.0)

1 (0.2)

0

9 (1.0)

5 (0.6)

1(0.2)

3 (0.3)

2 (0.3)

BARI 2 mg, n=721d

5 (0.7)

1 (0.1)

0

5 (0.6)

2 (0.3)

0

1 (0.1)

3 (0.4)

BARI 4 mg Placebo-Controlled

Placebo, n=743e

7 (0.8)

1 (0.2)

0

7 (0.8)

4 (0.5)

1 (0.2)

3 (0.3)

2 (0.3)

BARI 4 mg, n=489f

1 (0.2)

1 (0.2)

0

3 (0.5)

1 (0.2)

0

1 (0.2)

0

BARI 2 mg vs 4 mgg

BARI 2 mg, n=576h

3 (0.4)

1 (0.1)

0

5 (0.6)

2 (0.3)

0

1 (0.1)

2 (0.3)

BARI 4 mg, n=489f

1 (0.2)

1 (0.2)

0

3 (0.5)

1 (0.2)

0

1 (0.2)

0

BARI 2 mg vs 4 mg extended

BARI 2 mg, n=576h

5 (0.8)

1 (0.1)

0

9 (1.2)

3 (0.4)

0

1 (0.1)

2 (0.3)

BARI 4 mg, n=489f

8 (1.5)

1 (0.2)

0

8 (1.5)

2 (0.4)

0

2 (0.4)

1 (0.2)

All BARI AD, n (%)

All doses, N=2531i

40 (1.6)

5 (0.2)

1 (0.0)

40 (1.6)

15 (0.6)

3 (0.1)

10 (0.4)

10 (0.4)

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

 

 



 

 

 

 

 

 


BARI 2 mg Placebo-Controlleda
n (adj %)

BARI 4 mg Placebo-Controlleda
n (adj %)
b

BARI 2 vs 4a
n (adj %)
b

BARI 2 vs 4 ext
n (adj %)
b [adj IR]

All BARI AD
n (%) [IR]

n (adj %)b

Placebo
n=889

BARI 2 mg
n=721

Placebo
n=743

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

All doses
N=2531

Hepatic TEAE

14 (1.7)

7 (0.8)

12 (1.4)

13 (2.3)

7 (0.8)

13 (2.3)

13 (1.9) [2.9]

27 (4.9) [5.7]c

83 (3.3) [3.7]

Serious AE

0

0

0

0

0

0

0

0

1 (0.0) [0.0]

Led to temp int

1 (0.1)

0

1 (0.1)

0

0

0

1 (0.2) [0.3]

4 (0.8) [0.7]

7 (0.3) [0.3]

Led to perm D/C

1 (0.2)

0

1 (0.2)

0

0

0

0

2 (0.4) [0.4]

7 (0.3) [0.3]

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.

Based on case evaluations in all patients treated with at least one dose of BARI, no cases met Hy’s Law criteria for drug-induced liver injury after assessment of any patient with laboratory measures of

  • 3X ULN for maximum ALT or AST, and

  • 2X ULN for maximum total bilirubin2

No events termed drug-induced liver injury, hepatocellular injury, liver injury, or liver disorder were reported in the AD clinical trials.2

Integrated Safety Datasets Table

Table 4. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AD = atopic dermatitis

ALP = alkaline phosphate

ALT = alanine aminotransferase

AST = aspartate aminotransferase

BARI = baricitinib

MedDRA = Medical Dictionary for Regulatory Activities

SMQ = standardized MedDRA query

TEAE = treatment-emergent adverse event

ULN = upper limit of normal

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: June 25, 2020


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