Olumiant ® (baricitinib)

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What was the incidence of hepatobiliary adverse events in the Olumiant® (baricitinib) rheumatoid arthritis clinical development program?

In the All-BARI-RA dataset with over 14,744 patient-years of exposure to baricitinib, 8.6% of patients reported a treatment-emergent adverse event related to hepatobiliary disorders.

UK_cFAQ_BAR110A_HEPATIC_TEAE_RA
UK_cFAQ_BAR110A_HEPATIC_TEAE_RA
en-GB

Warnings and Precautions Related to Liver Enzyme Elevations

Dose dependent increases in blood alanine transaminase (ALT) and aspartate transaminase (AST) activity were reported in patients treated with baricitinib.1

Increases in ALT and AST to ≥ 5 and ≥ 10 x upper limit of normal (ULN) were reported in clinical trials. In rheumatoid arthritis clinical studies, 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, treatment should be temporarily interrupted until this diagnosis is excluded.1

No dose adjustment is required in patients with mild or moderate hepatic impairment. Baricitinib is not recommended for use in patients with severe hepatic impairment.1

Baricitinib Rheumatoid Arthritis Clinical Development Program

Each of the 4 phase 3 studies in the clinical program evaluated a distinct treatment population of patients with moderate-to-severe rheumatoid arthritis (RA).

  • RA-BEGIN compared baricitinib 4-mg monotherapy, baricitinib 4 mg plus methotrexate (MTX), and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other disease-modifying antirheumatic drugs (DMARDs).2
  • RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.3
  • RA-BUILD compared baricitinib 2 mg and 4 mg vs placebo, with background conventional synthetic DMARD (csDMARD) therapy, in patients with inadequate response to csDMARDs.4
  • RA-BEACON compared baricitinib 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one tumor necrosis factor (TNF) inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.5

Exclusion Criteria Related to Hepatic Function

In the 4 phase 3 clinical trials, RA-BEGIN, RA-BEAM, RA-BUILD, and RA-BEACON, eligibility criteria relating to hepatic function excluded patients who had a history of

  • chronic liver disease with the most recent available AST or ALT >1.5x ULN or the most recent available total bilirubin ≥1.5x ULN
  • 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.6

Hepatic Analyte Mean Values in 4 Phase 3 Trials

In phase 3 trials, compared to placebo, both the baricitinib 2-mg and baricitinib 4-mg groups had mean value

Mean Change From Baseline of Hepatic Analytes in 4 Phase 3 Clinical Trials6

LSM Change (SE) [95% CI]

ALT (U/L)

AST (U/L)

ALP (U/L)

Total Bilirubin (µmol/L)

Albumin (g/L)

RA-BEGIN, 0-52 weeks with data up to rescue

MTX monotherapy (n=210)

4.0 (2.4) [-0.7, 8.6]

2.7 (1.2) [0.3, 5.1]

-4.2 (1.7) [-7.6, -0.8]

1.0 (0.2) [0.6, 1.5]

0.8 (0.2) [0.4, 1.2]

BARI 4-mg monotherapy (n=159)

3.4 (2.7) [-1.9, 8.7]

3.3 (1.4) [0.6, 6.0]

-10.2 (2.0) [-14.1, -6.4]a

0.6 (0.2) [0.2, 1.1]

2.3 (0.2) [1.9, 2.8]a

BARI 4 mg plus MTX (n=215)

15.0 (2.3) [10.4, 19.6]ab

9.4 (1.2) [7.0, 11.7]ab

-12.3 (1.7) [-15.6,-8.9]a

1.0 (0.2) [0.6, 1.4]

3.0 (0.2) [2.6, 3.4]a

RA-BEAM, 0-24 weeks with data up to rescue

Placebo (n=488)

0.4 (1.2) [-2.0, 2.7]

1.1 (0.8) [-0.5, 2.6]

-0.8 (0.8) [-2.4, 0.8]

0.0 (0.1) [-0.3, 0.3]

-0.2 (0.1) [-0.4, 0.0]

BARI 4 mg (n=487)

6.7 (1.2) [4.4, 9.1]c

6.1 (0.8) [4.6, 7.7]cd

-8.8 (0.8) [-10.4, -7.2]cd

0.4 (0.1) [0.2, 0.7]cd

2.2 (0.1) [2.0, 2.4]cd

Adalimumab (n=330)

4.5 (1.5) [1.6, 7.3]c

3.7 (1.0) [1.8, 5.5]c

-6.0 (1.0) [-7.9, -4.1]d

1.1 (0.2) [0.7, 1.4]d

1.1 (0.1) [0.8, 1.3]c

RA-BUILD, 0-24 weeks with data up to rescue

Placebo (n=228)

-1.2 (1.4) [-3.9, 1.5]

-0.7 (0.9) [-2.5, 1.1]

0.8 (1.2) [-1.6, 3.2]

-0.4 (0.2) [-0.8, -0.0]

-0.6 (0.2) [-0.9, -0.3]

BARI 2 mg (n=229)

1.7 (1.4) [-0.9, 4.4]

1.5 (0.9) [-0.3, 3.2]

-6.2 (1.2) [-8.5, -3.8]c

0.5 (0.2) [0.2, 0.9]c

1.2 (0.2) [0.8, 1.5]c

BARI 4 mg (n=227)

6.0 (1.4) [3.3, 8.7]c

5.4 (0.9) [3.6, 7.2]c

-6.5 (1.2) [-8.9, -4.1]c

0.8 (0.2) [0.4, 1.1]c

1.4 (0.2) [1.1, 1.8]c

RA-BEACON, 0-24 weeks with data up to rescue

Placebo (n=176)

-0.6 (0.8) [-2.2, 1.0]

0.2 (0.9) [-1.4, 1.9]

-1.2 (1.2) [-3.7, 1.2]

0.1 (0.2) [-0.3, 0.4]

-0.8 (0.2) [-1.2, -0.4]

BARI 2 mg (n=174)

1.9 (0.8) [0.4, 3.5]c

1.6 (0.9) [-0.1, 3.2]

-2.0 (1.2) [-4.4, 0.5]

0.3 (0.2) [-0.1, 0.7]

0.5 (0.2) [0.1, 0.9]c

BARI 4 mg (n=177)

3.3 (0.8) [1.8, 4.9]c

4.2 (0.9) [2.6, 5.9]c

-7.1 (1.2) [-9.6, -4.7]c

0.3 (0.2) [-0.1, 0.6]

1.6 (0.2) [1.2, 2.0]c

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BARI = baricitinib; LSM = least-squares mean; MTX = methotrexate.

ap<.05 vs MTX.

bp<.05 vs BARI 4 mg.

cp<.05 vs placebo.

dp<.05 vs adalimumab.

Hepatic Analyte Elevations With Baricitinib Use

Analyses of the 3 integrated datasets were used to assess changes in hepatic treatment-emergent adverse events (TEAEs) and analyte abnormalities. These datasets are described in detail in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.6

Information on the frequency of elevated ALT, AST, ALP, and total bilirubin in the baricitinib RA clinical trials is provided in Frequency of Treatment-Emergent Elevated Alanine Aminotransferase and Frequency of Treatment-Emergent Increased Hepatic Analytes.

Frequency of Treatment-Emergent Elevated Alanine Aminotransferase6,7

 

ALT ≥3x ULN

n/N-obs (%)

ALT ≥5x ULN

n/N-obs (%)

ALT ≥10x ULN

n/N-obs (%)

7-Study Placebo-Controlled Dataset up to Week 24

Placebo (N=1215)

15/1203 (1.2)

4/1203 (0.3)

0/1203

BARI 4 mg (N=1142)

17/1132 (1.5)

7/1132 (0.6)

2/1132 (0.2)

BARI 2 mg (N=479)

7/474 (1.5)

3/477 (0.6)

1/477 (0.2)

4-Study Extended Dataset

BARI 2 mg (N=479)

12/478 (2.5)

4/478 (0.8)

1/478 (0.2)

BARI 4 mg (N=479)

9/474 (1.9)

4/474 (0.8)

1/474 (0.2)

All-BARI-RA Dataset

All BARI RA (N=3770)

188/3741 (5.0)

55/3741 (1.5)

10/3741 (0.3)

Abbreviations: ALT = alanine aminotransferase; BARI = baricitinib; RA = rheumatoid arthritis; ULN = upper limit of normal.

Frequency of Treatment-Emergent Increased Hepatic Analytes6,7

 

AST ≥3x ULN

n/N-obs (%)

Total Bilirubin ≥2x ULN

n/N-obs (%)

ALP ≥1.5x ULN

n/N-obs (%)

7-Study Placebo-Controlled Dataset up to Week 24

Placebo (N=1215)

13/1203 (1.1)

1/1203 (0.1)

59/1203 (4.9)

BARI 4 mg (N=1142)

12/1132 (1.1)

0/1132

55/1132 (4.9)

BARI 2 mg (N=479)

6/477 (1.3)

0/477

12/477 (2.5)

4-Study Extended Dataset

BARI 2 mg (N=479)

8/478 (1.7)

0/478

17/478 (3.6)

BARI 4 mg (N=479)

9/474 (1.9)

0/474

28/474 (5.9)

All-BARI-RA Dataset

All BARI RA (N=3770)

113/3741 (3.0)

3/3741 (0.1)

265/3741 (7.1)

Abbreviations: ALP = alkaline phosphatase; AST = aspartate aminotransferase; BARI = baricitinib; MTX = methotrexate; RA = rheumatoid arthritis; ULN = upper limit of normal.

Adverse Events Related to Hepatic Function

Treatment-emergent adverse events are presented from the hepatobiliary system organ class and do not include hepatitis or hepatic neoplasia. Hepatitis and malignancies of all types are covered in separate responses.

7-Study Placebo-Controlled Dataset

Through 24 weeks of treatment or until rescue, the proportion of patients who had

  • a TEAE related to hepatobiliary disorders was
    • 1.7% in the baricitinib 4-mg group
    • 1.0% in the baricitinib 2-mg group, and
    • 1.2% in the placebo group, and
  • a TEAE of hepatic steatosis was
    • 0.3% (n=3) in the baricitinib 4-mg group
    • 0% in the baricitinib 2-mg group, and
    • 0% in the placebo group.6

All-BARI-RA Dataset

In the All-BARI-RA dataset, 324 (8.6%) patients [exposure-adjusted incidence rate (EAIR)=2.14] had a TEAE related to hepatobiliary disorders, which included

  • 58 (1.5%) [EAIR=0.38] serious adverse events
  • 40 (1.1%) [EAIR=0.26] TEAEs that led to temporary interruption of study drug
  • 29 (0.8%) [EAIR=0.19] TEAEs that led to permanent discontinuation of study drug, and
  • 88 (2.3%) [EAIR=0.58] TEAEs of hepatic steatosis.6

A large majority of treatment-emergent hepatic disorders were limited to increases of liver enzymes and were typically 1-time elevations that resolved while continuing therapy or only had a temporary interruption, or an alternative etiology that accounted for the increase. About one-half of the treatment-emergent hepatic disorders were reported as possibly related to the study drug, out of which few were serious (2.4%) or severe (5.0%) and none were fatal.6

Information From the Label

Adverse Reactions

The frequency of ALT ≥ 3 x ULN was common (≥ 1/100 to < 1/10). The frequency of AST ≥ 3 x ULN was uncommon (≥ 1/1 000 to < 1/100).1

The frequencies shown above are based on integrated data from1

  • clinical trials and/or
  • postmarketing setting

across

  • rheumatoid arthritis, 
  • atopic dermatitis, and
  • alopecia areata

indications unless stated otherwise.1 

Hepatic Transaminase Elevations

Dose dependent increases in blood ALT and AST activity were reported in studies extended over week 16. Elevations in mean ALT/AST remained stable over time. Most cases of hepatic transaminase elevations ≥ 3 x ULN were asymptomatic and transient.1

In patients with rheumatoid arthritis, the combination of baricitinib with potentially hepatotoxic medicinal products, such as methotrexate, resulted in increased frequency of these elevations.1 

References

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

2Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953

3Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345

4Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1

5Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247

6Data on file, Eli Lilly and Company and/or one of its subsidiaries.

7Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):e347-e357. https://doi.org/10.1016/S2665-9913(20)30032-1

8Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Ann Rheum Dis. 2020;79(suppl 1):642-643. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

9Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276

Appendix

Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials6-9

Analysis Set

Descriptiona

7-Study Placebo-Controlled Dataset

Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

Compares BARI 4 mg vs placebo

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

  • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
  • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or
  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

  • through the 12-week placebo-controlled period in phase 2 studies
  • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
  • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

BARI 2 mg Analysis Set

BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or
  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.

All BARI RA Dataset

Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

No between-group comparisons

Includes patients with RA (N=3770, PYE=14,744 PY exposure to BARI and 15,114 PY overall observation including time on BARI and follow up, median exposure=4.6 yrs, maximum exposure=9.3 yrs) from 1 phase 1b, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

  • BARI 4 mg (n=3401, PYE=11,872)
  • BARI 2 mg (n=1077, PYE=2678), and
  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

Evaluation time period is all exposure time points including after rescue or changes in study drug unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PY = patient-years; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

Date of Last Review: 03 December 2021


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