Olumiant ® (baricitinib)

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What is the effect of Olumiant® (baricitinib) on haemoglobin in patients with atopic dermatitis?

Decreases in haemoglobin levels to <8 g/dL were reported uncommonly with baricitinib treatment. Avoid use of baricitinib treatment in patients with haemoglobin <4.9 mmol/L (8.0 g/dL), which is equivalent to a grade 3 low haemoglobin level.

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en-GB

Baricitinib Label Information Related to Haemoglobin

Treatment should not be initiated, or should be temporarily interrupted, in patients with haemoglobin < 8 g/dL observed during routine patient management. Treatment may be initiated or restarted once value has improved above this limit.1

Haemoglobin Changes in the Baricitinib Atopic Dermatitis Clinical Trials

Baricitinib is a selective and reversible inhibitor of the janus kinase (JAK) family of protein tyrosine kinases, specifically JAK1 and JAK2.2 Janus kinase 2 is a tyrosine kinase that engages with multiple cytokine receptors including the erythropoietin (EPO) receptor.3 Therefore, close monitoring and follow-up of hematologic parameters were incorporated into the baricitinib atopic dermatitis (AD) development program.

In the baricitinib AD trials, hemoglobin assessments were performed at scheduled visits and evaluated in 3 integrated datasets as described in Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials.4

Mean change from baseline in haemoglobin

Through 16-week placebo-controlled period, the change from baseline in hemoglobin (least square mean difference (SE) [95% CI]) was significantly decreased (p<.001) with BARI treatment. The change from baseline in hemoglobin comparisons were

  • placebo -0.1 (0.02) [-0.10, -0.04] vs baricitinib 2 mg -0.2 (0.02) [-0.21, -0.14]
  • placebo -0.1 (0.02) [-0.11, -0.03] vs baricitinib 4 mg -0.3 (0.02) [-0.32, -0.23], and
  • baricitinib 2 mg -0.2 (0.02) [-0.22, -0.14] vs baricitinib 4 mg -0.3 (0.02) [-0.32, -0.23].5

Decreases in haemoglobin, not below the lower limit of normal, were noted after 4 weeks of treatment with baricitinib and maintained throughout the duration of the extended time period (see Mean Changes in Hemoglobin Over Time in Patients Treated With Baricitinib in the Extended Dataset in the Atopic Dermatitis Clinical Trials).4

No changes of clinical relevance were noted over the longer observation period through 120 weeks.5

Mean Changes in Hemoglobin Over Time in Patients Treated With Baricitinib in the Extended Dataset in the Atopic Dermatitis Clinical Trials5

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; ext = extended.

Treatment-emergent changes in haemoglobin

Categorical changes in hemoglobin values were assessed by determining the proportion of patients who had a treatment-emergent increase in Common Terminology Criteria for Adverse Events (CTCAE) grade for low hemoglobin.5

As presented in Overview of CTCAE Grade Shifts in Haemoglobin From BREEZE-AD Clinical Development Program, most haemoglobin changes were to CTCAE grades 1 or 2 in all datasets.4,5

Overview of CTCAE Grade Shifts in Haemoglobin From BREEZE-AD Clinical Development Program4,5

Worsened to Grade ≥1
n/NAR (%)

Worsened to Grade ≥2
n/NAR (%)

Worsened to Grade ≥3
n/NAR (%)

Placebo-Controlled (to week 16)

Placebo, n=743

31/688 (4.5)

2/728 (0.3)

0/728 (0)

BARI 2 mg, n=576

31/538 (5.8)

1/569 (0.2)

0/570 (0)

BARI 4 mg, n=489

44/456 (9.6)

4/486 (0.8)

0/486 (0)

BARI 2 mg vs 4 mg Extended (up to 3.9 years)

BARI 2 mg, n=584

54/544 (9.9)

3/577 (0.5)

0/578 (0)

BARI 4 mg, n=497

78/463 (16.8)

7/494 (1.4)

1/494 (0.2)

All BARI AD (up to 3.9 years)

All doses, N=2636

307/2405 (12.8)

35/2596 (1.3)

1/2602 (0)

Abbreviations: AD = atopic dermatitis; adj =adjusted; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal; NAR = number of patients at risk for specified abnormality; TE = treatment emergent.

CTCAE grading for low hemoglobin includes:
Grade 0: (normal) ≥7.27 mmol/L (12.0 g/dL) for women (≥8.18 mmol/L [13.5 g/dL] for men).
Grade 1: <7.27 mmol/L (12 g/dL) for women (<8.18 mmol/L [13.5 g/dL] for men) and ≥6.2 mmol/L (10.0 g/dL).
Grade 2: <6.2 mmol/L (10.0 g/dL) and ≥4.9 mmol/L (8.0 g/dL).
Grade 3: <4.9 mmol/L (8.0 g/dL) and ≥4.0 mmol/L (6.5 g/dL).
Grade 4: <4.0 mmol/L (6.5 g/dL).

Treatment-emergent adverse events related to anemia

Summary of Anemia in the Atopic Dermatitis Clinical Trials describes treatment-emergent adverse events (TEAEs) related to anemia reported by investigators in the baricitinib AD trials.

In the All BARI AD dataset, 18 patients (incidence rate = 0.4) reported TEAEs of anemia.

Of these 18 cases, 

  • none were reported as serious adverse events
  • 1 led to temporary interruption of baricitinib, and
  • none led to permanent discontinuation of baricitinib.5
Summary of Anemia in the Atopic Dermatitis Clinical Trials5

 

Placebo-Controlled
(to week 16)
n (adj %)a

BARI 2 mg and 4 mg Extended
(up to 3.9 years)
n [adj IR]a

All BARI AD
(up to 3.9 years)
n [IR]


Placebo
n=743

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=584

BARI 4 mg
n=497

All doses
N=2636

Anemia

1 (0.1)

1 (0.2)

2 (0.3)

3 [0.4] 

3 [0.3]

18 [0.4]

Iron deficiency anemia

0

0

0

0

 3 [0.4]

 10 [0.2]

Macrocytic anemia

0

1 (0.1)

0

 1 [0.1]

0

 1 [0.0]

Normocytic anemia

0

1 (0.1)

0

 1 [0.1]

0

 1 [0.0]

Microcytic anemia

0

0

0

0

0

 1 [0.0]

Autoimmune hemolytic anemia

0

0

0

0

0

1 [0.0]

Hypochromic Anemia

0

0

0

0

0

1 [0.0]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate.

aFor 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. 

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials4-7

Analysis Set

Description

16-Week Placebo-Controlled BARI AD

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

Compares BARI 2 mg, BARI 4 mg and placebo.

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)
  • BARI 4 mg (n=489, PYE=147.1), or
  • placebo (n=743, PYE=211.8).

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

BARI 2 mg and 4 mg Extended ADa

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=584, PYE=727.1), or
  • BARI 4 mg (n=497, PYE=800.1).

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-AD6a

No between-group comparisons

Includes 2636 (total PYE=4628.4) 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=605, PYE=441.5)
  • BARI 2 mg (n=1703, PYE=2420.9), and
  • BARI 4 mg (n=1012, PYE=1766.8).

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.

aData cut as of November 3, 2021 for BREEZE-AD3 and December 15, 2021 for BREEZE-AD4

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

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

2Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

3Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature Rev Cancer. 2007;7(9):673-683. http://dx.doi.org/10.1038/nrc2210

4Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

6King B, Maari C, Lain E, et al. Extended safety analysis of baricitinib 2 mg in adult patients with atopic dermatitis: an integrated analysis from eight randomized clinical trials. Am J Clin Dermatol. 2021;22(3):395-405. https://doi.org/10.1007/s40257-021-00602-x

7Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 and up to 3.9 years treatment: an updated integrated analysis of 8 clinical trials. Poster presented at: 31st Annual European Academy of Dermatology and Venereology Congress; September 7-10, 2022; Milan, Italy.

Date of Last Review: 30 August 2022


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