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): Changes in Haemoglobin in the Atopic Dermatitis Clinical Trial Program

Decreases in haemoglobin, not below the lower limit of normal, were noted after 4 weeks of treatment with baricitinib in patients with atopic dermatitis.

Baricitinib Label Information Related to Haemoglobin

Haemoglobin should be assessed before treatment initiation and thereafter according to routine patient management.1

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

Hemoglobin Changes in the Baricitinib BREEZE-AD Clinical Development Program

Baricitinib is a selective and reversible inhibitor of the 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 EPO receptor.3 Therefore, close monitoring and follow-up of hematologic parameters were incorporated into the BARI BREEZE-AD clinical development program.

Integrated Safety Dataset Descriptions

The integrated datasets used to evaluate hemoglobin changes, the incidence of hemoglobin and anemia TEAEs are described in Table 3.

Mean Change From Baseline in Hemoglobin

Placebo Controlled Dataset

Through 16-week placebo control 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 BARI 2 mg -0.2 (0.02) [-0.21, -0.14]

  • placebo -0.1 (0.02) [-0.11, -0.03] vs BARI 4 mg -0.3 (0.02) [-0.32, -0.23], and

  • BARI 2 mg -0.2 (0.02) [-0.22, -0.14] vs BARI 4 mg -0.3 (0.02) [-0.32, -0.23].4

Extended Dataset

Decreases in hemoglobin, not below the lower limit of normal, were noted after 4 weeks of treatment with BARI.

Decreased hemoglobin levels were maintained throughout the duration of the extended time period (see Figure 1).4,5

Figure 1. Mean Changes in Hemoglobin Over Time in Patients Treated With BARI 4 mg and BARI 2 mg in the Extended Dataset in the Atopic Dermatitis Clinical Trials4

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; LLN = lower limit of normal; PC = placebo controlled; ULN = upper limit of normal.

Treatment-Emergent Low Hemoglobin Values

Categorical changes in hemoglobin values were assessed by determining the proportion of patients who had a

  • TE value below the LLN, and

  • TE increase in CTCAE grade for low hemoglobin.4

Treatment-emergent low hemoglobin were noted in the BREEZE-AD clinical development program (see column 1 Table 3).

Most hemoglobin shifts were to CTCAE grades 1 or 2, and there were no shifts to CTCAE grade 3 (see Table 1).4,5

Table 1. Overview of Treatment-Emergent Abnormal Low and CTCAE Grade Shifts in Hemoglobin From BREEZE-AD Clinical Development Program4,5


Treatment-Emergent Abnormal Low
n/NAR (adj %)
a

Shift From:
Grade <1 to Grade ≥1
n/NAR (%)

Shift From:
Grade <2 to Grade ≥2
n/NAR (%)

Shift From:
Grade <3 to Grade ≥3
n/NAR (%)

BARI 2 mg Placebo-Controlledb

Placebo, n=889

33/832 (4.0)

38/818 (4.6)

4/870 (0.5)

0/870 (0)

BARI 2 mg, n=721

37/674 (5.0)

42/659 (6.4)

3/706 (0.4)

0/708 (0)

BARI 4 mg Placebo-Controlledb

Placebo, n=743

27/702 (3.3)

31/688 (4.5)

2/728 (0.3)

0/728 (0)

BARI 4 mg, n=489

33/464 (5.8)c

44/456 (9.6)d

4/486 (0.8)

0/486 (0)

BARI 2 mg vs 4 mgb

BARI 2 mg, n=576

27/549 (3.6)

31/538 (5.8)

1/569 (0.2)

0/570 (0)

BARI 4 mg, n=489

33/464 (5.8)

44/456 (9.6)e

4/486 (0.8)

0/486 (0)

BARI 2 mg vs 4 mg extended

BARI 2 mg, n=576

37/549 (5.2)

48/538 (8.9)

4/569 (0.7)

0/570 (0) 

BARI 4 mg, n=489

45/464 (8.0)

64/456 (14.0)e

5/486 (1.0)

0/486 (0)

All BARI AD

All doses, N=2531

166/2362 (7.0)

221/2320 (9.5)

22/2492 (0.9)

0/2497 (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).

a Treatment-emergent abnormal low was defined as number of cases with postbaseline scores <LLN. Percent is number at risk for the TE abnormal low was defined as the number of patients with a value ≥ to the LLN at all baseline visits. The LLN values are different by patient depending on age and sex.

b Data through 16-week placebo-controlled period.

c p<.05 BARI 4 mg vs placebo.

d p<.01 BARI 4 mg vs placebo.

e p<.05 BARI 2 mg vs BARI 4 mg.

Anemia Treatment Emergent Adverse Events

Evaluation of TEAEs of anemia included MedDRA preferred terms, anemia, macrocytic anemia, normocytic anemia and iron deficiency anemia, from the Blood and Lymphatic System Disorders System Organ Class.4

In the integrated datasets, the incidence of anemia did not increase with BARI treatment (see Table 2).4

In the All BARI AD dataset, none of the anemia-related TEAEs were considered serious or led to permanent discontinuation. One (0%) TEAE of anemia led to temporary interruption of BARI treatment.4

Table 2. Summary of Anemia in the Atopic Dermatitis Clinical Trials4

 

 

 

 

 

 

 

 

 

 

 

BARI 2 mg Placebo-Controlleda
n (adj %)
b

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

BARI 2 mg vs 4 mgan (adj %)b

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

All BARI AD
n (%) [IR]


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

Anemia

1 (0.1)

1 (0.2)

1 (0.1)

2 (0.3)

1 (0.2)

2 (0.3)

2 (0.4) [0.5] 

3 (0.5) [0.6]

11 (0.4) [0.5]

Macrocytic Anemia

0

1 (0.1)

0

0

1 (0.1)

0

1 (0.1) [0.2]

0

1 (0.0) [0.0]

Normocytic Anemia

0

1 (0.1)

0

0

1 (0.1)

0

1 (0.1) [0.2]

0

1 (0.0) [0.0]

Iron Deficiency Anemia

0

0

0

0

0

0

0

1 (0.2) [0.2]

2 (0.1) [0.1]

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

a Data through 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 adverse events to provide appropriate direct comparisons between treatment groups. 

Integrated Safety Datasets Table

Table 3. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials4,5

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

3. Levine 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

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

5. Bieber 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

Glossary

AD = atopic dermatitis

BARI = baricitinib

CTCAE = Common Terminology Criteria for Adverse Events

EPO = erythropoietin

JAK = Janus kinase

LLN = lower limit of normal

MedDRA = Medical Dictionary for Regulatory Activities

TE = treatment-emergent

TEAE = treatment-emergent adverse event

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: February 04, 2021


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