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 Lymphocytes and Neutrophils in Atopic Dermatitis

Mean neutrophil counts decreased but stabilized over the 68-week period, whereas mean lymphocyte counts initially increased with baricitinib and returned to baseline values over the course of the extended period.

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Baricitinib Label Information Related to Neutrophils and Lymphocytes

Warnings and Precautions

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L and Absolute Lymphocyte Count (ALC) < 0.5 x 109 cells/L were reported in less than 1 % of patients in clinical trials.1

Treatment should not be initiated, or should be temporarily interrupted, in patients with an

  • ANC < 1 x 109 cells/L, or
  • ALC < 0.5 x 109 cells/L 

observed during routine patient management.1

Neutropenia

In rheumatoid arthritis and atopic dermatitis controlled studies, for up to 16 weeks, decreases in neutrophil counts below 1 x 109 cells/L occurred in

  • 0.2 % of patients treated with baricitinib compared to
  • 0 % of patients treated with placebo.1

There was no clear relationship between decreases in neutrophil counts and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L.

The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including in the long-term extension study.1

Assessment of Lymphocytes and Neutrophils in the Baricitinib BREEZE-AD Clinical Program

Interruption of Treatment During Atopic Dermatitis Clinical Trials

In phase 3 clinical trials, study treatment was temporarily interrupted in patients with an

  • ALC <0.5 x 109 cells/L (500 cells/mm3), or
  • ANC <1.0 x 109cells/L (1000 cells/mm3).

In the phase 3 clinical trials, study treatment was permanently discontinued in patients with an

  • ALC <0.2 x 109 cells/L (200 cells/mm3), or
  • ANC <0.5 x 109 cells/L (500 cells/mm3).

Integrated Safety Datasets

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials describes the integrated datasets that were used to evaluate lymphocyte and neutrophil changes, CTCAE grade shifts of abnormal lymphocyte and neutrophil values, and the incidence of lymphopenia and neutropenia.

Mean Changes in Lymphocytes and Neutrophils Over Time

Changes in Lymphocytes Over Time

Mean ALC

2Time Course of Lymphocyte Levels in Patients from the BREEZE-AD Clinical Program Through 68-Week2

Abbreviations: AD = atopic dermatitis; LLN = lower limit of normal; ULN = upper limit of normal.
Note: X109 cells/L.

Changes in Neutrophils Over Time

Mean ANC

2Time Course of Neutrophil Levels in Patients From the BREEZE-AD Clinical Program Through 68-Week2

Abbreviations: AD = atopic dermatitis; LLN = lower limit of normal; ULN = upper limit of normal.
Note: X109 cells/L.

Patients With CTCAE Grade Shifts and Abnormal Lymphocyte and Neutrophil Values

CTCAE Grade Shifts in Lymphocytes and Neutrophils

Categorical changes in TE abnormal laboratory values were analyzed based on the

  • TE shifts in CTCAE grades, and
  • ULN and LLN.2

Abnormal Lymphocyte Levels

Significant differences in TE abnormal high were reported in patients treated with BARI compared with placebo and between BARI doses. No significant differences were observed in TE abnormal low (see column 1 and 2 of Overview of Treatment-Emergent Abnormal Low and High and CTCAE Grade Shifts in Lymphocytes From BREEZE-AD Clinical Development Program).3

Most lymphocyte shifts were to CTCAE grade 1 or 2, and there were no shifts to CTCAE grade 4 (Overview of Treatment-Emergent Abnormal Low and High and CTCAE Grade Shifts in Lymphocytes From BREEZE-AD Clinical Development Program).3

 

 

Overview of Treatment-Emergent Abnormal Low and High and CTCAE Grade Shifts in Lymphocytes From BREEZE-AD Clinical Development Program2,3

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

Treatment-Emergent Abnormal High
n/NAR (adj %)

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 (%)

Shift From:
Grade <4 to Grade ≥4
n/NAR (%)

BARI 2 mg placebo-controlleda


Placebo, n=889

63/766 (8.1)

20/859 (2.3)

71/710(10.0)

28/844 (3.3)

2/868 (0.2)

0/869 (0)

BARI 2 mg, n=721

55/619 (8.7)

23/693 (3.2)

66/566 (11.7)

15/692 (2.2)

1/707 (0.1)

0/708 (0)

BARI 4 mg placebo-controlleda


Placebo, n=743

50/641 (6.3)

18/719 (2.1)

59/593 (9.9)

21/707 (3.0)

1/726 (0.1)

0/727 (0)

BARI 4 mg, n=489

30/414 (5.8)

27/481 (5.0)b

35/387 (9.0)

14/470 (3.0)

3/487 (0.6)

0/487 (0)

BARI 2 mg vs 4 mga


BARI 2 mg, n=576

44/496 (7.2)

16/558 (2.3)

51/452 (11.3)

8/557 (1.4)

0/570 (0)

0/570 (0)

BARI 4 mg, n=489

30/414 (5.8)

27/481 (5.0)c

35/387 (9.0)

14/470 (3.0)

3/487 (0.6)

0/487 (0)

BARI 2 mg vs 4 mg extended


BARI 2 mg, n=576

74/496 (12.7)

22/558 (3.2)

452/82 (18.1)

16/557 (2.9)

0/570 (0)

0/570 (0)

BARI 4 mg, n=489

57/414 (11.8)

32/481 (5.9)c

387/66 (17.1)

30/470 (6.4)d

4/487 (0.8)c

0/487 (0)

All BARI AD


All doses, N=2531                                   

291/2130 (13.7)e

128/2453 (5.2)

1969/332 (16.9)

116/2406 (4.8)

12/2492 (0.5)

0/2496 (0)

Abbreviations: AD = atopic dermatitis; adj =adjusted; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality.

aData through 16-week placebo-controlled period.

bp<.05 vs placebo.

cp<.05 BARI 4 mg vs BARI 2 mg.

dp<.01 BARI 4 mg vs BARI 2 mg.

eData are shown as n/NAR (%).

Abnormal Neutrophil Levels

Significant differences in TE abnormal low were reported in patients treated with BARI compared with placebo and between BARI doses (see column 1 of Overview of Treatment-Emergent Abnormal Low and CTCAE Grade Shifts in Neutrophils From BREEZE-AD Clinical Development Program).3

Most neutrophil shifts were to CTCAE grade 1 or 2, and there were no shifts to CTCAE grade 4 (Overview of Treatment-Emergent Abnormal Low and CTCAE Grade Shifts in Neutrophils From BREEZE-AD Clinical Development Program).3


Overview of Treatment-Emergent Abnormal Low and CTCAE Grade Shifts in Neutrophils From BREEZE-AD Clinical Development Program2,3

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 (%)

Shift From
Grade <4 to Grade ≥4
n/NAR (%)

BARI 2 mg placebo-controlledb


Placebo, n=889

45/846 (5.5)

41/847 (4.8)

7/863 (0.8)

0/868 (0)

0/869 (0)

BARI 2 mg, n=721

57/686 (8.3)c

52/687 (7.6)d

14/704 (2.0)c

1/707 (0.1)

0/707 (0)

BARI 4 mg placebo-controlledb


Placebo, n=743

37/710 (4.5)

34/711 (4.8)

6/723 (0.8)

0/727 (0)

0/727 (0)

BARI 4 mg, n=489

52/470 (8.9)e

50/471 (10.6)e

14/486 (2.9)c

1/487 (0.2)

0/487 (0)

BARI 2 mg vs 4 mgb


BARI 2 mg, n=576

45/556 (6.7)

41/556 (7.4)

8/568 (1.4)

1/570 (0.2)

0/570 (0)

BARI 4 mg, n=489

52/470 (8.9)

50/471 (10.6)

14/486 (2.9)

1/487 (0.2)

0/487 (0)

BARI 2 mg vs 4 mg extended


BARI 2 mg, n=576

61/556 (9.1)

58/556 (10.4)

14/568 (2.5)

1/570 (0.2)

0/570 (0)

BARI 4 mg, n=489

81/470 (14.6)f

79/471 (16.8)f

26/486 (5.3)g

3/487 (0.6)

0/487 (0)

All BARI AD


All doses, N=2531                                   

295/2376 (12.4)h

286/2382 (12.0)

87/2476 (3.5)

6/2491 (0.2)

0/2495 (0)

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality.

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 (eg, 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.

bData through 16-week placebo-controlled period.

cp<.05 vs placebo.

dp<.01 vs placebo.

ep<.001 vs placebo.

fp<.01 BARI 4 mg vs BARI 2 mg.

gp<.05 BARI 4 mg vs BARI 2 mg.

hData are n/NAR (%).

Adverse Events of Lymphopenia and Neutropenia

Overview of Treatment-Emergent Adverse Events of Lymphopenia and Neutropenia provides rates of TEAEs as well as treatment interruption and permanent discontinuation of study treatment due to TEAEs of lymphopenia and neutropenia for all of the integrated analysis datasets.

Overview of Treatment-Emergent Adverse Events of Lymphopenia and Neutropenia3

Lymphopenia

Neutropenia


TEAE

Temporary Interruption of Treatment

Permanent DC of Treatment

TEAE

Temporary Interruption of Treatment

Permanent DC of Treatment

BARI 2 mg placebo-controlled,a n (adj %)b



Placebo, n=889

4 (0.4)

0

3 (0.3)

2 (0.2)

0

0

BARI 2 mg, n=721

2 (0.3)

0

0

1 (0.1)

0

1 (0.1)

BARI 4 mg placebo-controlled,a n (adj %)b



Placebo, n=743

4 (0.4) 

0

3 (0.3)

2 (0.2)

0

0

BARI 4 mg, n=489

3 (0.4)

0

0

2 (0.2)

0

0

BARI 2 mg vs 4 mg,a n (adj %)b



BARI 2 mg, n=576

2 (0.3)

0

0

1 (0.1)

0

1 (0.1)

BARI 4 mg, n=489

3 (0.4)

0

0

2 (0.2)

0

0

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



BARI 2 mg, n=576

2 (0.3) [0.5]

0

0

2 (0.2) [0.4]

0

1 (0.1) [0.2]

BARI 4 mg, n=489

4 (0.6) [0.8]

0

0

4 (0.6) [1.0]

1 (0.2) [0.3]

0

All BARI AD, n (%) [IR]



All doses, N=2531                                   

11 (0.4) [0.5]

1 (0) [0]

0

11 (0.4) [0.5]

1 (0) [0]

1 (0) [0]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; DC = discontinuation; IR = incidence rate; TEAE = treatment-emergent adverse event.

aData through 16-week placebo-controlled period.

bFor 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 (eg, 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 Dataset Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,3

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

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

2Bieber 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

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Glossary

AD = atopic dermatitis

ALC = absolute lymphocyte count

ANC = absolute neutrophil count

BARI = baricitinib

CTCAE = Common Terminology Criteria for Adverse Events

LLN = lower limit of normal

TE = treatment-emergent

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: February 02, 2021


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