Olumiant® ▼ (baricitinib): Changes in Lymphocytes and Neutrophils in the Rheumatoid Arthritis Clinical Development Program

Warnings and Precautions Related to Lymphocytes and Neutrophils

It is recommended to avoid initiation or interrupt BARI treatment in patients with an

• ALC <0.5 billion cells/L (500 cells/mm³), or

• ANC <1.0 billion cells/L (1000 cells/mm³).¹

Mean Changes in Lymphocytes and Neutrophils Over Time

The 5-study pooled dataset included patients with RA randomized to BARI 4 mg or placebo from 1 phase 2 study and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with data through 13 February 2018.²

BARI 2 mg data is pooled from 3 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (1 phase 2 study as well as RA-BUILD and RA-BEACON).²

Mean Lymphocyte Count Changes

Mean absolute lymphocyte count increased by 1 week after starting treatment with baricitinib, returned to baseline by week 24, and then remained stable through at least 104 weeks. For most patients, changes in lymphocyte count occurred within the normal reference range.¹

As shown in Figure 1, mean lymphocyte counts increased within 4 weeks of initiation of BARI treatment, then stabilized and returned to baseline with prolonged administration.^2-5

Figure 1. Time Course of Lymphocyte Levels in Patients From 5-Study Pooled Dataset²

Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error; yrs = years.
Notes: *10⁹ cells/L

Mean Neutrophil Count Changes

As shown in Figure 2, mean neutrophil counts decreased within 4 weeks of initiation of BARI treatment, followed by stabilization and an increase to baseline after treatment discontinuation.^2-5

Figure 2. Time Course of Neutrophil Levels in Patients From 5-Study Pooled Dataset²

Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error; yrs = years.
Notes: *10⁹ cells/L

Adverse Events of Lymphopenia and Neutropenia

Evaluation of TEAEs included MedDRA preferred terms identified from the Blood and Lymphatic System Disorders System Organ Class.²

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 are provided in  . 

Table 1. Overview of Treatment-Emergent Adverse Events of Lymphopenia and Neutropenia^2,6,7

Abbreviations: BARI = baricitinib; DC = discontinuation; EAIR = exposure-adjusted incidence rate; MONO = monotherapy; MTX = methotrexate; RA = rheumatoid arthritis; TEAE = treatment-emergent adverse event.

^a The 7-study pooled dataset included patients with RA randomized to BARI 4 mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Patients in the placebo group could have been taking background MTX or other conventional DMARDs. Evaluation time periods included throughthe 12-week placebo-controlled period in phase 2 studies16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and24 weeks of assigned treatment or until rescue in phase 3 studies.

^b Data from BARI 2 mg (N=479, PYE=185.8) is derived from 4 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).

^c The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and 2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension study (RA-BEYOND). The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.

^d The All BARI RA analysis set included 3770 patients with RA who received BARI at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with 13,148 PYE, median exposure of 4.2 yrs, maximum exposure of 8.4 yrs, and data through 01 September 2019.

^e One additional event of febrile neutropenia was reported.

Information from the label

ALC and ANC should be monitored before treatment initiation and thereafter according to routine patient management.¹ 

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. Haemoglobin < 8 g/dL was reported in less than 1 % of patients in rheumatoid arthritis clinical trials.¹

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

• ANC < 1 x 10⁹ cells/L,

• ALC < 0.5 x 10⁹ cells/L or

• haemoglobin < 8 g/dL

observed during routine patient management.¹

The risk of lymphocytosis is increased in elderly patients with rheumatoid arthritis. Rare cases of lymphoproliferative disorders have been reported.¹

In controlled studies, for up to 16 weeks, neutropenia (<1 x 10⁹ cells/L) was uncommonly reported (≥ 1/1000). ¹

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

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.

3. Kremer J, Huizinga TWJ, Chen L, et al. Analysis of neutrophils, lymphocytes, and platelets in pooled phase 2 and phase 3 studies of baricitinib for rheumatoid arthritis. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 14-17, 2017; Madrid, Spain.

4. Eli Lilly and Company. Lilly FDA Advisory Committee Meeting NDA 207924 Briefing Document. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf. Accessed May 2, 2018a. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf

5. Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment [published online September 15, 2018]. J Rheumatol. https://dx.doi.org/10.3899/jrheum.171361

6. Genovese 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 [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. https://ard.bmj.com/content/79/Suppl_1/642.1

7. Genovese 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. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

Glossary

ALC = absolute lymphocyte count

ANC = absolute neutrophil count

BARI = baricitinib

RA = rheumatoid arthritis

SAE = serious adverse event

TEAE = treatment-emergent adverse event

VTE = venous thromboembolism

▼ 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.