Tips for searching:
• You have to select a product and type at least 2 words to activate the search
• Use only words that are specific to the information you are looking for
• Avoid typing questions or sentences
Please do not use this field to report adverse events or product complaints. Adverse events and product complaints should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the Google play or Apple app store. Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315 000.
Olumiant ® (baricitinib)
This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
How does Olumiant® (baricitinib) impact lymphocytes and neutrophils in patients with rheumatoid arthritis?
Changes in lymphocyte count occurred within the normal range for most patients. But low or high lymphocyte counts have been reported, as well as neutropaenia. Lymphocytes and neutrophils need monitoring.
Content in overview
- What are the overall changes to lymphocytes and neutrophils?
- How to monitor neutrophils and lymphocytes and what are the related actions?
- How do lymphocytes and neutrophils change over time?
- How often adverse events of lymphopenia and neutropenia have been observed?
- Description of the Integrated Safety Dataset
- References
What are the overall changes to lymphocytes and neutrophils?
Regarding the lymphocytes, low or high lymphocyte counts have been reported:1
- Low absolute lymphocyte counts (ALC) < 0.5 x 109 cells/L were reported and the ALC should be monitored.
- In general however, the mean absolute lymphocyte count increased by 1 week after starting treatment, 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.
The risk of lymphocytosis is increased in elderly patients with rheumatoid arthritis. - Rare cases of lymphoproliferative disorders have been reported.
Regarding the neutrophils,1
- absolute Neutrophil Count (ANC) < 1 x 109 cells/L were reported in clinical trials and the ANC should be monitored.
- Neutropaenia < 1 x 109 cells/L is a known adverse reaction listed in the SmPC.
Including changes detected during laboratory monitoring, neutropaenia < 1 x 109 cells/L is uncommon and affects ≥ 1/1,000 to < 1/100 of patients. - Mean neutrophil counts decreased at 4 weeks and remained stable at a lower value than baseline over time. There was no clear relationship between neutropaenia and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L.
Other laboratory measure such as lipids, haemoglobin or hepatic transaminases may also need monitoring. Furthermore, thrombocytosis > 600 x 109 cells/L and other changes have been observed.
For full information on safety profile and required monitoring please refer to the summary of product characteristics (SmPC).1
How to monitor neutrophils and lymphocytes and what are the related actions?
The absolute neutrophil count (ANC) and the absolute lymphocyte count (ALC) should be measured before initiation of treatment, and thereafter checked according to routine patient management.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
observed during routine patient management.1
Treatment may be restarted once the laboratory value return above these values.1
For full information on monitoring and laboratory measures please refer to the SmPC.1
How do lymphocytes and neutrophils change over time?
Which data have been evaluated? (The Integrated Safety Dataset)
The 5-study pooled dataset included patients with rheumatoid arthritis (RA) randomized to baricitinib 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
Baricitinib 2 mg data is pooled from 3 of these studies in which both baricitinib 2 mg and baricitinib 4 mg were options during randomization (1 phase 2 study as well as RA-BUILD and RA-BEACON).2
How did the Lymphocyte Count Change?
As shown in Time Course of Lymphocyte Levels in Patients From 5-Study Pooled Dataset, mean lymphocyte counts increased within 4 weeks of initiation of baricitinib treatment, then stabilized and returned to baseline with prolonged administration.2-5
Figure 1 description: Baricitinib treatment was associated with a mean increase of lymphocytes during the first 4 weeks which then stabilized and returned to or below baseline by 12 to 24 weeks and remained at this level through 216 weeks.
Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error; yrs = years.
Notes: Mean values ×109 cells/L.
How did the Neutrophil Count Change?
As shown in Time Course of Neutrophil Levels in Patients From 5-Study Pooled Dataset, mean neutrophil counts decreased within 4 weeks of initiation of baricitinib treatment, followed by stabilization and an increase to baseline after treatment discontinuation.2-5
Figure 2 description: Mean neutrophil counts decreased within 4 weeks of initiation of baricitinib treatment which then stabilized at a level below baseline but within normal limits through 216 weeks.
Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error; yrs = years.
Notes: Mean values ×109 cells/L.
How often adverse events of lymphopenia and neutropenia have been observed?
The subsequent information uses safety data from clinical trials that were combined in datasets. A more detailed description of datasets to evaluate the safety in rheumatoid arthritis clinical trials is provided in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.
Patients with shifts in lymphocyte and neutrophil values
Lymphocyte and neutrophil shifts are shown in Overview of CTCAE Grade Shifts in Lymphocyte and Neutrophil Counts From Placebo-Controlled Datasets for 7-study placebo-controlled dataset and All BARI RA dataset. Most lymphocyte and neutrophil shifts were to CTCAE grade 1 or 2.2
|
Shift from: |
Shift from: |
Shift from: |
7-Study Dataset Through 24 Weeks of Treatmenta |
|||
Lymphocytes |
|||
Placebo (N=1215) |
180/929 (19.4) |
85/1137 (7.5) |
11/1196 (0.9) |
BARI 4 mg (N=1142) |
164/905 (18.1) |
74/1080 (6.9) |
11/1130 (1.0) |
BARI 2 mg (N=479)b |
49/392 (12.5) |
24/454 (5.3) |
4/476 (0.8) |
Neutrophils |
|||
Placebo (N=1215) |
44/1159 (3.8) |
11/1172 (0.9) |
2/1174 (0.2) |
BARI 4 mg (N=1142) |
105/1085 (9.7) |
35/1098 (3.2) |
3/1101 (0.3) |
BARI 2 mg (N=479)b |
34/474 (7.2) |
14/477 (2.9) |
3/477 (0.6) |
All BARI RA (N=3770)a |
|||
Lymphocytes |
1580/3148 (50.2) |
935/3609 (25.9) |
193/3736 (5.2) |
Neutrophils |
747/3563 (21.0) |
297/3608 (8.2) |
48/3620 (1.3) |
Abbreviations: BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality; RA = rheumatoid arthritis.
Notes: No consecutive abnormal observations = next result was at a lower grade or normal and no consecutive abnormalities were observed for the patient at any other time.
CTCAE grades definitions for lymphopenia: grade 0 (≥1.1 billion cells/L); grade 1 (<1.1 and ≥0.8 billion cells/L); grade 2 (<0.8 and ≥0.5 billion cells/L; grade 3 (<0.5 and ≥0.2 billion cells/L).
CTCAE grades definitions for neutropenia: grade 0 (≥2 billion cells/L); grade 1 (<2 and ≥1.5 billion cells/L); grade 2 (<1.5 and ≥1.0 billion cells/L; grade 3 (<1.0 and ≥0.5 billion cells/L).
aPlease refer to the integrated safety dataset table for treatment exposure information.
bThrough 16 weeks of treatment.
Adverse Events of lymphopenia and neutropenia
Evaluation of treatment emergent adverse events (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 (described in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials) are provided in Overview of Treatment-Emergent Adverse Events of Lymphopenia and Neutropenia.
|
Lymphopenia |
Neutropenia |
||||
|
TEAE n [EAIR] |
Temporary interruption of treatment n [EAIR] |
Permanent DC of treatment n [EAIR] |
TEAE n [EAIR] |
Temporary interruption of treatment n [EAIR] |
Permanent DC of treatment n [EAIR] |
7-Study Dataset through 24 weeks of assigned treatmenta |
||||||
Placebo (N=1215) |
11 [2.4] |
3 [0.7] |
0 |
2 [0.4] |
1 [0.2] |
0 |
BARI 2 mg (N=479) |
3 [1.6] |
1 [0.5] |
1 [0.5] |
0 |
0 |
0 |
BARI 4 mg (N=1142) |
7 [1.5] |
3 [0.6] |
0 |
7 [1.5] |
0 |
0 |
4-Study Extended Dataseta |
||||||
BARI 2 mg (N=479) |
8 [0.95] |
3 [0.37] |
1 [0.12] |
0 |
0 |
0 |
BARI 4 mg (N=479) |
10 [1.19] |
2 [0.24] |
2 [0.24] |
3 [0.36] |
0 |
0 |
All BARI RA dataseta |
||||||
All BARI RA (N=3770) |
154 [1.02] |
49 [0.32] |
13 [0.09] |
60 [0.40] |
10 [0.07] |
8 [0.05]b |
Abbreviations: BARI = baricitinib; DC = discontinuation; EAIR = exposure-adjusted incidence rate; RA = rheumatoid arthritis; TEAE = treatment-emergent adverse event.
aPlease refer to the integrated safety dataset table for treatment exposure information.
bOne additional event of febrile neutropenia was reported.
Description of the Integrated Safety Dataset
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
Patients in the placebo group could have been taking
Evaluation time periods included
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
Evaluation time period included randomization through last available observation incorporating extension data through October 21, 2020 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
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.
References
1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Kremer 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.
4Smolen 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. J Rheumatol. 2019;46(1):7-18. https://dx.doi.org/10.3899/jrheum.171361
5Kay J, Harigai M, Rancourt J, et al. Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observed in patients with rheumatoid arthritis treated with baricitinib. RMD Open. 2020;6:e001370. http://dx.doi.org/10.1136/rmdopen-2020-001370
6Genovese 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
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
8Taylor 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
Date of Last Review: 30 September 2022