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Olumiant ® ▼ (baricitinib)
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Olumiant Summary of Product Characteristics (SmPC)
Olumiant®▼(baricitinib): Platelet Changes
Platelet increases from baseline were noted in patients with rheumatoid arthritis treated with baricitinib.
UK_cFAQ_BAR117A_PLATELETS_CHANGES_RA
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Platelet Changes in the Rheumatoid Arthritis Clinical Development Program
Mean Platelet Changes Over Time
In controlled studies, for up to 16 weeks, increases in platelet counts above 600 x 109 cells/L occurred in 2.0 % of patients treated with baricitinib 4 mg and 1.1 % of patients treated with placebo. No association was observed between increased platelet counts and adverse events of a thrombotic nature. The pattern and incidence of increases in platelet counts remained stable at a higher value than baseline over time including in the long term extension study. 1
5-Study Pooled Dataset
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
Based on the 5-study pooled dataset, mean platelet counts
- increased early with a peak at week 2
- returned towards baseline at week 4, and
- stabilized after week 8 at levels higher than baseline with extended BARI exposure (5-Study Pooled Dataset Mean (SE) Platelet Levels Over Time).2-4
Abbreviations: BARI = baricitinib; PBO = placebo; SE = standard error Notes: BARI 2-mg, placebo censored at rescue or dose change, and BARI 4-mg censored at any dose change (including step-down) or rescue in long-term extension study. Lilly-defined large clinical trial population based reference ranges were used.
6-Study Placebo-Controlled Dataset
The 6-study placebo-controlled dataset compared BARI 4 mg vs placebo and included patients with RA who were randomized to BARI 4 mg (N=997) or placebo (N=1070) from 3 phase 2 and 3 phase 3 studies. In the majority of the studies, patients were on background therapy either with MTX or another csDMARD. The BARI 2-mg data is derived from 4 studies in which both BARI 2 mg (N=479) and BARI 4 mg were options during randomization.5
Reversibility was evaluated in a subgroup of patients from the 6-Study placebo-controlled dataset who discontinued treatment by Week 24. Reversibility of increased platelet count was observed with the return of mean values to baseline after treatment discontinuation (Platelet Count Reversibility in a Patient Subgroup from the 6-Study Placebo-Controlled Dataset).3,6
Notes: Platelet counts were pooled from 6 placebo-controlled phase 2 and 3 studies, including the long-term extension study period, with data through January 1, 2016. Reversibility was evaluated in patients who discontinued study treatment by week 24.
Changes in Mean Platelet Volume
Mean Platelet Changes Over Time
The relationship of platelet count to MPV was assessed, over 16 weeks, in study RA-BEAM, a 52-week, randomized, placebo- and active-controlled study of patients with moderate to severe active rheumatoid arthritis.7
The objective of this analysis was to determine if the observed platelet changes were consistent with altered
- platelet synthesis
- platelet release, or
- platelet clearance.7
In RA-BEAM, after initiation of BARI treatment
- platelet count increased at week 2, then returned toward baseline at week 4
- MPV decreased at week 2, then returned toward baseline at week 4, and
- both platelet count and MPV remained stable after week 4 through the 16-week observation period (Changes in Mean Platelet Count and Platelet Volume for Baricitinib 4 mg (Study RA-BEAM) ).6,7
According to the authors, the pattern of mirrored changes for platelet count and MPV suggests decreased platelet clearance rather than increased platelet production. As a potential explanation, the increase in platelet count at week 2 may represent a transient increase in smaller and older circulating platelets, which might account for the observed MPV decline.6,7
Abbreviations: CI=confidence interval; MPV= mean platelet volume
Note: Includes patients with MPC or MPV >0 and with baseline data available.
*p<0.001 for within-group change from baseline.
Patients With Abnormal High Platelet Values
Dataset Descriptions
7-Study Placebo-Controlled Dataset
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 could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through
- the 12-week placebo-controlled period in phase 2 studies
- 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
- 24 weeks of assigned treatment or until rescue in phase 3 studies.8
Data from BARI 2 mg (N=479, PYE=185.8) were 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).8
4-Study Extended Dataset
The extended dataset included patients with RA randomized to BARI 2 mg (N=479, PYE=675.6, median exposure duration=257 days, maximum exposure duration=1805 days) or BARI 4 mg (N=479, PYE=698.6, median exposure duration=342 days, maximum exposure duration=2520 days ) 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 13 February 2018 unless otherwise specified. Data were censored at rescue or dose change.8
All BARI RA Dataset
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
- 10,127 PYE,
- median exposure of 3.1 yrs,
- maximum exposure of 6.9 yrs, and
- data through 13 February 2018.8
Treatment Emergent Abnormally High Platelet Value Analyses
Analyses of treatment emergent high platelet counts (>ULN) across integrated safety datasets are presented in Treatment Emergent Abnormal High Platelet Values. 2
Normal limits were defined according to
- lab methodology
- age
- gender, and
- ethnicity.2
7-Study Placebo-Controlled Dataset, Week 24 PBO (N=1215) (NAR=1033) |
7-Study Placebo-Controlled Dataset, Week 24 BARI 2 mg (N=479) (NAR=420) |
7-Study Placebo-Controlled Dataset, Week 24 BARI 4 mg (N=1142) (NAR=974) |
4-Study Extended Dataset BARI 2 mg (N=479) (NAR=421) |
4-Study Extended Dataset BARI 4 mg (N=479) (NAR=426) |
All BARI RA Dataset (N=3770) (NAR=3296) |
|
Abnormal High, n (%) |
98 (9.5%) |
71 (16.9)a |
237 (24.3)a |
82 (19.5) |
129 (30.3)b |
1025 (31.1) |
Abbreviations: BARI = baricitinib; N = number of patients in the analysis population; n = number of patients with the specified abnormality; NAR = number of patients at risk for the abnormality in each treatment group; PBO = placebo; RA = rheumatoid arthritis
Note: For the 7-Study Placebo-ControlledDataset, the OR is versus placebo. For the 4-Study Extended Dataset, the OR is versus BARI 2 mg.
aP-value ≤ 0.05 and OR > 1 (missing ORs are considered >1).
bBARI incidence ≥10% before rounding and OR >1 (missing ORs are considered >1).
The proportions of patients experiencing a change from ≤ 600 billion cells/L to > 600 billion cells/L are presented in Proportion of Patients with Platelet Value Changes from ≤ 600 billion cells/L to > 600 billion cells/L. 2
7-Study Placebo-Controlled Dataset, Week 24 PBO (N=1215) (NAR=1198) |
7-Study Placebo-Controlled Dataset, Week 24 BARI 2 mg (N=479) (NAR=472) |
7-Study Placebo-Controlled Dataset, Week 24 BARI 4 mg (N=1142) (NAR=1127) |
4-Study Extended Dataset BARI 2 mg (N=479) (NAR=473) |
4-Study Extended Dataset BARI 4 mg (N=479) (NAR=473) |
All BARI RA Dataset (N=3770) (NAR=3716) |
|
≤ 600 billion cells/L to > 600 billion cells/L |
17 (1.4) |
5 (1.1)a |
27 (2.4) |
8 (1.7) |
19 (4.0) |
127 (3.4) |
Abbreviations: BARI = baricitinib; N = number of patients in the analysis population; n = number of patients with the specified abnormality; NAR = number of patients at risk for the abnormality in each treatment group; PBO = placebo; RA = rheumatoid arthritis
aThrough Week 16
Relationship of Increased Platelets to Thrombotic Events
Thrombocytosis and Thromboembolic Adverse Events
In controlled studies, for up to 16 weeks, thrombocytosis (>600 x 109 cells/L) was commonly reported (≥ 1/100 to <1/10). 1
DVT and PE are listed as uncommon in the table of adverse reactions in the summary of product characteristics. 1
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.1
Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as
- older age,
- obesity,
- a medical history of DVT/PE, or
- patients undergoing surgery and immobilisation.1
If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.1
The association between thrombocytosis and adverse events of a thrombotic nature were evaluated in patients from the All BARI RA 12-month safety update analysis set.3
Among the 31 patients in the All BARI RA dataset with a reported adverse event of VTE through September 1, 2016, the proportion of patients with high platelet levels was comparable between patients with VTE vs those without VTE (Proportions of BARI-Treated Patients With and Without a DVT/PE Adverse Event According to Thrombocytosis Criteria Applied at Baseline and Post Baseline). No association was observed between increased platelet counts and VTE events.3,9
Abbreviations: BARI = baricitinib; DVT/PE = deep venous thromboembolism/pulmonary embolism.
Note: Data from the All BARI RA analysis set with data through September 1, 2016.
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.
4Eli 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
5Smolen 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. http://dx.doi.org/10.3899/jrheum.171361
6Kay 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
7Giles JT, Nurmohamed MT, Rinder HM, et al. Mean platelet volume changes with baricitinib indicate reduced new platelet production in baricitinib-treated rheumatoid arthritis patients. Presented at American College of Rheumatology (ACR/ARHP) Annual Meeting; November 19-24, 2018. Chicago, IL.
8Genovese 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
9Smolen 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
Glossary
BARI = baricitinib
csDMARD = conventional synthetic disease-modifying antirheumatic drug
DMARD = disease-modifying antirheumatic drug
MPV = mean platelet volume
MTX = methotrexate
PYE = patient-years of exposure
RA = rheumatoid arthritis
ULN = upper limit of normal
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.
Date of Last Review: March 14, 2021
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