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Olumiant ® (baricitinib)
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Olumiant® (Baricitinib): Incidence of Tuberculosis in Rheumatoid Arthritis
Baricitinib should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of BARI treatment in patients with previously untreated latent TB.
Short Summary
In patients with RA who received BARI in clinical trials with maximum exposure of 8.4 years, events consistent with clinically overt TB infection
- were reported in 20 out of 3770 patients, and
- occurred at an incidence rate of 0.15 per 100 PYs of exposure (total of 13,148 PYE).1
The observed incidence rates of TB in the RA clinical trial program were consistent with the expected background rates in patients with RA from the various countries where TB was reported. Cases of TB primarily occurred in countries where TB is endemic.2
Use of Baricitinib in Patients With Active Tuberculosis
Tuberculosis in Rheumatoid Arthritis Population
The incidence of TB is estimated to be 4 to 10 times higher in patients with RA than in the general population.4-8
Rheumatoid Arthritis Clinical Trial Exclusion Criteria Related to Tuberculosis
Patients were excluded from participation in phase 3 RA studies if they had evidence of
Patients could participate in the studies if they had
- latent TB with at least 4 weeks of appropriate treatment completed prior to randomization, and agreed to complete the remainder of treatment while in the study, or
- a history of active or latent TB with documented evidence of completed appropriate treatment.9
Across the RA phase 3 studies,
- 0.6 to 0.9% of screened patients were excluded from randomization due to active TB
- 1.1 to 4.5% of screened patients were excluded from randomization due to latent TB
- 7 to 12% of randomized patients had evidence of latent TB, and
- 2 to 13% of patients were receiving isoniazid as treatment during enrollment.2,9
Cases of Tuberculosis in Rheumatoid Arthritis Clinical Trials
Safety Analysis Identification of Potential Tuberculosis Infections
Cases potentially representing TB infection were identified using a sponsor-defined list of MedDRA preferred terms from the Tuberculous Infections High Level Term and the Investigations System Organ Class.2
Description of ALL BARI RA Analysis Set
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
Incidence of Tuberculosis Infections
In patients with RA who received BARI in clinical trials, events consistent with clinically overt TB infection
- were reported in 20 out of 3770 patients, and
- occurred at an incidence rate of 0.15 per 100 PYs of exposure.1
Tuberculosis Case Details
Case details were analyzed from 15 cases of TB reported in the All BARI RA dataset using data from 3770 patients with up to 6.9 years of maximum exposure and 10,127 PYE.11
In the majority of countries where the 15 TB cases were reported,
- there were high rates of screen failure due to detection of latent TB, and
- the observed incidence rates of TB were consistent with the expected background rates in patients with RA, see Incidence Rates of Tuberculosis by Country for country details.2
Country IRa |
TB in General Populationb |
Estimated TB in RA Populationc |
TB in BARI-Treated RA Patientsd (n/N) |
Argentina |
.026 |
.104 to .26 |
.134 (2/467) |
Taiwan |
.044e |
.176 to .44 |
1.02 (3/92) |
Russian Federation |
.060 |
.24 to .60 |
.229 (1/130) |
South Korea |
.070 |
.28 to .70 |
.389 (1/84) |
India |
.204 |
.816 to 2.04 |
1.22 (3/131) |
South Africa |
.567 |
2.27 to 5.67 |
1.57 (3/65) |
China |
.063 |
.252 to .63 |
.191 (1/269) |
United States |
.003f |
.012 to .03 |
.056 (1/784) |
Abbreviations: BARI = baricitinib; IR = incidence rate; RA = rheumatoid arthritis; TB = tuberculosis; US = United States; WHO = World Health Organization.
aIncidence rate per 100 people/year.
bSource: WHO 2017 unless otherwise specified. Data converted from 100,000 to 100 people/year.
cIncidence rate in RA population is estimated to be 4 to 10 fold higher than general population (Winthrop, 2013).
dIncludes countries where the 15 cases of TB were reported in the All BARI RA dataset using data from 3770 patients with up to 6.9 years of maximum exposure , 10,127 PYE and data through 13 February 2013.
eSource: Centers for Disease Control, R.O.C. (Taiwan) 2016.
fSource: Centers for Disease Control, US, 2017.
Nine of the 15 cases were associated with extra-pulmonary involvement, including
Of the 15 cases,
- 2 patients had deviations in TB screening and did not receive treatment for latent TB
- 2 patients started and completed 6 months of treatment for latent TB based on screening test results
- 1 patient had a past medical history of TB treated with isoniazid, and
- 10 patients had negative TB test results at screening.2,9
All 15 TB cases occurred on BARI 4 mg treatment and were reported on BARI treatment day ranging from 137 to 1300, including
- 5 cases reported prior to day 500
- 7 cases reported between day 500 to 1000, and
- 3 cases reported after day 1000.2
Safety Analysis of concomitant Isoniazid Treatment for Latent Tuberculosis in RA Clinical Trials
Description of Pooled Safety Analysis From RA-BEAM, RA-BUILD and RA-BEACON
A post hoc analysis evaluated changes in ALT in patients with latent TB who were treated with isoniazid for 4 weeks prior to randomization and during the clinical trials.9
A total of 2516 patients were pooled from 3 phase 3 studies and included
Changes in ALT levels were measured from baseline up to week 24 for all patients analyzed. The proportions of patients with ALT levels ≥1X, ≥3X, ≥5X, and ≥10X ULN were calculated for each treatment group by concomitant isoniazid treatment or no isoniazid treatment.9
Alanine Aminotransferase Results in Isoniazid-Treated Patients
Of the 2516 patients analyzed, 246 were positive for latent TB, and 169 received isoniazid treatment. Isoniazid- treated patients with ALT levels ≥1X ULN included
Across all treatment groups, a higher number of isoniazid-treated patients had ALT levels ≥1X ULN than patients not taking isoniazid. However, there were no treatment interruptions or discontinuations due to abnormal hepatic laboratory results in patients taking concomitant isoniazid and BARI or ADA treatment.9,15
There were no reports of ALT levels ≥3X, ≥5X, and ≥10X ULN in patients treated with BARI 4 mg and isoniazid.9 Additional results on the proportion of patients with ALT levels ≥3X, ≥5X, and ≥10X ULN are provided in Alanine Tramsaminase Levels in Patients With and Without Isoniazid Treatment in RA Clinical Trials.
Changes from baseline to 24 weeks n (%) |
BARI 4 mgb |
BARI 4 mg c |
BARI 2 mgd |
BARI 2 mge |
Adalimumabf |
Adalimumabg |
Placebob |
Placebo h |
INH |
No INH |
INH |
No INH |
INH |
No INH |
INH |
No INH |
|
ALT ≥1X ULN |
24 (41.4) |
260 (31.2) |
9 (33.3) |
82 (21.8) |
12 (44.4) |
91 (30.0) |
21 (36.8) |
183 (21.9) |
ALT ≥3X ULN |
0 |
13 (1.6) |
2 (7.4) |
6 (1.6) |
2 (7.4) |
9 (3.0) |
2 (3.5) |
13(1.6) |
ALT ≥5X ULN |
0 |
5 (0.6) |
1 (3.7) |
1 (0.3) |
1 (3.7) |
3 (1.0) |
2 (3.5) |
3 (0.4) |
ALT ≥10X ULN |
0 |
2 (0.2) |
1 (3.7) |
0 |
0 |
1 (0.3) |
0 |
0 |
Abbreviations: ALT = alanine transaminase; BARI = baricitinib; INH = isoniazid; RA = rheumatoid arthritis; ULN = upper limit of normal.
aAll patients were on background conventional disease-modifying antirheumatic drugs, mainly methotrexate.
bPatient population from RA-BEAM, RA-BUILD, and RA-BEACON.
cPatient population from RA-BEAM, RA-BUILD, and RA-BEACON.
dPatient population from RA-BUILD and RA-BEACON.
ePatient population from RA-BUILD and RA-BEACON.
fPatient population from RA-BEAM.
gPatient population from RA-BEAM.
hPatient population from RA-BEAM, RA-BUILD, and RA-BEACON.
References
1Genovese 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
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
4Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumor necrosis factor therapy in USA. Ann Rheum Dis. 2013;72(1):37-42. https://dx.doi.org/10.1136/annrheumdis-2011-200690
5Brassard P, Lowe AM, Bernatsky S, et al. Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebex, Canada. Arthritis Rheum. 2009;61(3):300-304. https://dx.doi.org/10.1002/art.24476
6Carmona L, Hernandez-Garcia C, Vadillo C, et al. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol. 2003;30(7):1436-1439. http://www.jrheum.org/content/30/7/1436.long
7Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52(7):1986-1992. https://dx.doi.org/10.1002/art.21137
8Seong SS, Choi CB, Woo JH, et al. Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers. J Rheumatol. 2007;34(4):706-711. http://www.jrheum.org/content/34/4/706.long
9Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. Published online August 11, 2020. http://dx.doi.org/10.1136/annrheumdis-2019-216852
10Genovese 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.
11Genovese 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
12World Health Organization. Global tuberculosis report 2017. World Health Organization website. https://www.who.int/tb/publications/global_report/gtbr2017_main_text.pdf. Accessed May 9, 2019.
13Centers for Disease Control and Prevention: Tuberculosis Data and Statistics 2017. CDC.gov website. https://www.cdc.gov/tb/statistics/default.htm. Accessed May 9, 2019.
14Taiwan Centers for Disease Control. CDC.gov.tw website. https://nidss.cdc.gov.tw/en/. Accessed May 9, 2019.
15Hsieh TY, Huang WN, Tony HP, et al. Hepatic safety in patients with rheumatoid arthritis who received isoniazid for latent tuberculosis: post-hoc analysis from phase 3 baricitinib studies [abstract]. Ann Rheum Dis. 2018;77(suppl 2):098. https://ard.bmj.com/content/77/Suppl_2/593.1.abstract
Glossary
ADA = adalimumab
ALT = alanine aminotransferase
BARI = baricitinib
MedDRA = Medical Dictionary for Regulatory Activities
PYE = patient-years of exposure
RA = rheumatoid arthritis
TB = tuberculosis
ULN = upper limit of normal
Date of Last Review: 18 August 2020
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