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Olumiant ® (baricitinib)
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What is the incidence of herpes zoster with Olumiant® (baricitinib) in rheumatoid arthritis patients?
Herpes zoster is a common side effect of baricitinib. The incidence rate was 3.0 per 100 patient-years at risk and remained stable over time based on data up to 9.3 years of treatment and 14,744 patient-years of exposure.
Content overview
How to address risk of herpes zoster during treatment with baricitinib?
Herpes zoster (HZ) was commonly reported with baricitinib (≥ 1/100 to < 1/10). Frequency for herpes zoster is based on rheumatoid arthritis clinical trials.1
Serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.1
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex), were reported in clinical studies. In rheumatoid arthritis clinical studies, herpes zoster was reported more commonly in patients ≥ 65 years of age who had previously been treated with both biologic and synthetic conventional DMARDs .1
If a patient develops herpes zoster, treatment should be temporarily interrupted until the episode resolves.1
Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.1
If an infection develops, the patient should be monitored carefully and therapy should be temporarily interrupted if the patient is not responding to standard therapy. Treatment should not be resumed until the infection resolves.1
What was the Incidence of Herpes Zoster in Baricitinib Rheumatoid Arthritis Clinical Trials?
How was the incidence evaluated?
The HZ cluster of preferred terms was used to identify cases of HZ in the BARI safety database.2
Incidence rates (IRs) were calculated as the number of patients with an event per 100 patient-years of exposure (PYE) time, with exposure censored at time of event.3
Exposure-adjusted incidence rates (EAIRs) were calculated as the number of patients with an event per 100 PYE time, with exposure not censored at time of event.3
What are the datasets that have been evaluated?
Analyses were conducted using integrated safety datasets including the
- 7-study placebo-controlled dataset, which compares the safety of BARI 4 mg or 2 mg vs placebo through 24 weeks
- 4-study extended dataset, which compares the safety of BARI 4 mg vs 2 mg including long-term extension data, and
- All-BARI-RA dataset, the largest dataset that included 3770 patients with RA who received any dose of BARI from 9 randomized studies and 1 long-term extension study.3,4
More details on each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.
Results from the 7-Study Placebo-Controlled Dataset
Herpes zoster was the only preferred term from the HZ cluster of terms reported in the 7-study dataset.5
Through 24 weeks of assigned treatment or until rescue, the HZ IR for BARI 4-mg group (4.4) was statistically significantly higher than the placebo group (1.1; p<.05) and numerically higher than the BARI 2-mg group (3.1).4
Results form the All-BARI-RA Dataset
In the All-BARI-RA dataset, 422 patients treated with BARI reported a case of HZ with an IR of 3.0 per 100 patient-years at risk (PYR).3
The IR for HZ was highest in Asia with an IR of 5.2 per 100 PYR. Frequency of HZ was highest particularly in patients from Japan, Taiwan, and South Korea.3,6
Of the 422 HZ cases reported, a majority
- were mild (39.8%) or moderate (54.5%) in severity
- occurred mostly in older patients (75.6% in patients ≥50 years)
- occurred in patients without prior episodes (96.0%), and
- recovered (91%).3
Further details are provided in Herpes Zoster by Patient Characteristic in All-BARI-RA Dataset.
|
All BARI RA |
||
n (%) |
Patients With HZ |
Patients Without HZ |
IR per 100 PY (95% CI) |
Age in years |
|||
<50 |
103 (24.4) |
1273 (38.0) |
1.88 (1.54, 2.28) |
≥50 |
319 (75.6) |
2075 (62.0) |
3.66 (3.27, 4.09) |
Gender categories |
|||
Male |
89 (21.1) |
698 (20.8) |
2.87 (2.31, 3.54) |
Female |
333 (78.9) |
2650 (79.2) |
3.01 (2.69, 3.35) |
Region |
|||
US + Canada |
89 (21.1) |
751 (22.4) |
3.70 (2.97, 4.55) |
Asia including Japan |
169 (40.0) |
790 (23.6) |
5.17 (4.42, 6.01) |
Central America |
68 (16.1) |
692 (20.7) |
1.95 (1.51, 2.47) |
EU |
67 (15.9) |
716 (21.4) |
1.99 (1.54, 2.53) |
Rest of world |
29 (6.9) |
399 (11.9) |
1.77 (1.19, 2.54) |
Corticosteroid dose at baseline |
|||
0 mg/day |
198 (46.9) |
1661 (49.6) |
2.91 (2.52, 3.34) |
0.1-4.9 mg/day |
56 (13.3) |
287 (8.6) |
4.44 (3.36, 5.77) |
≥5 mg/day |
168 (39.8) |
1400 (41.8) |
2.75 (2.35, 3.20) |
Baseline lymphocytes categories |
|||
≥1 (109/L) |
375 (88.9) |
3072 (91.8) |
2.86 (2.58, 3.16) |
<1 (109/L) |
47 (11.1) |
276 (8.2) |
4.46 (3.27, 5.92) |
Methotrexate use |
|||
No |
81 (19.2) |
710 (21.2) |
2.69 (2.14, 3.35) |
Yes |
341 (80.8) |
2638 (78.8) |
3.05 (2.74, 3.40) |
Diabetes |
|||
No |
387 (91.7) |
3047 (91.0) |
2.98 (2.69, 3.29) |
Yes |
35 (8.3) |
301 (9.0) |
2.96 (2.06, 4.11) |
Cigarette smoking (current) |
|||
No |
348 (82.5) |
2819 (84.2) |
2.99 (2.69, 3.32) |
Yes |
74 (17.5) |
529 (15.8) |
2.90 (2.28, 3.65) |
Lines of therapy categories |
|||
Conventional DMARD - inadequate response |
302 (71.6) |
2438 (72.8) |
2.99 (2.66, 3.34) |
DMARD naive |
54 (12.8) |
482 (14.4) |
2.42 (1.82, 3.16) |
Biologic DMARD - inadequate response |
66 (15.6) |
428 (12.8) |
3.60 (2.79, 4.58) |
Prior herpes zoster |
|||
No |
405 (96.0) |
3286 (98.1) |
2.92 (2.64, 3.21) |
Yes |
17 (4.0) |
62 (1.9) |
5.99 (3.49, 9.59) |
Prior vaccination (herpes zoster) |
|||
No |
407 (96.4) |
3232 (96.5) |
2.99 (2.71, 3.30) |
Yes |
15 (3.6)a |
116 (3.5) |
2.63 (1.47, 4.34) |
Methotrexate average weekly dose categories |
|||
≤10 mg |
104 (24.6) |
781 (23.3) |
3.35 (2.74, 4.06) |
>10 mg |
237 (56.2) |
1857 (55.5) |
2.94 (2.58, 3.34) |
Abbreviations: BARI = baricitinib; DMARD = disease modifying antirheumatic drug; HZ = herpes zoster; IR = incidence rate; PY = patient years; PYE = patient-years of exposure; RA = rheumatoid arthritis.
a6 (9.5%) of 63 patients received immunization within 6 weeks before randomization, and 9 (14.5%) of 62 patients received immunization >6 weeks before randomization.
There were 15 complicated cases of HZ with
- 10 ocular/ophthalmic (2 were serious adverse events [SAEs])
- 1 HZ meningitis that was also a SAE, and
- 4 palsy.3
There were 42 cases of multidermatomal HZ, of which 18 were disseminated.3
The EAIR per 100 PYE for HZ was lower in patients in the BARI 2-mg group than the BARI 4-mg group as seen in Exposure-Adjusted Incidence Rates of Herpes Zoster in the Baricitinib 2-mg and Baricitinib 4-mg subsets of the All-BARI-RA Analysis Set.
|
Ever-on-BARI-2-mg |
Ever-on-BARI-4-mg |
Overall |
Herpes zoster |
64 (5.9) |
345 (10.1) |
422 (11.2) |
Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate.
The median time to first HZ event was >1.5 years. The HZ incidence rate remained stable over time (see Herpes Zoster Incidence Rate in the All-BARI-RA Dataset by Reporting Time Period).3,7
Abbreviation: PYE = patient-years of exposure.
Incidence by Immunization Status
See Herpes Zoster by Patient Characteristic in All-BARI-RA Dataset for detailed information on HZ immunization status.
No information is available regarding the use of BARI with a non-live HZ vaccine, such as Shingrix, because
- non-live HZ vaccine was not available at the time of the RA phase 3 studies, and
- no additional studies with the non-live vaccine have been conducted.
How was Herpes Zoster managed in the Clinical Trials?
Clinical Trial Exclusion Criteria Related to Herpes Zoster
Patients with symptomatic HZ infections within 12 weeks prior to study entry were excluded.2
Live vaccines, including HZ vaccination, were prohibited during the phase 3 studies of BARI for the treatment of rheumatoid arthritis (RA). Patients were excluded from the studies if they
- were exposed to HZ vaccination within 30 days of planned randomization
- had symptomatic HZ infection within 12 weeks prior to study entry, or
- had history of disseminated or complicated HZ, defined as
- multidermatomal involvement
- ophthalmic zoster
- central nervous system involvement, or
- postherpetic neuralgia.5
In the phase 3 clinical studies, investigators were instructed to
Only live HZ vaccine was available at the time of the studies.
Monitoring and treatment of Herpes Zoster in the clinical trials
In the originating phase 3 clinical studies, investigators were instructed to
However, in the long-term extension study, if a patient was diagnosed with HZ, the investigator was instructed to
- interrupt the study treatment
- initiate standard of care
- monitor for multidermatomal involvement or other evidence of dissemination, and
- follow-up until clinical recovery of skin lesions or vesicles.5
Study treatment could be resumed when skin lesions were crusted and resolving.2
Detailed instructions for interruption and resumption of study treatment upon clinical recovery were applied only in the long-term extension study.5
Description of datasets used to evaluate safety
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 01 September 2019 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.
Note: BARI 1 mg was studied in pivotal trials, however it is not approved in adult patients. 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.
2Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. 2020;79:1290-1297. http://dx.doi.org/10.1136/annrheumdis-2019-216852
3Taylor 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
4Genovese 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
5Data on file, Eli Lilly and Company and/or one of its subsidiaries.
6Chen YH, Chen YM, Smolen J, et al. Incidence rate and characterization of herpes zoster in patients with moderate-to-severe rheumatoid arthritis: an update from baricitinib clinical studies. Ann Rheum Dis. 2019;78(2):755. European League Against Rheumatism abstract FRI0164. http://dx.doi.org/10.1136/annrheumdis-2019-eular.1130.
7Chen YH, Chen YM, Smolen J, et al. Incidence rate and characterization of herpes zoster in patients with moderate-to-severe rheumatoid arthritis: an update from baricitinib clinical studies. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.
8Genovese 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
Date of Last Review: 29 October 2021