Olumiant ® (baricitinib)

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What is the incidence of herpes zoster with Olumiant® (baricitinib) in rheumatoid arthritis patients?

In all baricitinib treated patients with data up to 9.3 years of treatment and 14,744 patient-years of exposure, the incidence rate of herpes zoster was 3.0 per 100 patient-years at risk and remained stable over time.

UK_cFAQ_BAR120A_HERPES_ZOSTER_RA
UK_cFAQ_BAR120A_HERPES_ZOSTER_RA
en-GB

Information on Adverse Reaction from the Label

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

    Monitoring and Treatment of Herpes Zoster Occurrence

    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 conventional disease-modifying anti-rheumatic drugs (DMARDs).1

    If a patient develops herpes zoster, treatment should be temporarily interrupted until the episode resolves.1

    Incidence of Herpes Zoster in Baricitinib Rheumatoid Arthritis Clinical Trials

    The HZ cluster of preferred terms was used to identify cases of HZ in the BARI safety database. 

    Incidence rates (IRs) were calculated as the number of patients with an event per 100 patient-years of exposure time, with exposure censored at time of event.2

    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

    Dataset Descriptions

    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.2,3

    More details on each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.

    7-Study Placebo-Controlled Dataset

    Herpes zoster was the only preferred term from the HZ cluster of terms reported in the 7-study dataset.4

    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 BARI 2-mg group (3.1).2

    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.3,5

    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.

    Herpes Zoster by Patient Characteristic in All-BARI-RA Dataset4

     

    All BARI RA
    N=3770

    n (%)

    Patients With HZ
    n=422

    Patients Without HZ
    n=3348

    IR per 100 PY (95% CI)
    PYE

    Age in years

    <50

    103 (24.4)

    1273 (38.0)

    1.88 (1.54, 2.28)
    5467.37

    ≥50

    319 (75.6)

    2075 (62.0)

    3.66 (3.27, 4.09)
    8707.70

    Gender categories

    Male

    89 (21.1)

    698 (20.8)

    2.87 (2.31, 3.54)
    3096.38

    Female

    333 (78.9)

    2650 (79.2)

    3.01 (2.69, 3.35)
    11,078.69

    Region

    US + Canada

    89 (21.1)

    751 (22.4)

    3.70 (2.97, 4.55)
    2405.14

    Asia including Japan

    169 (40.0)

    790 (23.6)

    5.17 (4.42, 6.01)
    3271.25

    Central America

    68 (16.1)

    692 (20.7)

    1.95 (1.51, 2.47)
    3495.59

    EU

    67 (15.9)

    716 (21.4)

    1.99 (1.54, 2.53)
    3365.67

    Rest of world

    29 (6.9)

    399 (11.9)

    1.77 (1.19, 2.54)
    1637.41

    Corticosteroid dose at baseline

    0 mg/day

    198 (46.9)

    1661 (49.6)

    2.91 (2.52, 3.34)
    6809.55

    0.1-4.9 mg/day

    56 (13.3)

    287 (8.6)

    4.44 (3.36, 5.77)
    1260.74

    ≥5 mg/day

    168 (39.8)

    1400 (41.8)

    2.75 (2.35, 3.20)
    6104.78

    Baseline lymphocytes categories

    ≥1 (109/L)

    375 (88.9)

    3072 (91.8)

    2.86 (2.58, 3.16)
    13,120.08

    <1 (109/L)

    47 (11.1)

    276 (8.2)

    4.46 (3.27, 5.92)
    1054.99

    Methotrexate use

    No

    81 (19.2)

    710 (21.2)

    2.69 (2.14, 3.35)
    3008.57

    Yes

    341 (80.8)

    2638 (78.8)

    3.05 (2.74, 3.40)
    11,166.50

    Diabetes

    No

    387 (91.7)

    3047 (91.0)

    2.98 (2.69, 3.29)
    12,991.94

    Yes

    35 (8.3)

    301 (9.0)

    2.96 (2.06, 4.11)
    1183.13

    Cigarette smoking (current)

    No

    348 (82.5)

    2819 (84.2)

    2.99 (2.69, 3.32)
    11,627.01

    Yes

    74 (17.5)

    529 (15.8)

    2.90 (2.28, 3.65)
    2548.06

    Lines of therapy categories

    Conventional DMARD - inadequate response

    302 (71.6)

    2438 (72.8)

    2.99 (2.66, 3.34)
    10,111.58

    DMARD naive

    54 (12.8)

    482 (14.4)

    2.42 (1.82, 3.16)
    2230.69

    Biologic DMARD - inadequate response

    66 (15.6)

    428 (12.8)

    3.60 (2.79, 4.58)
    1832.81

    Prior herpes zoster

    No

    405 (96.0)

    3286 (98.1)

    2.92 (2.64, 3.21)
    13,891.15

    Yes

    17 (4.0)

    62 (1.9)

    5.99 (3.49, 9.59)
    283.92

    Prior vaccination (herpes zoster)

    No

    407 (96.4)

    3232 (96.5)

    2.99 (2.71, 3.30)
    13,605.54

    Yes

    15 (3.6)a

    116 (3.5)

    2.63 (1.47, 4.34)
    569.53

    Methotrexate average weekly dose categories

    ≤10 mg

    104 (24.6)

    781 (23.3)

    3.35 (2.74, 4.06)
    3102.15

    >10 mg

    237 (56.2)

    1857 (55.5)

    2.94 (2.58, 3.34)
    8064.35

    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.

    Exposure-Adjusted Incidence Rates of Herpes Zoster in the Baricitinib 2-mg and Baricitinib 4-mg subsets of the All-BARI-RA Analysis Set4

     

    Ever-on-BARI-2-mg
    N=1077
    n (%)
    [EAIR]

    Ever-on-BARI-4-mg
    N=3401
    n (%)
    [EAIR]

    Overall
    N=3770
    n (%)
    [EAIR]

    Herpes zoster

    64 (5.9)
    [2.39]

    345 (10.1)
    [2.91]

    422 (11.2)
    [2.79]

    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).3,6

    Herpes Zoster Incidence Rate in the All-BARI-RA Dataset by Reporting Time Period3

    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.

    Appendix

    Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials2-4,7

    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

    • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
    • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

    Patients in the placebo group could have been taking

    • background MTX, or
    • in some studies, other conventional DMARD therapy.

    Evaluation time periods included

    • through the 12-week placebo-controlled period in phase 2 studies
    • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
    • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

    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

    • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or
    • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

    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

    • BARI 4 mg (n=3401, PYE=11,872)
    • BARI 2 mg (n=1077, PYE=2678), and
    • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

    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.

    2Genovese 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

    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

    4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    5Chen 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.

    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. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.

    7Genovese 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


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