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).

What is the incidence of infection with Olumiant® (baricitinib) treatment in rheumatoid arthritis?

In all BARI treated patients with data up to 9.3 years of treatment and 14,744 patient-years of exposure, infections were the most common TEAE and the IR of serious infections was 2.6 per 100 patient-years at risk and remained stable over time.

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Baricitinib and Infections 

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In rheumatoid arthritis clinical studies, in treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.1

The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections.1

If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.1

Infections in Rheumatoid Arthritis Clinical Trials

Safety Dataset Descriptions

Exposure-adjusted incidence rates (EAIRs) were calculated as the number of patients with an event per 100 patient-years of exposure (PYE) time, with exposure not censored at time of event.2

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

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 versus placebo through 24 weeks
  • 4-study extended dataset, which compares the safety of BARI 4 mg versus 2 mg including long-term extension data, and
  • All-BARI-RA dataset, the largest dataset that included 3770 patients with rheumatoid arthritis (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.

Overall Infection in Rheumatoid Arthritis Clinical Trials

Information regarding the number of infections leading to temporary treatment interruption and treatment discontinuation is available in Overview of Treatment-Emergent Infections From Rheumatoid Arthritis Integrated Analysis Sets.

Overview of Treatment-Emergent Infections From Rheumatoid Arthritis Integrated Analysis Sets2,4

 

7-Study Dataset (to Week 24)


4-Study Extended Dataset

All-BARI-RAa

n (%) [EAIR]b

Placebo
N=1215

PYE=450.8

BARI 2 mgc
N=479
PYE=185.8

BARI 4 mg
N=1142
PYE=471.8

BARI 2 mgd
N=479
PYE=774.9

BARI 4 mge
N=479
PYE=781.1

N=3770
PYE=14,744

All TE infection

340 (28.0) [75.4]

156 (32.6) [84.0]

423 (37.0) [89.7]

238 (49.7) [30.2]

271 (56.6) [34.0]

2590 (68.7) [17.1]

Led to temporary interruption of study treatment

54 (4.4) [12.0]

34 (7.1)[18.3]

69 (6.0)[14.6]

71 (14.8) [9.2]

75 (15.7) [9.6]

827 (21.9) [5.5]

Led to permanent discontinuation

8 (0.7) [1.8]

7 (1.5) [3.8]

23 (2.0) [4.9]

12 (2.5) [1.5]

22 (4.6) [2.8]

185 (4.9) [1.2]

Serious infection,f n (IR)

19 (1.6) [4.1]

8 (1.7) [4.2]

19 (1.7) [4.0]

22 (4.6) [EAIR=2.8]

33 (6.9) [EAIR=4.1]

372 (9.9) [2.5]

Infection leading to death

4 (0.3) [0.9]

0

3 (0.3) [0.6]

1 (0.2) [0.1]

1 (0.2) [0.1]

19 (0.5) [0.1]

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; IR = incidence rate; PYE = patient-years of exposure; RA = rheumatoid arthritis; TE = treatment emergent.

aData from the All-BARI-RA dataset included maximum of 9.3 years of exposure.

bExposure-adjusted incidence rate unless otherwise specified.

cBaricitinib 2-mg data in the placebo-controlled analysis set are derived from 4 studies in which both BARI 2 mg and 4 mg were options during randomization.

dIncludes data through September 1, 2019 with a maximum of 2370 days exposure.

eIncludes data through September 1, 2019 with a maximum of 3085 days exposure.

fIdentified as serious by International Conference on Harmonization criteria.

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment or until rescue, the number of patients with any type of treatment-emergent (TE) infection was

  • 423 (37.0%) [EAIR=89.7] in the BARI 4-mg group
  • 156 (32.6%) [EAIR=84.0] in the BARI 2-mg group, and
  • 340 (28.0%) [EAIR=75.4] in the placebo group.3

Additional details are provided in Overview of Treatment-Emergent Infections From Rheumatoid Arthritis Integrated Analysis Sets.

Commonly reported infections with BARI treatment include

  • upper respiratory tract infections
  • HZ infection
  • herpes simplex infections, and
  • urinary tract infections.4

Through 24 weeks of assigned treatment or until rescue, the proportion of TE infections requiring antimicrobial treatment was

  • 22.3% in the BARI 4-mg group
  • 20.3% in the BARI 2-mg group, and
  • 15.5% in the placebo group.4

Details regarding TE infections and incidence of upper respiratory tract infections HZ, urinary tract infection, and herpes simplex infection through 24 weeks are provided in Overview of Treatment-Emergent Infections From Rheumatoid Arthritis Integrated Analysis Sets and Upper Respiratory Tract Infection, Herpes Zoster Infection, Urinary Tract Infection, and Herpes Simplex Infection Clusters Reported in the Rheumatoid Arthritis Clinical Program.

Upper Respiratory Tract Infection, Herpes Zoster Infection, Urinary Tract Infection, and Herpes Simplex Infection Clusters Reported in the Rheumatoid Arthritis Clinical Program3,4

n (%) [EAIR]

Upper Respiratory Tract Infectiona

Herpes Zoster Infectionb

Urinary Tract Infection

Herpes Simplex Infectionc

7-study placebo-controlled dataset (weeks 0-24)


Placebo (N=1215)

184 (15.1) [40.8]

5 (0.4) [1.1]

34 (2.8) [9.9]

10 (0.8) [2.2]

BARI 2 mgd (N=479)

91 (19.0) [49.0]

6 (1.3) [3.1]

17 (3.5) [12.4]

4 (0.8) [2.9]

BARI 4 mg (N=1142)

224 (19.6) [47.5]

21 (1.8) [4.4]

40 (3.5) [11.9]

23 (2.0) [4.9]

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate.

Note: Herpes zoster data include all available observation time, including follow-up where available and applicable. Otherwise, analyses do not include post-BARI follow-up observation time.

aIncludes acute sinusitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinobronchitis, tonsillitis, tracheitis, and upper respiratory tract infection.

bIncludes herpes zoster, ophthalmic herpes zoster, and herpes zoster oticus.

cIncludes eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes simplex, and oral herpes.

dBaricitinib 2-mg data in the placebo-controlled analysis set are derived from 4 studies in which both BARI 2 mg and 4 mg were options during randomization.

4-Study Extended Dataset

The EAIR of TE infection was

  • 30.2 per 100 PYEs in the BARI 2-mg group (N=479, total PYE=774.9), and
  • 34.0 per 100 PYEs in the BARI 4-mg group (N=479, total PYE=781.1).4

Additional details are provided in Overview of Treatment-Emergent Infections From Rheumatoid Arthritis Integrated Analysis Sets.

All-BARI-RA Dataset

In the All-BARI-RA dataset, 2590 (68.7%) patients treated with BARI reported treatment-emergent infections with an EAIR of 17.1. Infections were the most common treatment-emergent adverse event (TEAE).2

Serious Infections in Rheumatoid Arthritis Trials

Infections were defined as serious infections if they met the International Conference on Harmonization criteria for a serious adverse event (AE).5

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment or until rescue, the number of patients with a TE serious infection was

  • 19 (1.7%) [IR=4.0] in the BARI 4-mg group
  • 8 (1.7%) [IR=4.2] in the BARI 2-mg group, and
  • 19 (1.6%) [IR=4.1] in the placebo group.3

All-BARI-RA Dataset

Of the 3770 patients in the All-BARI-RA dataset, 372 patients had a serious infection with an IR of 2.6 per 100 PYE. The IR for serious infections did not increase with prolonged exposure as seen in Serious Infections Over Time in All-BARI-RA Dataset.

The most frequent serious infections reported were

  • pneumonia, n=84 (2.2%) [EAIR 0.56]
  • HZ, n=44 (1.2%) [EAIR 0.29]
  • urinary tract infection, n=25 (0.7%) [EAIR 0.17]
  • cellulitis, n=23 (0.6%) [EAIR 0.15]
  • sepsis, n=19 (0.5%) [EAIR 0.13], and
  • gastroenteritis, n=16 (0.4%) [EAIR 0.11].2,4
Serious Infections Over Time in All-BARI-RA Dataset2

Abbreviations: BARI = baricitinib; IR = incidence rate; n/N = number of patients with events/total number of patients; PYR = patient-years at risk; RA = rheumatoid arthritis.

In the All-BARI-RA dataset, 3401 patients received BARI 4-mg dose and 1077 patients received BARI 2-mg dose at some point in the clinical trials.2

Serious infections were observed in

Treatment-Emergent Infections by Dose in the ALL-BARI-RA Dataset4

Subjects with ≥1 event, n (%) [EAIR]

Ever on BARI 2-mg
N=1077
PYE=2678.1

Ever on BARI 4-mg
N=3401
PYE=11872.2

Overall
N=3770
PYE=15114.1

Serious infection

57 (5.3)
[2.13]

311 (9.1)
[2.62]

372 (9.9)
[2.46]

Opportunistic Infectiona

8 (0.7)
[0.30]

58 (1.7)
[0.49]

69 (1.8)
[0.46]

Herpes Zoster

5 (0.5)
[0.19]

35 (1.0)
[0.29]

41 (1.1)
[0.27]

Tuberculosis

0

19 (0.6)
[0.16]

19 (0.5)
[0.13]

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; PYE = patient-years of exposure

aIncluding multidermatomal herpes zoster.

Risk factors that appeared to be associated with an increased risk for serious infection are presented in Serious Infection Risk Factor Analysis in the All-BARI-RA Analysis Set.

Serious Infection Risk Factor Analysis in the All-BARI-RA Analysis Set4

Risk Factors

Patients With Serious Infection
N=372
n (%)

Patients Without Serious Infection
N=3398
n (%)

Patients With Risk Factors Incidence Rate per 100 PYR [95% CI]

Age ≥65 years

113 (30.4)

519 (15.3)

5.49 [4.53, 6.60]

Male

95 (25.5)

692 (20.4)

3.08 [2.49, 3.76]

HAQ-DI score ≥1.5a

198 (53.2)

1537 (45.2)

3.05 [2.64, 3.50]

Region

Asia excluding Japan

57 (15.3)

388 (11.4)

3.45 [2.62, 4.47]

Japan

53 (14.2)

461 (13.6)

3.01 [2.25, 3.94]

Rest of the world

48 (12.9)

380 (11.2)

3.00 [2.21, 3.98]

Corticosteroids

No use

138 (37.1)

1721 (50.6)

1.98 [1.67, 2.34]

<5 mg/day

42 (11.3)

301 (8.9)

3.24 [2.34, 4.38]

≥5 mg/day

192 (51.6)

1376 (40.5)

3.12 [2.70, 3.60]

Abbreviations: BARI = baricitinib; HAQ-DI = Health Assessment Questionnaire-Disability Index; N = number of patients in the safety analysis set; n = number of patients in the specified category; PYR = patient-years at risk; RA = rheumatoid arthritis.

aScores ranged from 0-3, with higher scores indicating greater disability.

Lymphopenia and Neutropenia and Infection Risk in Rheumatoid Arthritis Trials

To assess the potential association between TE infection and decreased lymphocyte or neutrophil counts, the proportion of patients with an infection was evaluated based on the worst observed Common Terminology Criteria for Adverse Events (CTCAE) grade at any time postbaseline with data through February 13, 2018. The worst CTCAE grade value could have

  • preceded
  • occurred simultaneously with, or
  • occurred after the infection.4

Although this approach may be sensitive in detecting any relationship between lymphopenia or neutropenia and risk of infection, it may lack specificity as the time between events could affect the biologic plausibility of the relationship.4 Common Terminology Criteria for Adverse Event grades for lymphopenia and neutropenia are defined in Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia and Neutropenia in Rheumatoid Arthritis Clinical Trials.

Increasing grades of lymphopenia were associated with an increase in frequency of any TE infection and serious infection in BARI-treated patients.4 Additional information is presented in Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia and Neutropenia in Rheumatoid Arthritis Clinical Trials.

Increasing grades of neutropenia were not consistently associated with an increase in frequency of any TE infection or serious infection in BARI-treated patients.4 Additional information is presented in Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia and Neutropenia in Rheumatoid Arthritis Clinical Trials.

Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia and Neutropenia in Rheumatoid Arthritis Clinical Trials4


Grade


All BARI RAa

Treatment-Emergent Lymphopenia
N=3756

Treatment-Emergent Neutropenia
N=3633

Worst Lymphocyte CTCAE Grade, n

Worst Neutrophil CTCAE Grade, n

Grade 0 (≥1.1 billion cells/L)

1521

2823

Grade 1 (<1.1 and ≥0.8 billion cells/L)

1106

491

Grade 2 (<0.8 and ≥0.5 billion cells/L)

905

267

Grade 3 (<0.5 and ≥0.2 billion cells/L)

222

39

Grade 4 (<0.2 billion cells/L)

2

13

Patients with ≥1 TE infection, n (%)

Grade 0 (≥1.1 billion cells/L)

919 (60.4)

1946 (68.9)

Grade 1 (<1.1 and ≥0.8 billion cells/L)

791 (71.5)

358 (72.9)

Grade 2 (<0.8 and ≥0.5 billion cells/L)

704 (77.8)

205 (76.8)

Grade 3 (<0.5 and ≥0.2 billion cells/L)

173 (77.9)

25 (64.1)

Grade 4 (<0.2 billion cells/L)

2 (100)

12 (92.3)

Patients with ≥1 serious infection, n (%)

Grade 0 (≥1.1 billion cells/L)

104 (6.8)

293 (10.4)

Grade 1 (<1.1 and ≥0.8 billion cells/L)

114 (10.3)

49 (10.0)

Grade 2 (<0.8 and ≥0.5 billion cells/L)

124 (13.7)

27 (10.1)

Grade 3 (<0.5 and ≥0.2 billion cells/L)

29 (13.1)

1 (2.6)

Grade 4 (<0.2 billion cells/L)

1 (50)

2 (15.4)

Abbreviations: BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; RA = rheumatoid arthritis; TE = treatment-emergent.

aData are for all treatment periods, including follow-up where applicable.

C-Reactive Protein Changes During Bacterial Infections in Rheumatoid Arthritis Clinical Trials

An analysis of patients from RA-BEAM, RA-BUILD, and RA-BEACON studies compared C-reactive protein (CRP) levels during a bacterial infection to levels during no infection.6

In the 36 BARI-treated patients with CRP values for both bacterial infection and no infection periods, the median CRP levels were significantly different for assays taken during the bacterial infection (6.2 mg/L) and during no infection (3.0 mg/L) (p<.001). No apparent blunting of CRP response during bacterial infections was observed with BARI treatment.6

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Taylor 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. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

3Genovese 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

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

5Winthrop 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

6Hendricks O, Chrysidis S, Gerwien J, et al. CRP changes during bacterial infections in baricitinib-treated patients with RA. Arthritis Rheumatol. 2018;70(suppl 10). American College of Rheumatology abstract 1530. https://acrabstracts.org/abstract/crp-changes-during-bacterial-infections-in-baricitinib-treated-patients-with-ra/

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):638. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

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.

Date of Last Review: 27 October 2021


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