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
Exposure-adjusted
incidence rates were calculated as the number of patients with an
event per 100 patient-years of exposure time, with exposure not
censored at time of event.2
Incidence
rates 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
Overall
Infection in RA Trials
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 in the placebo group 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.2
Data
from BARI 2 mg (N=479, PYE=185.8) is 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).2
Through
24 weeks of assigned treatment or until rescue, the number of
patients with any type of TE infection was
423
(EAIR=89.7) in the BARI 4-mg group
156
(EAIR=84.0) in the BARI 2-mg group, and
340
(EAIR=75.4) in the placebo group.2
Commonly
reported infections with BARI treatment include
upper
respiratory tract infections
HZ
infection
herpes
simplex infections, and
urinary
tract infections.3
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
13,148
PYE,
median
exposure of 4.2 years,
maximum
exposure of 8.4 years, and
data
through 01 September 2019.4,5
The
EAIR of TE infection was 19.0 per 100 PYEs in all patients
treated with BARI.3
Serious
Infection in RA Trials
Infections
were defined using MedDRA preferred terms in the infections and
infestations system organ class. Infections were defined as serious
infections if they met the International Conference on Harmonsation
criteria for a serious AE.6
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
(IR=4.0) in the BARI 4-mg group
8
(IR=4.2) in the BARI 2-mg group, and
19
(IR=4.1) in the placebo group.2
All
BARI RA Dataset
Of
the 3770 patients who received BARI in the RA clinical trials, there
were 344 patients with a TE serious infection with an IR per 100 PYE,
of 2.7. The most frequent serious infections reported were
pneumonia
(n=74, EAIR 0.55)
HZ
(n=41, EAIR 0.31)
urinary
tract infection (n=25, EAIR 0.19)
cellulitis
(n=21, EAIR 0.16)
sepsis
(n=21 including 17 cases of sepsis and 4 cases of urosepsis), and
gastroenteritis
(n=15, EAIR 0.11).3,4
In
the All BARI RA dataset 3400 patients received BARI 4 mg dose and
1077 patients received BARI 2 mg dose at some point in the clinical
trials.4
A
large group of clinical factors with the potential to affect the risk
of serious infection was evaluated using Cox models and data from the
All BARI RA dataset. The independent risk factors identified for
serious infection were
prior
biologic use
greater
number of csDMARD use
advanced
age
Asian
decent
Asian
region of study enrollment, excluding Japan
low
body mass index
longer
duration of RA, and
concomitant
corticosteroid use.3
Lymphopenia
and Neutropenia and Infection Risk in RA Trials
Increasing
grades of lymphopenia were associated with an increase in frequency
of any TE infection and serious infection in BARI-treated patients.3
Increasing
grades of neutropenia were not consistently associated with an
increase in frequency of any TE infection or serious infection
in BARI-treated patients.3
Additional
Information from the label
Treatment
should not be initiated in patients with
an
absolute lymphocyte count (ALC) less than 0.5 x 109
cells/L,
an
absolute neutrophil count (ANC) less than 1 x 109
cells/L, or who have
a
haemoglobin value less than 8 g/dL.1
Treatment
may be initiated once values have improved above these limits.1
Infections
In
controlled studies, for up to 16 weeks, the incidence rate of all
infections (rate of patients with ≥ 1 event per 100
patient-years of exposure) was
101
with baricitinib compared to
83
in the placebo group.1
Most
infections were mild to moderate in severity.1
In
studies which included both doses, infections were reported in 31.9
%, 28.8 % and 24.1 % of patients up to 16 weeks in the 4 mg, 2 mg and
placebo groups, respectively.1
Reporting
rates for baricitinib compared to placebo for the infection-related
ADRs were:
upper
respiratory tract infections (14.7 % vs. 11.7 %),
urinary
tract infections (3.4 % vs. 2.7 %),
gastroenteritis
(1.6 % vs. 0.8 %),
herpes
simplex (1.8 % vs. 0.7 %), and
herpes
zoster (1.4 % vs. 0.4 %).1
In
treatment-naïve patients, for up to 52 weeks, the frequency of
upper respiratory tract infections
was
greater for the combination treatment of methotrexate and
baricitinib (26.0 %) compared to
methotrexate
alone (22.9 %) or
baricitinib
alone (22.0 %).1
The
rate of serious infections
For
baricitinib, the most common serious infections were herpes zoster,
and cellulitis. The rate of serious infections remained stable during
long term exposure. The overall incidence rate of serious infections
in the clinical trial programme was 3.2 per 100 patient-years.1
Neutropaenia
In
rheumatoid arthritis, for up to 16 weeks, decreases in neutrophil
counts below 1 x 109
cells/L occurred in
0.2
% of patients treated with baricitinib compared to
0 %
of patients treated with placebo.1
There
was no clear relationship between decreases in neutrophil counts and
the occurrence of serious infections. However, in clinical studies,
treatment was interrupted in response to ANC < 1 x 109
cells/L.
The
pattern and incidence of decreases in neutrophil counts remained
stable at a lower value than baseline over time including in the
long-term extension study.1
References
1.
Olumiant [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Genovese 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
3.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4.
Genovese 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
5.
Genovese 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.
6.
Winthrop 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
Glossary
BARI
= baricitinib
DMARD
= disease-modifying antirheumatic drug
EAIR
= exposure-adjusted incidence rate
HZ =
herpes zoster
IR =
incidence rate
MTX
= methotrexate
PYE
= patient-years of exposure
RA =
rheumatoid arthritis
TB =
tuberculosis
TE =
treatment-emergent
▼ 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.