Baricitinib
Label Information Related to Infections, Viral Reactivation and
Herpes simplex
Warnings
and Precautions Related to 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
Warnings
and Precautions Related to Viral Reactivation
Viral
reactivation, including cases of herpes virus reactivation (e.g.,
herpes zoster, herpes simplex), were reported in clinical studies.1
Adverse
Drug Reaction of Herpes simplex
Herpes
simplex is a common (≥1% and <10%) adverse drug reaction with
baricitinib treatment.1
The
percentages of patients with atopic dermatitis reporting herpex
simplex for baricitinib 4 mg compared to placebo were 6.1 % vs.
2.7 %.1
Clinical
Trial Criteria
In
the phase 3 AD clinical trial program, patients with symptomatic
herpes simplex at time of randomization were excluded.2
Incidence
of Herpes Simplex in Atopic Dermatitis Clinical Trials
Herpes
simplex is a cluster of the MedDRA preferred terms of herpes simplex,
oral herpes, eczema herpeticum, Kaposi's varicelliform eruption,
ophthalmic herpes simplex, genital herpes, and genital herpes
simplex.3Information
specific to eczema herpeticum is described in a separate response.
The
integrated datasets used to evaluate cases of herpes simplex are
described more in Table 2.
Placebo-Controlled
Period
Through
16 weeks, the proportion of patients with treatment-emergent herpes
simplex was
not
significantly different between BARI 2 mg and placebo groups
significantly
higher in the BARI 4 mg group than the placebo group (p≤.01), and
significantly
higher in the BARI 4 mg group than the BARI 2 mg group (p≤.05).2
All
Baricitinib-Treated Patients With Extended Data
Of
the 2531 patients treated across all BARI doses studied in AD, 224
(IR=10.33) had a treatment-emergent report of herpes simplex. Of the
224 reports
93%
were mild to moderate in severity
11
(5%) were reported as serious, and
5
(2%) led to permanent discontinuation of study drug.2,3
Among
the herpes simplex cluster, the number of cases by each preferred
term was
110
(4.3%) oral herpes
91
(3.6%) herpes simplex
32
(1.3%) eczema herpeticum
11
(0.4%) Kaposi's varicelliform eruption
7
(0.3%) ophthalmic herpes simplex
1
(0.0%) herpes ophthalmic
4
(0.2%) genital herpes, and
3
(0.1%) genital herpes simplex.3
Table
1. Summary of Herpes Simplex in the Atopic Dermatitis Clinical
Trials2,3
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda
n
(adj %)b
|
BARI
4 mg Placebo-Controlleda
n
(adj %)b
|
BARI
2 mg vs 4 mga
n
(adj %)b
|
BARI
2 mg vs 4 mg ext
n (adj %)b
[adj IR]
|
All
BARI AD
n (%) [IR]c
|
|
|
Placebo
n=889
|
BARI
2 mg
n=721
|
Placebo
n=743
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
All
doses
N=2531
|
|
Herpes
Simplex
|
23
(2.8)
|
27
(3.8)
|
22
(2.7)
|
35
(6.1)d
|
25
(3.6)
|
35
(6.1)e
|
41
(5.8) [9.62]
|
59
(10.5) [14.47]f
|
224
(8.9) [10.33]
|
|
Serious
AE
|
2
(0.2)
|
0
|
2
(0.2)
|
0
|
0
|
0
|
1
(0.1) [0.16]
|
3
(0.6) [0.56]
|
11
(0.4) [0.48]
|
|
Led
to temp int
|
2
(0.2)
|
3
(0.5)
|
2
(0.2)
|
7
(1.2)g
|
3
(0.5)
|
7
(1.2)
|
6
(0.9) [1.37]
|
11
(1.9) [2.70]
|
39
(1.5) [1.70]
|
|
Led
to perm D/C
|
0
|
0
|
0
|
0
|
0
|
0
|
2
(0.2) [0.32]
|
2
(0.4) [0.51]
|
5
(0.2) [0.22]
|
|
Treated
with antiviral
|
13
(1.6)
|
14
(1.9)
|
12
(1.5)
|
16
(2.9)
|
14
(1.9)
|
16
(2.9)
|
27
(3.7) [6.12]
|
31
(5.7) [6.98]
|
131
(5.2) [5.86]
|
|
Recovered
or resolved
|
21
(2.6)
|
26
(3.6)
|
20
(2.5)
|
33
(5.9)h
|
24
(3.4)
|
33
(5.9)e
|
38
(5.5) [9.07]
|
55
(9.9) [13.59]f
|
213
(8.4) [9.80]
|
Abbreviations:
AD = atopic dermatitis; adj = adjusted; AE = adverse event; BARI =
baricitinib; D/C = discontinuation; ext = extended; IR = incidence
rate; temp int = temporary interruption.
a
Data through 16-week placebo-controlled period.
b
For the integrated controlled analysis sets where the
randomized ratio of patients receiving BARI to placebo or BARI to
active control is not the same across all the integrated studies
(example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages
were calculated for the adverse events to provide appropriate direct
comparisons between treatment groups.
c
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.
d
p≤.01 vs placebo.
e
p≤.05 vs BARI 2 mg.
f
p≤.01 vs BARI 2 mg.
g
p≤.05 vs placebo.
h
p≤.001 vs placebo.
Integrated
Safety Datasets
Table
2. Integrated Analysis Datasets Used to Evaluate Safety in Atopic
Dermatitis Clinical Trials2,3
|
Analysis
Set
|
Description
|
|
BARI
2 mg Placebo-Controlled
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and
BREEZE-AD7
|
Compares
BARI 2 mg vs placebo
Includes
patients with AD from 1 phase 2 and 5 phase 3 studies who were
randomized to
BARI
2 mg (n=721, PYE=210.6), or
placebo
(n=889, PYE=252.7).
Treatment
period was 0 to 16 weeks.
|
|
BARI
4 mg Placebo-Controlled
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7
|
Compares
BARI 4 mg vs placebo
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies who were
randomized to
BARI
4 mg (n=489, PYE=147.1), or
placebo
(n=743, PYE=211.8).
Treatment
period was 0 to 16 weeks.
|
|
BARI
2 mg vs 4 mg
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7
|
Compares
BARI 2 mg vs BARI 4 mg through 16 weeks
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies who were
randomized to
BARI
2 mg (n=576, PYE=169.1), or
BARI
4 mg (n=489, PYE=147.1).
Treated
for 0 to 16 weeks during the placebo-controlled period.
|
|
BARI
2 mg vs 4 mg Extended
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and
extension study BREEZE-AD3
|
Compares
BARI 2 mg vs BARI 4 mg including extended evaluations
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies and any
further exposure for those patients in the phase 3 extension
study, BREEZE-AD3, who were randomized to
BARI
2 mg (n=576, PYE=425.5), or
BARI
4 mg (n=489, PYE=459.3).
Data
censored at dose or treatment change (rescue, dose switch, or
re-randomization to a different BARI dose or placebo) for
BREEZE-AD4 and BREEZE-AD3.
|
|
All
BARI AD
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7,
and extension studies BREEZE-AD3, BREEZE-AD6
|
No
between-group comparisons
Includes
2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase
3, and 2 phase 3 extension studies who received BARI at a variety
of doses, including
BARI
1 mg (n=538, PYE=245.9)
BARI
2 mg (n=1580, PYE=1129.5), and
BARI
4 mg (n=914, PYE=872.8).
Includes
all patients who were exposed to any BARI dose at any time during
the studies, either from randomization or from switch or rescue
from placebo.
No
censoring of data at dose change.
|
Abbreviations:
AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of
exposure.
Note:
BARI 1 mg was studied in pivotal trials, however it is not approved.
Please refer to section 4.2 of the Olumiant Summary of Product
Characteristics for approved dosage.
References
1.
Olumiant [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3.
Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of
baricitinib in adult patients with atopic dermatitis from 8
randomized clinical trials. J Eur Acad Dermatol Venereol.
Published online September 14, 2020.
https://doi.org/10.1111/jdv.16948
Glossary
AD =
atopic dermatitis
BARI
= baricitinib
MedDRA
= Medical Dictionary for Regulatory Activities
▼ 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.