Baricitinib
Label Information Related to Treatment Interruption
Recommendations
Regarding Baricitinib Treatment Interruption
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
If a
patient develops herpes zoster, baricitinib treatment should be
temporarily interrupted until the episode resolves.1
If
clinical features of DVT/PE occur, baricitinib treatment should be
discontinued and patients should be evaluated promptly, followed by
appropriate treatment.1
Treatment
should not be initiated, or should be temporarily interrupted, in
patients with an
observed
during routine patient management.1
If
increases in ALT or AST are observed during routine patient
management and drug-induced liver injury is suspected, baricitinib
should be temporarily interrupted until this diagnosis is excluded.1
Individuals
of Reproductive Potential
Baricitinib
is contraindicated during pregnancy. Women of childbearing potential
have to use effective contraception during and for at least 1 week
after treatment.1
If a
patient becomes pregnant while taking baricitinib the parents should
be informed of the potential risk to the foetus.1
Clinical
Decision
The
treating physician may use the information provided, the patient’s
medical information, clinical presentation, and other individual
factors in formulating an assessment and approach for individual
treatment interruption and restart of therapy. The treating physician
should consider potential risks and benefits and use their best
clinical judgment regarding treatment.
Temporary
Interruption of Treatment in Atopic Dermatitis Clinical Trials
The
integrated datasets used to evaluate temporary treatment
interruptions are described in detail in Table
3.
Overall
Treatment Interruptions
Table
1 presents an overview of
temporary interruptions including reasons for interruption and
duration of interruptions across the integrated datasets.
Table
1. Overview of Temporary Interruption of Treatment From Atopic
Dermatitis Clinical Trials2
|
|
BARI
2 mg Placebo-Controlleda
|
BARI
4 mg Placebo-Controlleda
|
BARI
2 mg vs 4 mga
|
BARI
2 mg vs 4 mg Ext
|
All
BARI AD
|
|
|
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)
|
|
Total
treatment interruptions, n
|
35
|
35
|
30
|
33
|
31
|
33
|
65
|
86
|
345
|
|
Resumed
study treatment, n
|
30
|
28
|
25
|
30
|
26
|
30
|
54
|
73
|
301
|
|
≥2
interruptions, n
|
2
|
4
|
2
|
1
|
4
|
1
|
8
|
14
|
48
|
|
Reasons
for interruption, n (% of N)
|
|
AEb
|
19
(2.1)
|
27
(3.7)
|
16
(2.2)
|
25
(5.1)
|
25
(4.3)
|
25
(5.1)
|
48
(8.3)
|
54
(11.0)
|
229
(9.0)
|
|
Abnormal
lab result
|
7
(0.8)
|
3
(0.4)
|
5
(0.7)
|
3
(0.6)
|
2
(0.3)
|
3
(0.6)
|
2
(0.3)
|
9
(1.8)
|
27
(1.1)
|
|
Protocolc
|
3
(0.3)
|
0
|
3
(0.4)
|
0
|
0
|
0
|
4
(0.7)
|
2
(0.4)
|
9
(0.4)
|
|
Suspected
pregnancy
|
0
|
0
|
0
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.0)
|
|
Investigator
decision
|
4
(0.4)
|
0
|
4
(0.5)
|
0
|
0
|
0
|
1
(0.2)
|
4
(0.8)
|
13
(0.5)
|
|
Missing
|
0
|
1
(0.1)
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
3
(0.1)
|
|
Time
to first interruption, days
|
|
Mean
(SD)
|
40.1
(29.6)
|
50.6
(36.7)
|
40.5
(31.7)
|
49.2
(40.0)
|
49.7
(34.3)
|
49.2
(40.0)
|
134.2
(110.6)
|
180.4
(149.1)
|
166.0
(140.4)
|
|
Median
|
41.0
|
37.0
|
37.5
|
34.0
|
37.0
|
34.0
|
114.5
|
141.5
|
135.5
|
|
Duration
of interruption, days
|
|
Mean
(SD)
|
12.2
(9.9)
|
12.4
(12.3)
|
11.6
(7.8)
|
10.0
(5.9)
|
11.9
(11.9)
|
10.0
(5.9)
|
14.2
(14.7)
|
17.6
(35.4)
|
15.0
(22.3)
|
|
Median
|
10.0
|
7.5
|
10.0
|
8.0
|
7.5
|
8.0
|
8.5
|
9.0
|
9.0
|
Abbreviations:
AD = atopic dermatitis; AE = adverse events; BARI = baricitinib; ext
= extended.
a
Data through 16-week placebo-controlled period.
b
Include all AEs that led to interruption.
c
Criteria for temporary interruption of study drug were
included in all study protocols. Some of these criteria may not have
led to reports of AEs or abnormal laboratory findings.
Placebo-Controlled
Period
Through
16 weeks, the results were similar between the BARI 2 mg, BARI 4 mg,
and placebo groups in
number
of treatment interruptions
median
time to first interruption, and
mean
duration of interruption.2
Adverse
events were the most common reason for temporary interruption across
all treatment groups.2
All
Baricitinib-Treated Patients With Extended Data
Of
the 2531 patients treated across all BARI doses studied in AD
clinical trial, there were 345 total treatment interruptions. The
majority of patients only had 1 treatment interruption and resumed
treatment after the interruption.2
The
most common reasons for temporary interruption were AEs, which
resulted in 229 treatment interruptions.2,3
Treatment
Interruptions Due to Adverse Events
Adverse
events leading to temporary treatment interruption by MedDRA SOC are
presented in Table 2.
Table
2. Adverse Events Leading to Temporary Interruption of Treatment by
System Organ Class2,3
|
|
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]
|
|
|
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)
|
|
AEs
leading to treatment interruptionc
|
18
(2.0)
|
28
(3.5)
|
14
(1.6)
|
26
(4.6)d
|
27
(3.4)
|
26
(4.6)
|
47
(6.3) [10.4]
|
54
(9.7) [12.7]e
|
218
(8.6) [9.9]
|
|
Infections
and infestations
|
6
(0.6)
|
17
(2.2)f
|
4
(0.4)
|
15
(2.7)g
|
17
(2.2)
|
15
(2.7)
|
32
(4.2) [6.8]
|
31
(5.6) [7.3]
|
137
(5.4) [6.1]h
|
|
Skin
and subcutaneous tissue disorders
|
0
|
2
(0.2)
|
0
|
3
(0.6)f
|
2
(0.2)
|
3
(0.6)
|
4
(0.6) [0.9]
|
5
(1.0) [1.2]
|
16
(0.6) [0.7]i
|
|
Investigationsj
|
3
(0.3)
|
3
(0.3)
|
2
(0.2)
|
2
(0.4)
|
3
(0.3)
|
2
(0.4)
|
4
(0.5) [0.8]
|
5
(0.9) [1.1]
|
14
(0.6) [0.6]k
|
|
Respiratory,
thoracic and mediastinal disorders
|
2
(0.3)
|
1
(0.1)
|
1
(0.2)
|
2
(0.3)
|
1
(0.1)
|
2
(0.3)
|
1
(0.1) [0.2]
|
3
(0.5) [0.7]
|
12
(0.5) [0.5]
|
|
Gastrointestinal
disorders
|
3
(0.3)
|
3
(0.5)
|
3
(0.3)
|
0
|
3
(0.5)
|
0
|
3
(0.5) [0.7]
|
0
|
8
(0.3) [0.3]
|
|
Nervous
system disorders
|
1
(0.1)
|
1
(0.1)
|
1
(0.1)
|
1
(0.1)
|
1
(0.1)
|
1
(0.1)
|
2
(0.2) [0.4]
|
2
(0.3) [0.4]
|
8
(0.3) [0.3]
|
|
Injury,
poisoning and procedural complications
|
0
|
2
(0.2)
|
0
|
1
(0.2)
|
1
(0.1)
|
1
(0.2)
|
1
(0.1) [0.2]
|
1
(0.2) [0.2]
|
6
(0.2) [0.3]
|
|
Blood
and lymphatic system disorders
|
1
(0.1)
|
0
|
1
(0.1)
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
2
(0.4) [0.5]
|
5
(0.2) [0.2]
|
|
Surgical
and medical procedures
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
4
(0.2) [0.2]
|
|
Cardiac
disorders
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
3
(0.1) [0.1]
|
|
Eye
disorders
|
1
(0.1)
|
0
|
1
(0.1)
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
2
(0.3) [0.4]
|
3
(0.1) [0.1]
|
|
Ear
and labyrinth disorders
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
1
(0.2) [0.2]
|
2
(0.1) [0.1]
|
|
General
disorders and administration site conditions
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
2
(0.1) [0.1]
|
|
Hepatobiliary
disorders
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
2
(0.4) [0.4]
|
2
(0.1) [0.1]
|
|
Musculoskeletal
and connective tissue disorders
|
1
(0.1)
|
1
(0.0)
|
1
(0.1)
|
0
|
0
|
0
|
0
|
0
|
2
(0.1) [0.1]
|
|
Psychiatric
disorders
|
1
(0.1)
|
1
(0.1)
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
1
(0.1) [0.2]
|
0
|
2
(0.1) [0.1]
|
|
Renal
and urinary disorders
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.2]
|
2
(0.1) [0.1]
|
|
Vascular
disorders
|
0
|
0
|
0
|
0
|
0
|
0
|
1
(0.2) [0.3]
|
1
(0.2) [0.2]
|
2
(0.1) [0.1]
|
|
Neoplasms
benign, malignant, and unspecified
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
0
|
0
|
0
|
0
|
1
(0.0) [0.0]
|
Abbreviations:
AD = atopic dermatitis; adj = adjusted; AEs = adverse events; ALT =
alanine aminotransferase; BARI = baricitinib; CPK = creatine
phosphokinase; ext = extended; IR = incidence rate; LFT = liver
function tests.
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 (eg,
2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were
calculated for the AEs to provide appropriate direct comparisons
between treatment groups.
c
Include AEs which led to interruption after first dose
date but at or before the interruption date.
d
p≤.01 vs placebo.
e
p≤.05 vs BARI 2 mg.
f
p ≤.05 vs placebo.
g
p≤.001 vs placebo.
h
Most frequent include: herpes zoster (n=27), herpes
simplex (n=18), eczema herpeticum (n=13), and cellulitis (n=8).
i
Most frequent include: atopic dermatitis (n=3), blister
(n=2), dyshidrotic eczema (n=2), and toxic skin eruption (n=2).
j
Includes abnormal laboratory findings.
k
Includes: CPK increased (n=5), ALT increased (n=3),
neutrophil decreased (n=2), hepatic enzyme increased (n=1), LFT
increased (n=1), lymphocyte decreased (n=1), and biopsy (n=1).
Placebo-Controlled
Period
Through
16 weeks, compared to placebo, there was a significantly greater
number of
treatment
interruptions due to AEs in the BARI 4 mg group, and
interruptions
due to infections and infestations SOC in both the BARI 2 mg and
BARI 4 mg groups.2
There
was no significant difference in treatment interruptions by
individual infection preferred terms between BARI treatments and
placebo groups.2
All
Baricitinib-Treated Patients With Extended Data
In
the All BARI AD dataset, AEs in the infections and infestations SOC
were the most common cause for treatment interruptions. Herpes zoster
(n=27) and herpes simplex (n=18) were the most frequent infections
causing temporary interruptions.2,3
Impact
of Temporary Treatment Interruption on Efficacy and Safety
Analyses
on the impact of temporary treatment interruption on efficacy and
safety of BARI therapy in AD have not been conducted, therefore no
information is available.
Integrated
Safety Analysis Datasets
Table
3. 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.
2021;35(2):476-485. https://doi.org/10.1111/jdv.16948
Glossary
AD =
atopic dermatitis
AE =
adverse event
BARI
= baricitinib
MedDRA
= Medical Dictionary for Regulatory Activities
SOC
= system organ class
▼ 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.