Combined
Male and Female Animal Fertility Study
Male
rats were dosed with 0, 5, 15, or 50 mg/kg of BARI daily for 6 weeks
including 4 weeks prior to cohabitation with female rats treated with
0, 5, 25, or 100 mg/kg.1
The
NOAEL for male fertility was 15 mg/kg based on rat studies.1
Effects
on Reproductive Organs and Sperm
Histologic
studies found no change in male reproductive organs, and no effects
on sperm motility, concentration, and morphology at any BARI dose
level.1
Effects
on Fertility and Early Embryonic Development
Results
by Doses
At
doses of 50 and 100 mg/kg/day (approximately 113 and 169 times a
baricitinib dose of 2 mg in male and females, respectively),
reproductive performance was unaffected in both genders.1
At
doses of 15 mg/kg and 25 mg/kg (approximately 25 and 48 times a
baricitinib dose of 2 mg), fertility was unaffected in male and
female rats.1
Potential
Cause of Decreased Fertility
Based
on the study design, it could not be determined if fertility results
were attributable to toxicities in one sex or both. However, since
there were no effects on spermatogenesis or semen/sperm endpoints in
male rats, the decreased overall mating performance was likely the
result of fertility effects in female rats including
decreased
corpora lutea and implantation sites,
increased
pre-implantation loss, and
adverse
effects on intrauterine survival.1
The
NOAEL was 5 mg/kg for female fertility and early embryonic
development based on rat studies.1
Treatment-Emergent
Adverse Events
A
TEAE is an adverse event that either occurred or worsened in severity
after the first dose of study treatment and did not necessarily have
a causal relationship to study treatment.1
Rheumatoid
Arthritis
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 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) were 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
In
this safety analysis, through 24 weeks of treatment, sperm-related
AEs such as spermatogenesis abnormal (MedDRA preferred term) have not
been reported in any of the study arms (BARI 4 mg, BARI 2 mg, and
placebo).1
All
BARI RA Analysis Set
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, and 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 September 1, 2019.3,4
In
this safety analysis, sperm-related AEs such as spermatogenesis
abnormal (MedDRA preferred term) have not been reported.1
Sperm
analysis was not routinely conducted throughout the studies and male
participants were required to use birth control throughout the
duration of the study as described above.1
Atopic
Dermatitis
Placebo-Controlled
Analysis
The
largest placebo-controlled dataset included patients with AD from 1
phase 2 and 5 phase 3 studies (BREEZE-AD1, BREEZE-AD2, BREEZE-AD4,
BREEZE-AD5, and BREEZE-AD7). These patients were randomized to BARI
(n=721, PYE=210.6) and placebo (n=889, PYE=252.7); treatment period
was 0 to 16 weeks.1
In
this safety analysis, sperm-related AEs such as spermatogenesis
abnormal (MedDRA preferred term) have not been reported.1
All
BARI AD Analysis Set
The
All BARI AD analysis set includes 2531 patients (PYE=2274.4) with AD
who received at least 1 dose of BARI at different strengths from 1
phase 2, 5 phase 3 (BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5,
and BREEZE-AD7), and 2 phase 3 extension studies (BREEZE-AD3 and
BREEZE-AD6).1
In
this safety analysis, sperm-related AEs such as spermatogenesis
abnormal (MedDRA preferred term) have not been reported.1
Postmarketing
Spontaneous Reports
The
following information is valid for data received up through June 22,
2020. The data do not represent the number of AEs in a treated
population. They merely represent the number of a particular AE
reported to the company. The following MedDRA preferred terms have
not been reported to the Eli Lilly and Company spontaneous AE
database
spermatogenesis
abnormal, and
paternal
exposure during pregnancy.1
Spontaneous
reporting of AEs can be highly variable and is not controlled
clinical information on which to assess causality of a drug to an AE.
Spontaneous reporting has limitations due to bias in reporting
including incomplete information concerning the patient. When
verification of product manufactured by Lilly is not obtainable,
these cases are included in the spontaneous database.
Use
in Individuals of Reproductive Potential
Based
on the mechanism of action and findings in animals, BARI may cause
fetal harm.1
If
the patient becomes pregnant while taking BARI, inform the patient of
the potential for hazard to the fetus. BARI should only be continued
during pregnancy if the potential benefit justifies the potential
risk to the fetus.1
Women
of reproductive potential should take appropriate precautions to
avoid becoming pregnant during treatment with BARI and for at least 1
week after the final BARI treatment.1
Reference
1.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
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.
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
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. Poster presented at:
European League Against Rheumatism Virtual Congress; June 3-6, 2020.
Glossary
AD =
atopic dermatitis
AE =
adverse event
BARI
= baricitinib
DMARD
= disease-modifying antirheumatic drug
Lilly
= Eli Lilly and Company
MedDRA
= Medical Dictionary for Regulatory Activities
MRHD
= maximum recommended human dose
MTX
= methotrexate
NOAEL
= no observed adverse effect level
PYE
= patient-years of exposure
RA =
rheumatoid arthritis
TEAE
= treatment-emergent adverse event