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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).
Olumiant® (baricitinib): Reproductive Risks in Males
In animal studies, baricitinib did not have an effect on male reproductive organs or sperm endpoints. However, there is a potential to decrease male fertility.
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Baricitinib Label Information
Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertility while on treatment, but there was no effect on male spermatogenesis.1
In a combined male/female rat fertility study, baricitinib decreased overall mating performance (decreased fertility and conception indices).1
- In female rats there were decreased numbers of corpora lutea and implantation sites, increased pre-implantation loss, and/or adverse effects on intrauterine survival of the embryos.1
- Since there were no effects on spermatogenesis (as assessed by histopathology) or semen/sperm endpoints in male rats, the decreased overall mating performance was likely the result of these female effects.1
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.2
The NOAEL for male fertility was 15 mg/kg based on rat studies.2
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.2
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.2
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.2
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.2
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.2
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.3
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).3
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).2
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
In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.2
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.2
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.2
In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.2
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).2
In this safety analysis, sperm-related AEs such as spermatogenesis abnormal (MedDRA preferred term) have not been reported.2
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.2
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.2
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.2
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.2
Contraceptive Criteria in Clinical Trial Protocols
In BARI rheumatoid arthritis clinical trials, male patients agreed to use 2 forms of highly effective birth control while engaging in sexual intercourse with female partners of childbearing potential during the trial and for 28 days after the last dose of study medication.2
References
1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
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
4Genovese 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
5Genovese 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
Date of Last Review: 24 September 2020
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