Olumiant ® (baricitinib) tablets

1mg, 2mg

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OLUMIANT® (baricitinib): Use in Pregnancy and Lactation

Based on the mechanism of action and findings in animals, BARI may cause fetal harm. Women of reproductive potential should avoid becoming pregnant while receiving BARI.

Olumiant Prescribing Information

The limited human data on use of BARI in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage, therefore pregnancy should be avoided. Because of the potential for serious adverse reactions in nursing infants, advise an OLUMIANT-treated woman not to breastfeed.1

Use During Pregnancy

The effects of BARI on human fetal development are not known.1

Baricitinib is a potent, selective, and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK2.2 The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity, which can affect early embryonic development.3

It is unknown if BARI crosses the human placenta. In animal studies, following a 25-mg/kg dose of radioactivity-labeled [14C]-BARI in pregnant rats it has been observed that radioactivity was widely distributed to both maternal and fetal tissues, confirming transfer of [14C]-BARI across the placenta in pregnant rats.3

Based on the mechanism of action and findings of maternal and embryo-fetal toxicities, including skeletal anomalies in animals dosed in excess of the maximum human exposure, BARI should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.1,3

Use During Lactation

Lactation studies have not been conducted to assess the

  • presence of BARI in human milk

  • effects on the breastfed infant, or

  • effects on milk production.1

Baricitinib is present in the milk of lactating rats. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during BARI treatment.1

Use in Individual of Reproductive Potential

Based on the mechanism of action and findings in animals, BARI may cause fetal harm.3

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.1,3

Nonclinical Data Regarding Pregnancy and Lactation

Reproductive Toxicity in Animals

Animal Embryo-Fetal Development

In rat and rabbit reproductive toxicology studies, BARI was shown to

  • produce skeletal malformations and decrease fetal weights in pregnant rats at exposures equal to and greater than approximately 20 times the MRHD

  • produce embryo lethality, decreased fetal weights, and skeletal malformations in pregnant rabbits at exposures equal to and greater than approximately 84 times the MHRD.1

When treated with oral BARI during organogenesis, no developmental fetal effects were observed in

  • rats at approximately 5 times the MRHD, and

  • rabbits at approximately 13 times the MRHD.1

Animal Prenatal and Postnatal Development

In a prenatal and postnatal development study, at exposures approximately 43 times the MRHD, observed findings in pregnant female rats were

  • decreased postnatal survival

  • decrease fetal birth weight

  • decreased fetal body weight gain

  • decreased cytotoxic T cells on postnatal day 35 with recovery by postnatal day 65, and

  • developmental delays possibly attributed to decreased weight gain.1

The NOAEL was 25 mg/kg based on prenatal and postnatal development rat studies.3

Fertility Studies in Animals

In a combined male and female rat fertility study, BARI decreased overall mating performance as evidenced by decreased fertility and conception indices. In female rats there were

  • increased post-implantation losses, and

  • decreased numbers of mean viable embryos per litter.1

The NOAEL was 5 mg/kg for female fertility and early embryonic development based on rat studies.3

Since there were no effects on spermatogenesis, as assessed by histopathology, or semen or sperm endpoints in male rats, the decreased overall mating performance was likely the result of these female effects.3

The NOAEL for male fertility was 15 mg/kg based on rat studies.3

Juvenile Development Studies in Animals

In a juvenile rat development study, there were

  • decreased body weight at the doses of 5 and 25 mg/kg doses

  • decreased immune response at dose exposures ≥ 5 mg/kg dose, and

  • effects on bone at the 25 mg/kg dose.3

Safety monitoring measures assessing immune, growth, and bone effects are ongoing in pediatric clinical studies.3

In a juvenile rat development study, BARI had no adverse effects on clinical signs, sexual maturation, ophthalmology, behavioral performance, or reproductive performance.3

Clinical Data Regarding Pregnancy and Lactation

Incidence of Pregnancy in the Rheumatoid Arthritis and Atopic Dermatitis Clinical Development Programs

Exclusion and Permanent Discontinuation Clinical Trial Criteria Related to Pregnancy

Patients were excluded from participating in clinical studies if they were

  • pregnant or nursing at the time of study entry

  • women of childbearing potential who did not agree to use 2 forms of highly effective birth control when engaging in sexual intercourse while enrolled in the study and for at least 28 days following the last dose of study treatment, or

  • men who did not agree to use 2 forms of highly effective birth control while engaging in sexual intercourse with female partners of childbearing potential while enrolled in the study, and for at least 28 days following the last dose of study treatment.3

Pregnancy was a criterion for permanent discontinuation in all BARI clinical studies.

Incidence of Pregnancy

Data on fetal outcomes and breastfeeding were collected for all reported cases of pregnancy that occurred during maternal or paternal exposures to study treatment.

As of January 31,2020, there were 36 women who became pregnant and 8 pregnancies were reported for partners of male patients while in any BARI clinical trial (see details in Table 1). 

The pregnancy outcomes in maternal exposures included

  • 9 spontaneous abortions

  • 10 full-term normal infants

  • 7 pregnancies still in-utero

  • 5 elective abortions

  • 2 premature healthy infants

  • 1 intrauterine death (reported as fetal loss due to MTX), and

  • 2 unknown outcomes.3

Additionally, there were 8 pregnancy cases in partners of male patients exposed to BARI; the pregnancy outcomes included

  • 3 full term pregnancies without reported abnormalities

  • 2 cases of spontaneous abortion, and

  • 3 cases with outcomes unavailable.3

Table 1. Pregnancies in the Clinical Program3

Treatments Administereda

Clinical Study

Age

Concomitant DMARDS

Pregnancy Outcome

BARI 4 mg

Phase 3 RA study plus extension

31

MTX

Premature; no evidence of fetal adverse effect

BARI 4 mg + MTX
BARI 4 mg
 in extension

Phase 3 RA study plus extension

29

MTX as study drug in phase 3 study

Premature; no evidence of fetal adverse effect

BARI 1 mg part A; 2 mg BID part B; 4 mg escalated to 8 mg part C

Phase 2 RA study

20

MTX
sulfasalazine

Spontaneous abortion

ADA 40 mg in phase 3
BARI 4 mg in extension

Phase 3 RA study plus extension

38

MTX

Spontaneous abortion

BARI 4 mg

Phase 3 RA study

33

None

Spontaneous abortion

BARI 2 mg

Phase 3 RA study plus extension

30

MTX
leflunomide

Spontaneous abortion

BARI 10 mg

Phase 1 study in healthy subjects

48

None

Elective termination

BARI 4 mg + MTX

Phase 3 RA study

27

MTX as study drug in phase 3 study

Full term; no evidence of fetal AE

BARI 8 mg

Phase 2 RA study

27

MTX

Full term; no evidence of fetal AE

BARI 2 mg

Phase 2 psoriasis study

35

None

Full term; no evidence of fetal AE

ADA 40 mg

Phase 3 RA study

37

MTX

Full term; no evidence of fetal AE

ADA 40 mg

Phase 3 RA study

28

MTX
hydroxychloroquine

Spontaneous abortion

Placebo

Phase 3 RA study

31

MTX
hydroxychloroquine

Elective termination

Placebo in phase 3
BARI 4 mg in extension

Phase 3 RA study plus extension

34

hydroxychloroquine

Full-term pregnancy;  no evidence of fetal adverse effect

BARI 4 mg + MTX
BARI 4 mg in extension

Phase 3 RA study plus extension

32

MTX as study drug in phase 3 study

Pregnancy outcome unavailable

BARI 4 mg + MTX
BARI 4 mg in extension

Phase 3 RA study plus extension

29

None

Elective termination

MTX in phase 3
BARI 4 mg in extension

Phase 3 RA study plus extension

36

None

Elective termination

Placebo rescued to BARI 4 mg
BARI 4 mg in extension

Phase 3 RA study plus extension

39

None

Full-term pregnancy; no evidence of fetal adverse effect

ADA 40 mg rescued to BARI 4 mg
BARI 4 mg in extension

Phase 3 RA study plus extension

27

MTX

Spontaneous abortion

Placebo rescued to BARI 4 mg
BARI 4 mg in extension

Phase 3 RA study plus extension

29

MTX

Spontaneous abortion

Placebo rescued to BARI 4 mg
BARI 4 mg in extension

Phase 3 RA study plus extension

31

MTX
hydroxychloroquine

Spontaneous abortion

BARI 4 mg + MTX
BARI 4 mg in extension

Phase 3 RA study plus extension

26

MTX
leflunomide

Pregnancy outcome unavailable

Blinded study treatment

Phase 2 SLE study

28

Not reported

Spontaneous abortion

BARI 4 mg,
BARI 4 mg in extension

Phase 3 RA study plus extension

43

MTX

Not reported

BARI 4 mg, then step down to BARI 2 mg, rescued to BARI 4 mg in extension

Phase 3 RA study plus extension

39

MTX, leflunomide

Not reported

Placebo rescued to BARI 4 mg,
BARI 4 mg in extension

Phase 3 RA study plus extension

32

MTX

Full-term pregnancy, no evidence of fetal adverse effect

BARI 2 mg,
BARI 2 mg in extension

Phase 3 RA study plus extension

31

MTX

Full-term pregnancy, no evidence of fetal adverse effect

BARI 4 mg + MTX, BARI 4 mg then stepped down to 2 mg in extension

Phase 3 RA study plus extension

29

None

Premature, no evidence of fetal adverse effect

ADA,
BARI 4-mg in extension

Phase 3 RA study plus extension

34

None

Full-term pregnancy, no evidence of fetal adverse effect

BARI 4 mg,
BARI 4 mg in extension

Phase 3 RA study plus extension

37

MTX

Full-term pregnancy , no evidence of fetal adverse effect

BARI 1 mg

Phase 3 AD study

35

mucopolysaccharide polysulfuric acid ester, fexofenadine hydrochloride, hydrocortisone butyrate

Full-term pregnancy, no complications

BARI 1 mg

Phase 3 AD study

24

chlorpheniramine maleate, dextromethorphan hydrobromide, guaifenesin, phenylephrine hydrochloride

Elective termination

BARI 2 mg

Phase 3 AD study

29

avobenzone/octocrylene

Elective termination

Placebo

Phase 3 AD study

33

butyl hydroxybenzoate, cetyl alcohol, propylene glycol, sodium lauryl sulfate, stearyl alcohol, water purified, avena sativa fluid extract, salicylic acid

In-utero 

BARI 1 mg

Phase 3 AD study

31

citalopram, beclomethasone dipropionate, formoterol fumarate, desogestrel, ethinylestradiol

Unknown; patient refused follow‑up

Placebo

Phase 3 AD study

34

mucopolysaccharide polysulfuric acid ester, prednisolone valeroacetate, fluocinolone acetonide, fexofenadine hydrochloride, olopatadine hydrochloride

In-utero

BARI 4 mg (paternal exposure)

Phase 3 AD study

NRb

NR

Spontaneous abortion occurred at approximately 2 months gestation, 168 days from the patient’s first dose of BARI.

BARI 4 mg (paternal exposure)

Phase 3 AD study

NRb

NR

The partner became pregnant prior to the start of study; exposure to BARI 4 mg occurred at 2 months of pregnancy and the miscarriage occurred in the fifth month of pregnancy.

BARI (paternal exposure)

Non-AD study

NRb

NR

Full-term pregnancy normal infant

BARI (paternal exposure)

Non-AD study

NRb

NR

Full-term pregnancy normal infant

BARI (paternal exposure)

Non-AD study

NRb

NR

Full-term pregnancy normal infant

BARI 7 mg
(paternal exposure)

Phase 2 RA study

NRb

NR for female

Full-term pregnancy; no evidence of fetal AE

Placebo rescued to BARI 4 mg
BARI 4 mg in extension
(paternal exposure)

Phase 3 RA study plus extension

NRb

NR for female

Full-term pregnancy; no evidence of fetal AE

ADA 40 mg
BARI 4 mg in extension
(paternal exposure)

Phase 3 RA study plus extension

NRb

NR for female

Full-term pregnancy; no evidence of fetal AE

Abbreviations: AD = atopic dermatitis; ADA = adalimumab; BARI = baricitinib; BID = twice daily; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate; NR = not reported; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.

a Baricitinib was administered daily unless otherwise noted. Adalimumab was administered biweekly.

b Age of female not reported.

Postmarketing Reports of Pregnancy in Patients Treated With Baricitinib

As of January 31, 2020, 22 pregnancies were reported outside of clinical trials (postmarketing) that includes

  • 18 cases with an unknown outcome or in-utero

  • 1 case with a spontaneous abortion

  • 1 premature birth with a healthy infant, and

  • 2 healthy full-term infant.3 

The spontaneous abortion postmarketing case was reported as a congenital anomaly (anencephaly) in a 36-year-old female being treated for RA with BARI 4 mg who had a spontaneous abortion at 13.4 weeks of gestation. Concomitant medications included hydroxychloroquine, golimumab, prednisolone, MTX, folic acid, and ibuprofen. The fetus was exposed to BARI for 2 to 4.5 weeks of exposure.3

Literature Case Report of Pregnancy in Patient Treated With Baricitinib

As reported in the published literature, a 43-year-old woman with RA was reported to have maternal BARI exposure for several weeks before conception until the 17th week of gestation. At that time of confirmed pregnancy, BARI was discontinued. The infant has had no reported abnormalities.4

Enclosed Prescribing Information

OLUMIANT® (baricitinib) tablets, for oral use, Lilly

References

1. Olumiant [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

2. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4. Costanzo G, Firinu D, Losa F, et al. Baricitinib exposure during pregnancy in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2020;12:1759720X19899296. https://www.doi.org/10.1177/1759720X19899296

Glossary

BARI = baricitinib

JAK = Janus kinase

MTX = methotrexate

NOAEL = no observed adverse effect level

RA = rheumatoid arthritis

STAT = signal transducers and activators of transcription

Date of Last Review: June 30, 2020


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