Olumiant ® (baricitinib) tabletter

För fullständig produktresumé för Olumiant se FASS.

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Olumiant®▼ (baricitinib): Exponering under graviditet

Baricitinib är kontraindicerat under graviditet. Fertila kvinnor ska använda en effektiv preventivmetod under behandling samt i minst 1 vecka efter avslutad behandling.

Baricitinib Label Information Related to Pregnancy and Lactation

Pregnancy

The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development.1

  • There are no adequate data from the use of baricitinib in pregnant women.

  • Studies in animals have shown reproductive toxicity.

  • Baricitinib was teratogenic in rats and rabbits.

  • Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher dosages.1

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

Lactation

It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk.1

A risk to newborns/infants cannot be excluded and baricitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue baricitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.1

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.2

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.2

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.2

Table 1. Pregnancies in the Clinical Program2

Treatments Administereda

Clinical Study

Age

Concomitant therapy (e.g. 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

Non-RA/AD 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

Non-RA/AD 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-RA/AD study

NRb

NR

Full-term pregnancy normal infant

BARI (paternal exposure)

Non-RA/AD study

NRb

NR

Full-term pregnancy normal infant

BARI (paternal exposure)

Non-RA/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.

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.2

No exposure to BARI in lactating women was reported during the clinical studies.2

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.2 

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.2

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.3

Nonclinical Data Regarding Pregnancy and Lactation

Reproductive Toxicity in Animals

Animal Embryo-Fetal Development

In rat and rabbit reproductive toxicology studies, baricitinib was shown to reduce foetal growth/weight and produce skeletal malformations (at exposures of approximately 10 and 39 times the human exposure, respectively).1

No adverse foetal effects were observed at exposures 2 times the human exposure based on AUC.1

Animal Prenatal and Postnatal Development

In a prenatal and postnatal development study

  • decreased rat pup weights were observed at exposures of 4 times the human exposure, and

  • decreased postnatal survival was observed at exposures of 21 times the human exposure.1

The NOAEL was 25 mg/kg based on prenatal and postnatal development rat studies.2

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.2

Safety monitoring measures assessing immune, growth, and bone effects are ongoing in pediatric clinical studies.2

In a juvenile rat development study, BARI had no adverse effects on clinical signs, sexual maturation, ophthalmology, behavioral performance, or reproductive performance.2

Transfer Across the Placenta in Animals

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.2

Lactation in Animals

Baricitinib was detected in the milk of lactating rats. In a pre- and postnatal development study, decreased pup weights and decreased postnatal survival were observed at exposures 4 and 21 times, respectively, the human exposure.1

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. 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

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.

Datum fӧr senaste ӧversyn 2020 M08 03


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