Summary of Use during Lactation

Information from one maternal-infant pair with ivacaftor and lumacaftor indicates that maternal ivacaftor therapy produce low levels in milk. An international survey of cystic fibrosis centers found no adverse effects in breastfed infants of mothers taking these drugs. A task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] One breastfed infant had transient elevations in bilirubin and liver enzymes during maternal therapy that could not definitively be attributed to the drugs in breastmilk. Until more data are available, monitoring of infant bilirubin and liver enzymes might be advisable during breastfeeding with maternal ivacaftor therapy.[2] Examination of breastfed infants for cataracts has also been recommended.[3] Anecdotal evidence indicates that the drugs in breastmilk may moderate cystic fibrosis in breastfed infants.

Drug Levels

Maternal Levels. A woman with cystic fibrosis was treated with lumacaftor and ivacaftor during pregnancy and postpartum. The dosage was not stated, but it was probably the standard dosage of lumacaftor 400 mg and ivacaftor 250 mg orally every 12 hours. The average concentration of ivacaftor in breastmilk samples taken randomly over a 6-month period without regard to the times of the doses was 35.3 mcg/L (0.09 micromolar).[4]

Two nursing mothers with cystic fibrosis who were taking elexacaftor, ivacaftor and tezacaftor, had their milk samples analyzed 2 or 3 times between 15 and 60 days postpartum. Milk levels were all <1 micromolar in one woman at 15 and 60 days postpartum. The other woman had milk ivacaftor levels of <1 micromolar at 30 days postpartum. Milk levels of all drugs tended to increase slightly over time.[5]

Infant Levels. An infant was breastfed by a mother taking lumacaftor and ivacaftor. The percentage of breastfeeding varied between 25% and 100% during this time period. The average infant ivacaftor plasma concentration over the first 6 months of life, excluding day 1 postpartum, was 3.9 mcg/L (0.01 micromolar). This value corresponded to average of 0.5% of simultaneous maternal plasma levels.[4]

Two partially breastfed (extent not stated) infants whose mothers were taking elexacaftor, ivacaftor and tezacaftor had serum drug concentrations measured several times. Ivacaftor levels were between 0.1 and 1 micromolar at birth and dropped to 0.1 micromolar and below over time.[5]

Effects in Breastfed Infants

A woman with cystic fibrosis was treated with lumacaftor and ivacaftor during pregnancy and postpartum. Her infant was fully breastfed until day 29 postpartum when elevated direct and indirect bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase were found to be elevated. All values had been normal on days 1 and 14. The fraction of breastmilk the infant received was reduced to 25% and all values were normal on day 37. The fraction of breastfeeding was increased to 50% and then to 100%. On day 135, the infant's direct bilirubin was elevated during concurrent maternal levofloxacin and trimethoprim-sulfamethoxazole therapy. The fraction of breastfeeding was decreased to 75% and the direct bilirubin was normal on day 154. The authors noted that the abnormal test results could not definitively be attributed to lumacaftor and ivacaftor therapy.[4]

A survey was sent to lead clinicians of adult CF centers in Europe, the United Kingdom, United States of America, Australia and Israel requesting anonymized data on pregnancy outcomes in women using CFTR modulators during pregnancy and lactation. Responses were received from 31 centers and one woman with CF for a total of 64 pregnancies in 61 women resulting in 60 live births. Thirteen infants were breastfed on ivacaftor alone, 9 infants were breastfed on lumacaftor and ivacaftor, and 5 infants were breastfed on tezacaftor and ivacaftor for a total of 27 infants exposed to ivacaftor in breastmilk, all with no reported complications. The extent of breastfeeding was not reported.[6] An updated survey by the same authors asked CF clinicians to report on pregnant women exposed to the elexacaftor, tezacaftor and ivacaftor combination during pregnancy and breastfeeding. Twenty-six infants were breastfed (extent not stated) during maternal use of the combination. No adverse effects were reported in the breastfed infants.[7]

An infant was born to a mother taking elexacaftor, ivacaftor and tezacaftor for cystic fibrosis. The infant was breastfed (extent not stated). Although the infant had cystic fibrosis-causing CFTR mutations, the infant was healthy and tested negative for cystic fibrosis on newborn screening. The authors expressed concern that the drugs received transplacentally and in breastmilk caused a false negative screening test.[8]

A mother who was a heterozygous carrier of the F508del gene became pregnant with a homozygous infant. At 32 weeks of pregnancy, the mother began elexacaftor, ivacaftor and tezacaftor in the usual adult dosage to treat her fetus who had evidence of meconium ileus. The infant was born at 36 weeks and given pancreatic enzyme replacement therapy with breastfeeding while maternal treatment continued. The infant’s fecal elastase, transaminases and bilirubin were normal at about 1 month of age. The infant’s sweat chloride, although low, was nearer to normal than was expected. The authors hypothesized that the medications received in breastmilk moderated the disease process in the infant.[9]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

References

1.

Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55:1901208. [PubMed: 31699837]

2.

Jain R, Taylor-Cousar JL. Fertility, pregnancy and lactation considerations for women with CF in the CFTR modulator era. J Pers Med. 2021;11:418. [PMC free article: PMC8156060] [PubMed: 34063507]

3.

Taylor-Cousar JL. CFTR modulators: Impact on fertility, pregnancy, and lactation in women with cystic fibrosis. J Clin Med. 2020;9:2706. [PMC free article: PMC7563981] [PubMed: 32825766]

4.

Trimble A, McKinzie C, Terrell M, et al. Measured fetal and neonatal exposure to lumacaftor and ivacaftor during pregnancy and while breastfeeding. J Cyst Fibros. 2018;17:779–82. [PMC free article: PMC6354249] [PubMed: 29866531]

5.

Collins B, Fortner C, Cotey A, et al. Drug exposure to infants born to mothers taking elexacaftor, tezacaftor, and ivacaftor. J Cyst Fibros. 2022;21:725–7. [PMC free article: PMC9213569] [PubMed: 34952795]

6.

Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. J Cyst Fibros. 2020;19:521–6. [PubMed: 32151568]

7.

Taylor-Cousar JL, Jain R. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros. 2021;20:402–6. [PubMed: 33762125]

8.

Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. J Cyst Fibros. 2021;20:835–6. [PubMed: 33846105]

9.

Szentpetery S, Foil K, Hendrix S, et al. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros. 2022;21:721–4. [PubMed: 35422395]

Substance Name

Ivacaftor

CAS Registry Number

873054-44-5

Drug Class

Breast Feeding

Lactation

Milk, Human

Chloride Channel Agonists

Cystic Fibrosis Transmembrane Conductance Regulator Protein Modulator

CFTR Protein Modulator