Is Vanzacaftor, Tezacaftor and Deutivacaftor safe while breastfeeding?

Summary of use during breastfeeding

No information is available on milk or infant serum levels of vanzacaftor or deutivacaftor. Information from mother-infant pairs with elexacaftor, ivacaftor and tezacaftor indicates that tezacaftor has low levels in milk and infant serum. Deutivacaftor is a deuterated form of ivacaftor that has slower clearance, a longer half-life and greater maternal exposure. An international survey of cystic fibrosis (CF) centers found no adverse effects in breastfed infants of mothers taking these drugs and a task force respiratory experts from Europe, Australia and New Zealand found that these drugs are probably safe during breastfeeding.[1] Infants exposed to CFTR modulators through breastmilk should have periodic liver function testing and an examination by an ophthalmologist for cataracts. Because CFTR modulators can mask cystic fibrosis in breastfed infants, testing of breastfed infants for CF should be performed. Detailed monitoring recommendations have been published.[2]

Effects on the breastfed infant

Relevant published information on the combination of vanzacaftor, tezacaftor and deutivacaftor was not found as of the revision date. Information on other partially overlapping combination products is listed below.

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]

Three women with cystic fibrosis were taking elexacaftor, ivacaftor and tezacaftor in unspecified dosages during pregnancy and postpartum while breastfeeding. On routine visual examinations between 8 days and 6 months postpartum, their infants were found to have small ( < 1.0 mm) bilateral cataracts, in the central area in one and outside the visual axis in the other two. Breastfeeding was discontinued after diagnosis at 16 days, 9 weeks and 6 months postpartum. The contribution of breastfeeding to the cataracts could not be determined.[5]

A woman with cystic fibrosis began elexacaftor, ivacaftor and tezacaftor prior to conception and continued it throughout pregnancy. She partially breastfed (extent not stated) her infant. The infant had slowly increasing ALT values through 90 days of age, peaking at 65 units/L (upper limit of normal 30 units/L). Liver ultrasound and ophthalmologic exams were normal. Evaluation by a pediatric gastroenterologist did not identify a cause of increased ALT other than exposure to the drug combination. Levels normalized by age 158 days.[4]

Two women were reported by the British Columbia cystic fibrosis clinic who became pregnant and breastfed their infants. One took ivacaftor and breastfed (extent not stated) for 42 months. Her infant was physically normal and healthy, but had speech delay. The other woman took Tricafta (ivacaftor, elexacaftor, and tezacaftor). She breastfed (extent not stated) her infant for 6 months and her infant had no complications.[10]

A woman with cystic fibrosis took ivacaftor 150 mg, tezacaftor 100 mg and elexacaftor 200 mg in the morning and ivacaftor 150 mg at night during pregnancy and breastfeeding (extent not stated). The infant had not regained his birthweight at 10 days postpartum, his stools had a greasy rim, and he had pancreatic elastase levels below levels for pancreatic sufficiency but higher than expected for newborns homozygous for this mutation. The infant started on pancreatic enzymes and by day 20, he had normal elastase levels. By day 45 of life was gaining weight and stools were normal. At 6 months of age the infant was still being breastfed and doing well. The authors felt that when breastfeeding is stopped, a rebound in symptoms might occur because the infant will no longer be receiving small amounts of the mother’s medications through milk.[11]

A woman with cystic fibrosis received elexacaftor 100 mg, tezacaftor, 50 mg, ivacaftor 75 mg and additional ivacaftor 150 mg daily from 12 weeks of pregnancy and postpartum. The mother exclusively breastfed her infant while continuing therapy, and no significant side a pharmacovigilance effects related were observed in the infant up to at least 3 months of age.[6]

A pharmacovigilance center in France reported 2-fold or less liver enzyme elevations in 3 exclusively breastfed infants whose mothers were taking elexacaftor 200 mg, tezacaftor, 100 mg, ivacaftor 150 mg in the morning and additional ivacaftor 150 mg daily; two infants also had concurrent bilirubin elevation. The abnormalities had an onset ranging from days 4 to 90 postpartum. In one case, exclusive breastfeeding continued for up to 6 months with resolution of liver enzymes abnormalities beginning at about 6 months. In the second case, exclusive breastfeeding continued throughout the follow-up with spontaneous regression of liver enzyme disorders. In the third case, breastfeeding was stopped at day 9 with resolution of the elevated enzyme levels. The ophthalmological examination carried out at 1 and 6 months in the first two infants found no cataracts.[7]

Two breastfed infants whose mothers were taking elexacaftor, ivacaftor and tezacaftor developed mild liver enzyme elevations. In one mild, stable AST elevations were seen at 4 and 6 months of age (48 and 49 IU/L, respectively; normal: 15 to 41 IU/L) but all other parameters were normal. In the second, ALT (124 IU/L; normal: 10 to 35 IU/L), AST (94 IU/L, normal: 10 to 35 IU/L), and bilirubin (25 micromoles/L; normal: 0 to 20 micromoles/L) were seen at 3 months of age. At 4 months of age liver enzymes were still elevated but had improved slightly, with bilirubin in normal range (ALT 108 IU/L, AST 87 IU/L, bilirubin 15 micromoles/L). Enzyme levels continued to improve at month 6 (ALT 48 IU/L, AST 68 IU/L, bilirubin 5 micromoles/L) and at month 9 (ALT 25 IU/L, AST 53 IU/L, bilirubin 4 micromoles/L) with continued breastfeeding. The extent of breastfeeding was not stated for either infant.[12]

Effects on milk supply

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

Levels in milk

Deutivacaftor is a deuterated form of ivacaftor that has slower clearance and a longer half-life.[3] At recommend adult dosages, exposure to deutivacaftor is about 67% greater than with usual dosages of ivacaftor in a similar 3-drug combination product. Milk levels of deutivacaftor are probably increased by about the same amount, but no studies on milk excretion of deutivacaftor or on vanzacaftor have been reported. Information on ivacaftor can be found in the ivacaftor record and tezacaftor information is reported below.

Maternal Levels. 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. The tezacaftor milk level was <1 micromolar in one woman at 15 and 60 days postpartum. The other woman had a tezacaftor milk level of <1 micromolar at 30 and 45 days postpartum. Milk levels tended to increase slightly over time.[4]

Two nursing mothers with cystic fibrosis were taking elexacaftor, ivacaftor and tezacaftor in unspecified dosages. The tezacaftor concentration in milk at unreported times after a dose was 0.12 micromolar (62.5 mcg/L) and 0.39 micromolar (203 mcg/L).[5]

A woman with cystic fibrosis received elexacaftor 100 mg, tezacaftor, 50 mg, ivacaftor 75 mg and additional ivacaftor 150 mg daily while exclusively breastfeeding her 3-month-old infant. Fasting breastmilk samples were collected just before the morning dose of elexacaftor, tezacaftor, and ivacaftor. The tezacaftor concentration in milk was 761 mcg/L.[6]

Infant Levels. Two partially breastfed (extent not stated) infants whose mothers were taking elexacaftor, ivacaftor and tezacaftor had serum drug concentrations measured several times. Tezacaftor levels were highest of the 3 drugs, starting at about 1 micromolar at birth. Levels remained similar in one infant up to 100 days of age and dropped below 1 micromolar at 45 and 60 days postpartum in the other.[4]

A woman with cystic fibrosis received elexacaftor 100 mg, tezacaftor, 50 mg, ivacaftor 75 mg and additional ivacaftor 150 mg daily while exclusively breastfeeding her 3-month-old infant. An infant blood sample was collected before the morning dose of the combination. The infant was not breastfed 2 hours prior to blood collection. The infant’s plasma tezacaftor concentration was 13.9 mcg/L.[6]

A woman was taking elexacaftor 100 mg, tezacaftor, 50 mg, ivacaftor 75 mg and additional ivacaftor 150 mg daily. Drug levels were measured in her breastfed infant on day 15 of life. The infant’s serum concentration of tezacaftor was 0.92 mg/L.[7]