Tacrolimus Pregnancy and Breastfeeding Warnings

Tacrolimus is also known as: Astagraf XL, Hecoria, Prograf

Tacrolimus Pregnancy Warnings

FDA pregnancy category: C Use of tacrolimus is not recommended unless the benefit outweighs the risk to the developing fetus.

Some animal studies revealed an increased incidence of abortion, resorption, and malformations. However, maternal toxicity was also present. There are no controlled data in human pregnancy. Tacrolimus has been used successfully during pregnancy in a limited number of cases, although neonatal hyperkalemia and renal dysfunction have been reported. Tacrolimus should only be given during pregnancy when benefit outweighs risk. Tacrolimus is known to cross the placenta. In one case report, tacrolimus maternal and placental vein plasma concentrations were 0.49 ng/mL and 0.24 ng/mL, respectively, at delivery at 36 weeks gestation. The neonatal tacrolimus plasma concentration was 0.09 ng/mL three days after delivery and was undetectable at one week. The infant was normal at twelve months of age. In a study of 100 pregnancies in 84 mothers, 71 progressed to delivery, (68 live births, 2 neonatal deaths, and 1 stillborn), 24 were terminated (12 spontaneous and 12 induced), 2 pregnancies were ongoing, and 3 were lost to follow-up. The most common complications in the neonates were hypoxia, hyperkalemia, and renal dysfunction. All were transient in nature. Four neonates presented with malformations, without any consistent pattern of affected organs. In a series of nine pregnancies in nine liver transplant patients, tacrolimus was used as the primary immunosuppressive agent throughout gestation. Tacrolimus doses ranged from 4 to 64 mg per day. Corticosteroids were used concomitantly in four cases. Hyperkalemia was present in five of seven neonates for whom potassium levels were available. Potassium levels normalized over 24 to 48 hours after delivery without treatment. One neonate with high tacrolimus cord levels was anuric for 36 hours after delivery. Renal function was normal by one week of age. One infant, delivered at 22 weeks gestation, died two hours after birth. This pregnancy, conceived one month after transplantation, was complicated by cytomegalovirus infection. Eight of the nine infants were alive and developing normally at the time of the report. One woman maintained on tacrolimus gave birth to twins at 32 weeks of gestation. Both babies developed severe respiratory distress requiring ventilator assistance and went on to develop congestive heart failure. One of the twins did not survive. Autopsy revealed a thrombotic cardiomyopathy with degeneration of cardiac muscle. The cardiomyopathy was believed to be caused by the tacrolimus used by the mother. FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Tacrolimus Breastfeeding Warnings

A case has been reported of a 32-year-old woman who breast-fed. The highest and mean concentrations of tacrolimus measured in her milk were 0.57 ng/mL and 0.429 ng/mL, respectively. Based on these measurements, her exclusively breast-fed infant would ingest (on average) 0.06 microgram/kg/day, which would correspond to 0.06% of the mother's weight-adjusted dose. Because of the low oral bioavailability of tacrolimus, the maximum amount the baby would receive is 0.02% of the mother's weight adjusted dose. At two and a half months of age, the infant was developing well both physically and neurologically. Another case has been reported of a 29 year old woman who was exclusively breast-feeding her healthy three month old infant while on tacrolimus. The milk-to-blood ratio was 0.23 and average tacrolimus concentrations in milk were 1.8 mcg/L. The baby ingested approximately 0.5% of the weight-adjusted maternal dose. The author's conclusion was that infant exposure to tacrolimus in milk is very low, suggesting that maternal tacrolimus therapy may be compatible with breast-feeding. In one small study, tacrolimus whole blood concentrations in four breast-fed neonates were undetectable (less than 1.9 mcg/L). This study confirms findings from previous data suggesting that tacrolimus exposure in breast-fed babies is negligible.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Excreted into animal milk: Unknown The effects in the nursing infant are unknown.

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