Drugs in Pregnancy and Lactation: Tenth Edition

ERLOTINIB

Antineoplastic (Tyrosine Kinase Inhibitor)

PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk

BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity

PREGNANCY SUMMARY

Two reports describing the use of erlotinib in human pregnancy has been located. The animal data suggest risk, but the near absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. If a woman receives erlotinib during pregnancy, she should be informed of the unknown risk to her embryo–fetus.

FETAL RISK SUMMARY

Erlotinib is an oral antineoplastic agent that is indicated, in combination with gemcitabine, for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. The drug is a human epidermal growth factor type 1/epidermal growth factor receptor tyrosine kinase inhibitor in the same subclass as several other agents (see Appendix). Erlotinib is extensively metabolized by the liver to apparently inactive metabolites. The elimination half-life is about 32 hours. About 93% of erlotinib is bound to the plasma proteins albumin and alpha-1 acid glycoprotein (1,2).

Reproduction studies have been conducted in rats and rabbits. In pregnant rats and rabbits during organogenesis, there was no increased incidence of embryo–fetal lethality, abortion, or teratogenic effects with doses that achieved plasma concentrations that were about equal to those in humans from a 150 mg daily dose based on AUC (HDD). However, when pregnant rabbits were given a dose that produced exposures that were about three times the HDD, maternal toxicity with associated embryo–fetal lethality and abortion occurred. In addition, female rats given daily doses that were about 0.3 or 0.7 times the human dose based on BSA prior to mating, and through the first week of pregnancy had an increase in early resorptions resulting in a decrease in the number of live fetuses (1).

Carcinogenic studies have not been conducted with erlotinib. Multiple tests for genotoxicity were negative, as were the effects on male and female rat fertility (1).

It is not known if erlotinib crosses the human placenta. The molecular weight (about 394 for the free base) and long elimination half-life suggest that the drug will cross. However, the extensive metabolism and moderately high plasma protein binding may limit the amount of active drug reaching the embryo–fetus.

A woman with metastatic nonsmall cell lung cancer was treated with six cycles of cisplatin, gemcitabine, and bisphosphonates that resulted in stable disease (3). No additional therapy was given for 12 months until progressive disease was found and erlotinib 100 mg/day was started. Pregnancy was diagnosed 2 months later. Conception was thought to have occurred at about the same time that erlotinib had been started. The drug was discontinued for the remainder of the pregnancy. At 42 weeks’ gestation, a cesarean section delivered a normal, 3490-g female infant. No congenital malformations or other abnormalities were noted in the healthy infant (3).

A 2011 case report described a 38-year-old woman at 26 weeks’ gestation who was diagnosed with lung cancer (4). The woman had never smoked. She was initially treated with erlotinib 100 mg/day and then changed about 2 weeks later to gefitinib 250 mg/day. Gefitinib was continued through the remainder of her pregnancy. At 36 weeks’, she gave birth to a healthy 2.08-kg infant with an Apgar score of 9 at 1 minute. The baby weighed 2.98 kg 6 weeks later (4).

BREASTFEEDING SUMMARY

No reports describing the use of erlotinib during human lactation have been located. The molecular weight (about 394 for the free base) and long elimination half-life suggest that the drug will be excreted into breast milk. However, the extensive metabolism and moderately high plasma protein binding may limit the amount of active drug reaching the milk. The effects on a nursing infant are unknown, but there is a potential for severe toxicity. Moreover, the systemic bioavailability of erlotinib is markedly increased in adults when the dose is taken with food, and this might also occur in nursing infants. Therefore, until the amount of erlotinib in breast milk has been determined, the safest course is not to breastfeed.

References

1.Product information. Tarceva. Genentech, 2007.

2.Product information. Tarceva. OSI Pharmaceuticals, 2007.

3.Zambelli A, Antonio Da Prada G, Fregoni V, Ponchio L, Sagrada P, Pavesi L. Erlotinib administration for advanced non-small cell lung cancer during the first 2 months of unrecognized pregnancy. Lung Cancer 2008;60:455–7.

4.Lee CH, Liam CK, Pang YK, Chua KT, Lim BK, Lai NL. Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure. Lung Cancer 2011;74:349–51.



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