Antineoplastic (Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of sorafenib in human pregnancy have been located. The animal reproduction data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of embryo–fetal risk. It should be noted, though, that sorafenib inhibits angiogenesis, a critical component of embryonic and fetal development. The manufacturer recommends that adequate contraception should be used during therapy and for at 2 weeks after completing therapy (1). However, renal cell carcinoma can be fatal, so if a woman requires sorafenib and informed consent is obtained, treatment should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the potential risk for severe adverse effects in the embryo and fetus.
FETAL RISK SUMMARY
Sorafenib is an oral multikinase inhibitor that decreases tumor cell proliferation, probably by reducing angiogenesis. There are several other antineoplastics in the same subclass (see Appendix). Sorafenib is indicated for the treatment of patients with advanced renal cell carcinoma. The mean plasma elimination half-life is 25–48 hours. After hepatic metabolism, at least eight metabolites have been identified, one of which has activity similar to the parent compound. Plasma protein binding is 99.5% (1).
Reproduction studies have been conducted in rats and rabbits. In these species, doses that were about 0.008 times the AUC in cancer patients taking the recommended human daily dose (RHDD) resulted in postimplantation loss, resorptions, skeletal retardations, and restricted fetal weight. A no-observed-adverse-effect-level (NOAEL) was not determined (1).
Studies for carcinogenicity have not been conducted with sorafenib. The drug was clastogenic, in the presence of metabolic activation, in one test but was not mutagenic or clastogenic in other tests. An intermediate in the manufacturing process that also is present in the final product (<0.15%) was mutagenic when tested independently (1). Specific studies for fertility impairment have not been conducted, but sorafenib does adversely affect male and female reproductive organs. These effects, more pronounced in rats than in mice or dogs, included testicular atrophy and degeneration, oligospermia, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea, and arrested follicular development at doses that were about 0.3–0.5 times the RHDD (1).
It is not known if sorafenib crosses the human placenta. The molecular weight (433 for the free acid) and the long elimination half-life suggest that the drug will cross to the embryo and/or fetus.
BREASTFEEDING SUMMARY
No reports describing the use of sorafenib during human lactation have been located.
The molecular weight (433 for the free acid) and the long elimination half-life suggest that the drug will be excreted into breast milk. Because it is an acid, if excreted, the milk:plasma ratio should be <1. The effects of this exposure on a nursing infant are unknown, but severe toxicity may occur. In adults, hand–foot skin reaction and rash were the most common adverse events, but diarrhea, hemorrhage, and hypertension were also common.
Reference
1.Product information. Nexavar. Bayer Pharmaceuticals, 2007.