Vasopressin Receptor Antagonist
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of tolvaptan in human pregnancy have been located. The animal reproduction data suggests low risk because all of the toxic effects occurred in the presence of maternal toxicity and at doses that were much greater than 10 times the human dose. Although human pregnancy experience is needed for a better risk assessment, there does not appear to be a reason to withhold the drug in pregnancy if indicated.
FETAL RISK SUMMARY
Tolvaptan is an oral selective vasopressin receptor antagonist. It is in the same class as conivaptan. Tolvaptan is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and syndrome of in appropriate antidiuretic hormone. The drug is metabolized to inactive metabolites. Tolvaptan is highly plasma protein bound (99%) and has a terminal phase half-life of about 12 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats during organogenesis, decreased fetal body weights and delayed ossification were observed at the highest dose that was 162 times the maximum recommended human dose based on BSA (MRHD). Maternal toxicity (reduced body weight gain and food consumption) were noted at ≥16 times the MRHD. In rabbits during organogenesis, maternal toxicity (reduced body weight and food consumption) occurred with doses that were ≥32 times the MRHD and abortions at ≥97 times the MRHD. Increased rates of embryo–fetal death, microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at doses that were 324 times the MRHD (1).
Tolvaptan was not carcinogenic in 2-year studies in rats and mice. Tests also were negative for genotoxicity. No effect on fertility was noted in male rats but, in female rats a dose that was 162 times the MRHD caused significantly fewer corpora lutea and implants than controls (1).
It is not known if tolvaptan crosses the human placenta. The molecular weight (about 449) and long terminal phase half-life suggest that the drug will cross, but the high plasma protein binding should limit the embryo–fetal exposure.
BREASTFEEDING SUMMARY
No reports describing the use of tolvaptan during human lactation have been located. The molecular weight (about 449) and long terminal phase half-life (about 12 hours) suggest that it will be excreted into breast milk, but the high plasma protein binding (99%) should limit the amount. The effect of this exposure on a nursing infant is unknown. However, because the drug promotes urinary water excretion, dehydration and hypovolemia are potential complications.
Reference
1.Product information. Samsca. Otsuka America Pharmaceutical, 2009.