Vasopressin Receptor Antagonist
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of conivaptan during human pregnancy have been located. Developmental toxicity (death) was observed in one of two animal species. Because of the administration method, exposure of the embryo and fetus will probably occur. The absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. If a pregnant woman requires conivaptan therapy, she should be advised of the potential risk (abortion or fetal/neonatal death).
FETAL RISK SUMMARY
Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin receptors. It is indicated for the treatment of euvolemic hyponatremia (e.g., the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc) in hospitalized patients. It is given as a continuous IV infusion over several days. The mean terminal elimination half-life after conivaptan infusion is 5 hours. The drug is extensively bound to plasma proteins (99%). Some of the metabolites have activity equivalent to the parent compound but, overall, the activity of the metabolites was only 7% that of conivaptan (1).
Reproduction studies have been conducted in rats and rabbits. When female rats were given daily IV bolus doses that resulted in systemic exposures that were less than the human therapeutic exposure based on AUC (HTE) before mating and during the first 7 days of pregnancy, prolonged diestrus, decreased fertility, and increased pre- and postnatal implantation loss occurred. No effects were observed with these doses on male fertility. No significant maternal or fetal effects were observed at daily doses resulting in systemic exposures that were less than the HTE during organogenesis (days 7–17). When dosing was continued through lactation day 20 (weaning), no maternal toxicity was observed, but pups showed decreased neonatal viability, weaning indices, delayed growth and physical development (including sexual maturation), and delayed reflex development. No pup adverse effects were observed when the daily dose was reduced by one-half or more. In pregnant rabbits given daily IV doses resulting in systemic exposures less than the HTE during organogenesis, there were no fetal adverse effects, but maternal toxicity was evident at all doses tested (1).
During labor, daily doses given orally to rats that resulted in systemic exposures equivalent to the HTE delayed delivery. Daily IV doses that resulted in systemic exposures less than the HTE caused increased peripartum pup mortality. These effects may have been secondary to conivaptan activity on oxytocin receptors in rats (1).
No carcinogenicity was observed in mice and rats given daily doses by gavage for 2 years that resulted in systemic exposures that were up to six and two times, respectively, the HTE. Conivaptan was not mutagenic or clastogenic, with or without metabolic activation, in several tests (1).
Conivaptan crosses the rat placenta with fetal tissue concentrations <10% of maternal plasma levels, but placental levels were 2.2 times higher than maternal plasma levels. Moreover, conivaptan was slowly cleared from fetal tissues, suggesting that fetal accumulation may occur (1). It is not known if conivaptan crosses the human placenta. The molecular weight (about 499 for the free base) and the administration of a continuous intravenous infusion over several days suggest that the drug will cross to the human embryo and fetus.
BREASTFEEDING SUMMARY
No reports describing the use of conivaptan during human lactation have been located. It is not known if conivaptan is excreted into breast milk. The molecular weight (about 499 for the free base) and the administration of a continuous intravenous infusion over several days suggest that the drug will be excreted into milk. Although the effects on a nursing infant are unknown, there is a potential for severe toxicity in several organ systems as observed in adults receiving IV infusions. Moreover, as a weak base, ion trapping in the relatively acidic milk will allow conivaptan to accumulate in milk. Therefore, until data relating to milk concentrations are available, women receiving conivaptan should probably not breastfeed.
Reference
1.Product information. Vaprisol. Astellas Pharma US, 2007.