Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Although there is no human pregnancy experience, the animal reproduction data suggest low risk in the 1st trimester. Because aliskiren acts directly on the renin–angiotensin system, exposure in the 2nd and 3rd trimesters should be avoided except in those rare incidences in which the mother requires therapy with this agent. Two other classes of agents that act on this system, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA), are known to cause marked fetal toxicity in the 2nd and 3rd trimesters. (See Captopril and Losartan for representative agents.) Therefore, use of aliskiren during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity identical to that seen with ACE inhibitors and ARA drugs. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may be associated with fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to aliskiren. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
Aliskiren is a nonpeptide renin inhibitor. It is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents. Aliskiren is partially metabolized to inactive metabolites apparently by the CYP450 isoenzyme CYP3A4. Oral bioavailability is poor with only about 2.5% absorbed systemically (1). The mean elimination half-life is 30 hours (range 23–36 hours) and plasma protein binding is about 50% (2).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats and rabbits, there was no evidence of teratogenicity with oral doses ≤20 and ≤7 times, respectively, the maximum recommended human dose of 300 mg/day (MRHD) on a BSA basis (MRHD-BSA). However, in rabbit offspring fetal birth weights were reduced at 3.2 times the MRHD-BSA. In rabbits, the drug was present in the placenta, amniotic fluid, and fetuses (1).
Carcinogenic studies in mice and rats with doses producing exposures that were about 1.5 and 4 times, respectively, the MRHD based on AUC (MRHD-AUC) observed no significant increases in tumor incidence. However, tumors that are considered rare in the strain of rat studied were observed in two animals; a colonic adenoma in one and a cecal adenocarcinoma in the other. Mucosal epithelial hyperplasia of the lower gastrointestinal tract, with or without erosion/ulceration, was noted in both species at exposures that were about 0.75 and 2 times, respectively, the MRHD-AUC. No genotoxic potential was observed in multiple assays. In addition, no effect on the fertility of male and female rats was observed with doses ≤8 times the MRHD-BSA (1).
Although aliskiren crosses the placenta in rabbits (1), this has not been studied in humans. The molecular weight (about 552 for the free base), long elimination half-life, and moderate plasma protein binding suggest that the drug will cross to the embryo and fetus. However, the low lipid solubility should limit the amount transferred.
No reports have described the use of aliskiren in human pregnancy. However, use of the drug in the 2nd and 3rd trimesters is not recommended because of the potential for severe toxicity in the fetus and newborn.
BREASTFEEDING SUMMARY
No reports describing the use of aliskiren during human lactation have been located. The molecular weight (about 552 for the free base), long elimination half-life (mean 30 hours), and moderate plasma protein binding (about 50%) suggest that the drug will be excreted into breast milk. However, the low lipid solubility should limit the amount excreted. The effect on a nursing infant is unknown. The American Academy of Pediatrics, however, classifies ACE inhibitors, a closely related group of antihypertensive agents, as compatible with breastfeeding. (See Captopril or Enalapril.)
References
1.Product information. Tekturna. Novartis Pharmaceuticals, 2008.
2.Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24:243–56.