Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of azilsartan in human pregnancy have been located. The limited 1st-trimester experience with other agents in this class does not suggest a risk of major anomalies. The antihypertensive mechanisms of action of azilsartan and angiotensin converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1 receptors, whereas the latter prevents the formation of angiotensin II itself. Therefore, use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity identical to that seen with ACE inhibitors (e.g., see Captopril or Enalapril). Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce 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 valsartan. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
Azilsartan, an angiotensin II receptor blocker (ARB) given orally, is the active form of the commercially available prodrug azilsartan medoxomil. It is indicated, either alone or with other agents, for the treatment of hypertension. Azilsartan is in the same class of angiotensin II receptor blockers as candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. It is metabolized to inactive metabolites. Plasma protein binding, primarily to albumin, is high (>99%) and the elimination half-life is about 11 hours (1).
Animal reproduction studies have not been conducted with azilsartan. Long-term studies for carcinogenic potential in mice and rats were negative. Assays for mutagenicity have shown both positive and negative effects. The drug had no effect on the fertility of male and female rats (1).
It is not known if azilsartan crosses the human placenta. The molecular weight (about 607) and the elimination half-life suggest that the drug will cross to the embryo–fetus, even though the high plasma protein binding should limit the exposure. However, other agents in this class are known to cross the placenta and the same should be expected for azilsartan.
A 2012 review of the use of ACE inhibitors and ARBs in the 1st trimester concluded that there may be an elevated teratogenic risk, but the risk appeared to be related to other factors (2). The factors that typically coexist with hypertension in pregnancy included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of azilsartan during human lactation have been located. The molecular weight (about 607) and the elimination half-life (about 11 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding should limit the amount excreted. The effect of this exposure on a nursing infant is unknown. Diarrhea was the most common (2%) adverse reaction in adults (1). The American Academy of Pediatrics classifies ACE inhibitors, a closely related group of antihypertensive agents, as compatible with breastfeeding (see Captopril or Enalapril).
References
1.Product information. Edarbi. Takeda Pharmaceuticals America, 2011.
2.Polifka JE. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence. Birth Defects Res (Part A) 2012;94:576–98.