Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The antihypertensive mechanisms of action of olmesartan and angiotensin-converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1receptors, 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 (see Captopril or Enalapril). Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Anuria-associated 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 olmesartan. Newborn renal function and blood pressure should be closely monitored.
FETAL RISK SUMMARY
The prodrug olmesartan medoxomil is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. No additional metabolism occurs. Olmesartan is a selective angiotensin II receptor blocker (ARB) that is indicated, either alone or in combination with other antihypertensive agents, for the treatment of hypertension. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by preventing angiotensin II from binding to the AT1 receptors. Other drugs in this class include candesartan, eprosartan, irbesartan, telmisartan, and valsartan. The terminal elimination half-life is about 13 hours (1).
Reproduction studies with olmesartan have been conducted in rats and rabbits. No evidence of teratogenicity was observed in either species at doses up 240 and 0.5 times, respectively, the maximum recommended human dose based on BSA (MRHD). Higher doses in rabbits could not be administered because they caused maternal death. In rats, doses equal to or greater than about 0.4 times the MRHD caused fetal toxicity (decreases in pup birth weight and weight gain). Higher doses (equal to or greater than about twice the MRHD) resulted in delays in developmental milestones and dose-related increases in the incidence of dilation of the renal pelvis. The no-observed effect dose for developmental toxicity was about 0.1 times the MRHD (1).
The case report below strongly suggests that olmesartan crosses the human placenta. This would be consistent with the molecular weight (about 559) and relatively long terminal elimination half-life.
A woman took olmesartan (dose not specified) for hypertension in the last month of pregnancy (2). Severe oligohydramnios developed and she delivered a 3.045-kg female infant by cesarean section at 36 weeks’ gestation. Apgar scores were 7 and 7. The infant received dialysis for renal failure but died on day 45. Autopsy revealed severe tubular dysgenesis and the renal arteries and arteriole walls were thickened (2).
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 (3). The factors, that typically coexist with hypertension in pregnancy, included diabetes, advanced maternal age, and obesity.
BREASTFEEDING SUMMARY
No reports describing the use of olmesartan during human lactation have been located. The molecular weight (about 559) is low enough that excretion into breast milk should be expected. The effect of this exposure 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. Benicar. Sankyo Pharma, 2004.
2.Sinelli MT, Cattarelli D, Cortinovis S, Maroccolo D, Chirico G. Severe neonatal renal failure after maternal use of angiotensin II type 1 receptor antagonists. Ped Med Chir 2008;30:306–8.
3.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.