Risk Factor: CM*
Class: Cardiovascular drugs/ Antihypertensives/ Angiotensin ii receptor antagonists
Fetal Risk Summary
The prodrug, candesartan cilexetil, is hydrolyzed to the active drug, candesartan, during absorption from the gastrointestinal tract. Candesartan is a selective angiotensin II receptor antagonist that is used, either alone or in combination with other antihypertensive agents, for the treatment of hypertension. It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by preventing angiotensin II from binding to AT1 receptors.
Reproduction studies have been conducted with candesartan cilexetil in mice, rats, and rabbits at oral doses up to approximately 138, 2.8, and 1.7 times the maximum recommended human dose of 32 mg on a body surface area basis (MRHD), respectively (1). Rat offspring, exposed to the drug during late gestation and through lactation, had decreased survival and an increased incidence of hydronephrosis, whereas no maternal toxicity or fetal harm were observed in pregnant mice. In pregnant rabbits, maternal toxicity (decreased body weight and death) was noted but, in the offspring of surviving dams, no adverse effects were seen on fetal survival, fetal weight, or on external, visceral, or skeletal development (1). No effects on fertility or reproductive performance were observed in male and female rats given oral doses up to 83 times the MRHD (1).
It is not known if candesartan crosses the human placenta to the fetus. The molecular weight of candesartan (about 440 after hydrolysis of the prodrug, candesartan cilexetil) is low enough, however, that passage to the fetus should be expected.
No reports describing the use of candesartan cilexetil during human pregnancy have been located. The antihypertensive mechanisms of action of candesartan 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 that is identical to that seen with ACE inhibitors (e.g., see Captopril or Enalapril). Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth retardation, prematurity, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, that is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to candesartan cilexetil. Newborn renal function and blood pressure should be closely monitored.
[*Risk Factor DM if used in 2nd or 3rd trimesters.]
Breast Feeding Summary
No reports describing the use of candesartan cilexetil during human lactation have been located. The drug is excreted into rat milk (1). Because the molecular weight of the active drug, candesartan, is about 440, excretion into human breast milk should also be expected. The effects of this exposure on a nursing infant are unknown. The American Academy of Pediatrics, however, considers ACE inhibitors, a closely related group of antihypertensive agents, to be compatible with breast feeding (see Captopril or Enalapril).
- Product information. Atacand. AstraZeneca LP, 2000.