Hydrochlorothiazide / irbesartan Pregnancy and Breastfeeding Warnings

Hydrochlorothiazide / irbesartan is also known as: Avalide

Hydrochlorothiazide / irbesartan Pregnancy Warnings

Drugs, like irbesartan, that act directly on the renin-angiotensin-aldosterone (RAA) system can cause fetal and neonatal morbidity and death when administered during pregnancy. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme (ACE) inhibitors. A committee of the National Institutes of Health has recommended that these drugs be avoided during pregnancy. When pregnancy is detected or expected, HCTZ-irbesartan should be discontinued as soon as possible. The use of drugs that act directly on the RAA system during the second and third trimesters has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the use of these drugs. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist, such as irbesartan, only during the first trimester should be informed. Nonetheless, when a patient becomes pregnant, it is strongly recommended that physicians discontinue the use of HCTZ-irbesartan as soon as possible. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, of whom 233 were exposed to thiazide or related diuretics during the first trimester. An increased risk of malformations was found for thiazide diuretics. Use of thiazides after the first trimester does not seem to carry this risk. Thiazide diuretics may, however pose metabolic risks to the mother and fetus (hyponatremia, hypokalemia, thrombocytopenia, hyperglycemia), and may have a direct effect on smooth muscle, resulting in inhibition of labor. Data from the Michigan Medicaid Birth Defects Study has revealed an association between the use of hydrochlorothiazide (HCTZ) and congenital abnormalities (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). This was a retrospective study of 229,101 completed pregnancies between 1985 and 1992, of which 567 were exposed to HCTZ at some time during the first trimester, and 1,173 were exposed to the drug at any time during pregnancy. Of the 567 pregnancies, there were 24 total and 7 cardiovascular birth defects (22 and 6 were expected, respectively). There were no observations of cleft palate, spina bifida, limb reduction, or hypospadias. The one instance of polydactyly did not achieve statistical significance. These data are consistent with an association between the use of HCTZ and birth defects, although other factors, including underlying disease(s) of the mother are not accounted for. Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

Hydrochlorothiazide (HCTZ)-irbesartan has been assigned to pregnancy category D by the FDA. Animal data have revealed evidence of fetotoxicity associated with the use of irbesartan (renal pelvic cavitation, hydroureter and/or absence of renal papilla) after doses equivalent to maximum recommended human doses (MRHD) and maternal mortality and abortion after doses equivalent to 1.5 times the MRHD after correction for body surface area. Surviving females receiving 1.5 times the MRHD were observed to have an increased incidence of early fetal resorptions and a corresponding decrease in live births. There are no controlled data in human pregnancy. The manufacturer states that when used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. Retrospective reviews have shown an increased risk of malformations associated with thiazide diuretics. Use of HCTZ-irbesartan is considered contraindicated during pregnancy.

Hydrochlorothiazide / irbesartan Breastfeeding Warnings

In one case, a peak milk HCTZ concentration of 125 ng/mL was measured between 4 and 12 hours after a (usual daily) dose of HCTZ 50 mg in one subject. A simultaneously measured maternal serum HCTZ level was approximately 275 ng per mL. There were no detectable drug levels or electrolyte abnormalities in the baby's blood. The authors calculated that, if a 1-month-old infant takes approximately 600 mL of milk per day, and the average milk HCTZ level is approximately 80 ng per mL, the infant would be exposed to approximately 0.05 mg HCTZ a day. This usually represents an insignificant amount of HCTZ to the infant such that adverse effects in the nursing infant are unlikely with regard to this component of this combination drug.

There are no data on the excretion of irbesartan into human milk. Hydrochlorothiazide (HCTZ) is secreted into human milk in low concentrations. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue this combination drug, taking into account the importance of the drug to the nursing mother.

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