Hydrochlorothiazide / valsartan Pregnancy and Breastfeeding Warnings

Hydrochlorothiazide / valsartan is also known as: Diovan HCT

Hydrochlorothiazide / valsartan Pregnancy Warnings

Valsartan is similar to angiotensin converting enzyme (ACE) inhibitors, which are contraindicated during pregnancy. Because of the many reports of fetal deaths and malformations associated with the use of ACE inhibitors, a committee of the National Institutes of Health has recommended that these drugs be avoided during pregnancy. Drugs that act on the renin-angiotensin-aldosterone (RAA) system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking ACE inhibitors. When pregnancy is detected, valsartan-HCTZ should be discontinued as soon as possible. The use of drugs that act directly on the RAA system during the second and third trimesters of pregnancy 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 renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have been reported, although it is not clear whether these occurrences were due to exposure to the drug. 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 only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should advise the patient to discontinue the use of valsartan-HCTZ as soon as possible. Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the RAA system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, valsartan-HCTZ should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury! Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Animal data have failed to reveal evidence of teratogenicity when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The doses that were not associated with adverse effects (600, 200, and 2 mg/kg/day) in mice, rats and rabbits, represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. 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 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.

Valsartan-hydrochlorothiazide (HCTZ) has been assigned to pregnancy category D by the FDA. Animal data have revealed evidence of fetotoxicity, but have failed to reveal evidence of teratogenicity. There are no controlled data with the combination in human pregnancy. Spontaneous abortion, oligohydramnios and newborn renal dysfunction have been reported when pregnant women inadvertently took valsartan. 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 valsartan-HCTZ is considered contraindicated during pregnancy.

Hydrochlorothiazide / valsartan Breastfeeding Warnings

There are no data on the excretion of valsartan into human milk. Hydrochlorothiazide (HCTZ) is secreted into 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 the drug, taking into account the importance of valsartan-HCTZ therapy to the nursing mother.

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.

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