Hydrochlorothiazide / timolol Pregnancy and Breastfeeding Warnings

Brand names: Timolide, Timolide 10-25

Hydrochlorothiazide / timolol Pregnancy Warnings

One case in which timolol was administered during human pregnancy has been reported. A woman who was taking timolol ophthalmic drops, acetazolamide, and pilocarpine for glaucoma delivered at 36 weeks gestation. The neonate suffered hyperbilirubinemia, metabolic acidosis, hypocalcemia, and hypomagnesemia postpartum. These complications were believed to be secondary to acetazolamide therapy, and were reversible after treatment.

The use of some beta-blockers during human pregnancy has resulted in persistent bradycardia and other signs of beta-blockade. Close observation for signs and symptoms of beta-blockade for at least 48 hours of newborns whose mothers were taking timolol is recommended.

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.

The Michigan Medicaid surveillance study showed no association between some thiazide diuretics and congenital defects (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). This report is a summary of information from two studies, one in which 390 of 104,000 pregnant women from 1980 to 1983, and one in which 567 of 229,000 pregnant women from 1985 to 1992 received HCTZ. In the first study 28 total defects and 6 cardiovascular defects were observed (25 and 4 were expected, respectively). In the second study, 24 total defects and 7 cardiovascular defects were observed (22 and 6 were expected, respectively). Cleft palate was not observed in either study. These data do not support an association between HCTZ and congenital defects.

Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

Timolol-hydrochlorothiazide (HCTZ) has been assigned to pregnancy category C by the FDA. Animal studies have revealed no evidence of teratogenicity, embryotoxicity, fetotoxicity, or maternal toxicity associated with the combination product. Animal studies have, however, revealed evidence of fetotoxicity (delayed ossification), maternal toxicity, and increased rates of fetal resorptions when timolol alone was given in doses 50 to 1,000 times the maximum recommended human dose (on a per kg basis). Retrospective reviews of the use thiazide diuretics during human pregnancy have shown an increased risk of malformations. There are no controlled data in human pregnancy. Timolol-HCTZ should only be given during pregnancy when benefit outweighs risk.

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Hydrochlorothiazide / timolol Breastfeeding Warnings

Hydrochlorothiazide and timolol are excreted into human milk. No adverse reactions in nursing infants have been reported, but close observation for bradycardia and other signs of beta-blockade in infants exposed to timolol via breast milk is recommended. Timolol is considered compatible with breast-feeding by the American Academy of Pediatrics. Hydrochlorothiazide is considered compatible with breast-feeding by the American Academy of Pediatrics; however, the manufacturer recommends that due to the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Data reveal average milk to maternal plasma timolol level ratios of 0.80 to 0.83. In one series of nine patients, dosages of timolol of 5 mg three times a day were associated with an average milk timolol level of 15.9 ng/mL. After the dosage was increased to 10 mg three times a day in four of the nine patients, the average milk timolol level rose to 41.0 ng/mL.

A case report of a human milk timolol concentration of 5.6 ng/mL 1.5 hours after dosing has been reported in a woman who was receiving timolol 0.5% eye drops to the right eye twice daily. In this case, even if the infant nursed 4 times daily, receiving 75 mL each time, the daily dose to the nursing infant would be below that expected to produce beta-blockade.

A peak milk HCTZ level of 125 ng/mL was measured between 4 and 12 hours after a dose in a woman who was taking HCTZ 50 mg/day. A simultaneously measured maternal serum HCTZ level was approximately 275 ng/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 mean milk HCTZ level is approximately 80 ng/mL, the infant would be exposed to approximately 0.05 mg HCTZ daily. This should represent an insignificant amount of HCTZ to the infant such that adverse effects in the nursing infant are unlikely.

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Further information

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