Animal reproduction studies to determine the potential for fetal harm by triamterene and hydrochlorothiazide have not been conducted. However, a One Generation Study in the rat approximated composition of triamterene and hydrochlorothiazide by using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day); there was no evidence of teratogenicity at those doses which were, on a body-weight basis, 15 and 30 times, respectively, the MRHD, and on the basis of body surface area, 3.1 and 6.2 times, respectively, the MRHD.
The safe use of triamterene and hydrochlorothiazide in pregnancy has not been established since there are no adequate and well-controlled studies with triamterene and hydrochlorothiazide in pregnant women. Triamterene and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
Reproduction studies have been performed in rats at doses as high as 20 times the MRHD on the basis of body weight and 6 times the human dose on the basis of body surface area without evidence of harm to the fetus due to triamterene.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3,000 and 1,000 mg/kg/day, respectively. At these doses, which are multiples of the MRHD equal to 3,000 for mice and 1,000 for rats, based on body weight, and equal to 282 for mice and 206 for rats, based on body surface area, there was no evidence of harm to the fetus.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of thiazides and triamterene in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possible other adverse reactions which have occurred in the adult.
Thiazides and triamterene in combination have not been studied in nursing mothers. Triamterene appears in animal milk; this may occur in humans. Thiazides are excreted in human breast milk. If use of the combination drug product is deemed essential, the patient should stop nursing.
Long-term studies have not been conducted with the triamterene/hydrochlorothiazide combination or with triamterene alone.
Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP) treated mice and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body-weight basis, these doses are 600 times (in mice) and 100 times (in rats) the maximum recommended human dose (MRHD) for the hydrochlorothiazide component of triamterene and hydrochlorothiazide combination at 50 mg/day (or 1.0 mg/kg/day based on 50-kg individuals). On the basis of body surface area, these doses are 56 times (in mice) and 21 times (in rats) the MRHD. These studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.
Studies of the mutagenic potential of the triamterene/hydrochlorothiazide combination or of triamterene alone have not been performed.
Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1,300 mcg/mL.
Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.
Studies of the effects of the triamterene/hydrochlorothiazide combination or of triamterene alone on animal reproductive function have not been conducted.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding multiples of the MRHD are 100 (mice) and 4 (rats) on the basis of body weight and 9.4 (mice) and 0.8 (rats) on the basis of body surface area.
Adverse effects are listed in decreasing order of severity.
Hypersensitivity: Anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, photosensitivity.
Cardiovascular: Arrhythmia, postural hypotension.
Metabolic: Diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, hypochloremia.
Gastrointestinal: Jaundice and/or liver enzyme abnormalities, pancreatitis, nausea and vomiting, diarrhea, constipation, abdominal pain.
Renal: Acute renal failure (one case of irreversible renal failure has been reported), interstitial nephritis, renal stones composed primarily of triamterene, elevated BUN and serum creatinine, abnormal urinary sediment.
Hematologic: Leukopenia, thrombocytopenia and purpura, megaloblastic anemia.
Musculoskeletal: Muscle cramps.
Central Nervous System: Weakness, fatigue, dizziness, headache, dry mouth.
Miscellaneous: Impotence, sialadenitis.
Thiazides alone have been shown to cause the following additional adverse reactions:
Central Nervous System: Paresthesias, vertigo.
Ophthalmic: Xanthopsia, transient blurred vision.
Respiratory: Allergic pneumonitis, pulmonary edema, respiratory distress.
Other: Necrotizing vasculitis, exacerbation of lupus.
Hematologic: Aplastic anemia, agranulocytosis, hemolytic anemia.
Neonate and infancy: Thrombocytopenia and pancreatitis–rarely, in newborns whose mothers have received thiazides during pregnancy.
Skin: Erythema multiforme, including Stevens-Johnson syndrome; exfoliative dermatitis, including toxic epidermal necrolysis.
Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
