ium and greatly increase the risk of lithium toxicity. refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide. non-steroidal anti-inflammatory drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained. drug/laboratory test interactions: thiazides should be discontinued before carrying out tests for parathyroid function (see precautions, general ). carcinogenesis, mutagenesis, impairment of fertility: two-year feeding studies in mice and rats conducted under the auspices of the national toxicology program (ntp) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of approximately 100 mg/kg/day). the ntp, however, found equivocal evidence for hepatocarcinogenicity in male mice. hydrochlorothiazide was not genotoxic in vitro in the ames mutagenicity assay of salmonella typhimurium strains ta 98, ta 100, ta 1535, ta 1537, and ta 1538 and in the chinese hamster ovary (cho) test for chromosomal aberrations, or in vivo in 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 only in the in vitro cho sister chromatid exchange (clastogenicity) and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1,300 mcg/ml, and in the aspergillus nidulans non-disjunction assay at an unspecified concentration. 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, respectively, prior to conception and throughout gestation.

iction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. there is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. if this edema produces discomfort, increased recumbency will often provide relief. in rare instances this edema may cause extreme discomfort which is not relieved by rest. in these cases a short course of diuretics may provide relief and may be appropriate.

nts, thiazides may precipitate azotemia.

monitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. metabolic: electrolyte imbalance (see precautions ), hyperglycemia, glycosuria, hyperuricemia. musculoskeletal: muscle spasm. nervous system/psychiatric: vertigo, paresthesia, dizziness, headache, restlessness. renal: renal failure, renal dysfunction, interstitial nephritis (see warnings ). skin: erythema multiforme including stevens-johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia. special senses: transient blurred vision, xanthopsia. urogenital: impotence. whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn. postmarketing experience: the following adverse reaction has been identified during post-approval use of hydrochlorothiazide. because the reaction is reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure. non-melanoma skin cancer : 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. to report suspected adverse reactions, contact alembic pharmaceuticals limited at 1-866-210-9797 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

ium and greatly increase the risk of lithium toxicity. refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide. non-steroidal anti-inflammatory drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained. drug/laboratory test interactions: thiazides should be discontinued before carrying out tests for parathyroid function (see precautions, general ). carcinogenesis, mutagenesis, impairment of fertility: two-year feeding studies in mice and rats conducted under the auspices of the national toxicology program (ntp) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of approximately 100 mg/kg/day). the ntp, however, found equivocal evidence for hepatocarcinogenicity in male mice. hydrochlorothiazide was not genotoxic in vitro in the ames mutagenicity assay of salmonella typhimurium strains ta 98, ta 100, ta 1535, ta 1537, and ta 1538 and in the chinese hamster ovary (cho) test for chromosomal aberrations, or in vivo in 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 only in the in vitro cho sister chromatid exchange (clastogenicity) and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1,300 mcg/ml, and in the aspergillus nidulans non-disjunction assay at an unspecified concentration. 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, respectively, prior to conception and throughout gestation.

he drug to the mother. pediatric use: safety and effectiveness in pediatric patients have not been established. elderly use: a greater blood pressure reduction and an increase in side effects may be observed in the elderly (i.e., >65 years) with hydrochlorothiazide. starting treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) is therefore recommended. if further titration is required, 12.5 mg increments should be utilized.

failure. peak plasma concentrations are observed within 1 to 5 hours of dosing and range from 70 to 490 ng/ml following oral doses of 12.5 to 100 mg. plasma concentrations are linearly related to the administered dose. concentrations of hydrochlorothiazide are 1.6 to 1.8 times higher in whole blood than in plasma. binding to serum proteins has been reported to be approximately 40% to 68%. the plasma elimination half-life has been reported to be 6 to 15 hours. hydrochlorothiazide is eliminated primarily by renal pathways. following oral doses of 12.5 to 100 mg, 55% to 77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. in patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged. when hydrochlorothiazide capsule is administered with food, its bioavailability is reduced by 10%; the maximum plasma concentration is reduced by 20%, and the time to maximum concentration increases from 1.6 to 2.9 hours. pharmacodynamics: acute antihypertensive effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. with chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased. the exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known. thiazides do not affect normal blood pressure. onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours. clinical studies: in an 87 patient 4-week double-blind, placebo controlled, parallel group trial, patients who received hydrochlorothiazide capsule had reductions in seated systolic and diastolic blood pressure that were significantly greater than those seen in patients who received placebo. in published placebo-controlled trials comparing 12.5 mg of hydrochlorothiazide to 25 mg, the 12.5 mg dose preserved most of the placebo-corrected blood pressure reduction seen with 25 mg.