decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently caution should be observed in patients undergoing surgery. other considerations concurrent use of hydrochlorothiazide with amphotericin b or corticosteroids or corticotropin (acth) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect. thiazides may add to or potentiate the action of other antihypertensive drugs. see indications and usage for concomitant use with other antihypertensive drugs. the effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustments may be necessary. triamterene and hydrochlorothiazide may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout. the following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 meq of potassium per liter of plasma or up to 65 meq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 meq of potassium per liter); potassium-containing medications (such as parenteral penicillin g potassium); salt substitutes (most contain substantial amounts of potassium). exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake. chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene. the effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.

ere is no satisfactory evidence that they are useful in the treatment of developed toxemia. edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. dependent edema in pregnancy resulting from restriction 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.

amterene and hydrochlorothiazide should be discontinued immediately and a thiazide alone should be substituted. if the serum potassium exceeds 6.5 meq/liter more vigorous therapy is required. the clinical situation dictates the procedures to be employed. these include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. persistent hyperkalemia may require dialysis. the development of hyperkalemia associated with potassium-sparing diuretics is accentuated in the presence of renal impairment (see contraindications section). patients with mild renal functional impairment should not receive this drug without frequent and continuing monitoring of serum electrolytes. cumulative drug effects may be observed in patients with impaired renal function. the renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, the sulfate ester of hydroxytriamterene, have been shown to be reduced and the plasma levels increased following triamterene and hydrochlorothiazide administration to elderly patients and patients with impaired renal function. hyperkalemia has been reported in diabetic patients with the use of potassium-sparing agents even in the absence of apparent renal impairment. accordingly, serum electrolytes must be frequently monitored if triamterene and hydrochlorothiazide is used in diabetic patients. metabolic or respiratory acidosis potassium-sparing therapy should also be avoided in severely ill patients in whom respiratory or metabolic acidosis may occur. acidosis may be associated with rapid elevations in serum potassium levels. if triamterene and hydrochlorothiazide is employed, frequent evaluations of acid/base balance and serum electrolytes are necessary. acute myopia and secondary angle-closure glaucoma hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. untreated acute angle-closure glaucoma can lead to permanent vision loss. the primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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.

decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently caution should be observed in patients undergoing surgery. other considerations concurrent use of hydrochlorothiazide with amphotericin b or corticosteroids or corticotropin (acth) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect. thiazides may add to or potentiate the action of other antihypertensive drugs. see indications and usage for concomitant use with other antihypertensive drugs. the effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustments may be necessary. triamterene and hydrochlorothiazide may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout. the following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassium-sparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 meq of potassium per liter of plasma or up to 65 meq per liter of whole blood when stored for more than 10 days); low-salt milk (may contain up to 60 meq of potassium per liter); potassium-containing medications (such as parenteral penicillin g potassium); salt substitutes (most contain substantial amounts of potassium). exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake. chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene. the effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.

formed 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 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. nonteratogenic effects 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.

and hydrochlorothiazide capsule exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen ions. its natriuretic activity is limited by the amount of sodium reaching its site of action. although it blocks the increase in this exchange that is stimulated by mineralocorticoids (chiefly aldosterone), it is not a competitive antagonist of aldosterone and its activity can be demonstrated in adrenalectomized rats and patients with addison’s disease. as a result, the dose of triamterene required is not proportionally related to the level of mineralocorticoid activity, but is dictated by the response of the individual patients, and the kaliuretic effect of concomitantly administered drugs. by inhibiting the distal tubular exchange mechanism, triamterene maintains or increases the sodium excretion and reduces the excess loss of potassium, hydrogen, and chloride ions induced by hydrochlorothiazide. as with hydrochlorothiazide, triamterene may reduce glomerular filtration and renal plasma flow. via this mechanism it may reduce uric acid excretion although it has no tubular effect on uric acid reabsorption or secretion. triamterene does not affect calcium excretion. no predictable antihypertensive effect has been demonstrated for triamterene. duration of diuretic activity and effective dosage range of the hydrochlorothiazide and triamterene components are similar. onset of diuresis with triamterene and hydrochlorothiazide takes place within one hour, peaks at two to three hours and tapers off during the subsequent seven to nine hours. triamterene and hydrochlorothiazide capsule are well absorbed. upon administration of a single oral dose to fasted normal male volunteers, the following mean pharmacokinetic parameters were determined: auc (0-48) ng*hrs/ml (± sd) c max ng/ml (± sd) median t max hrs ae mg (±sd) triamterene 148.7 (87.9) 46.4 (29.4) 1.1 2.7 (1.4) hydroxytriamterene sulfate 1865 (471) 720 (364) 1.3 19.7 (6.1) hydrochlorothiazide 834 (177) 135.1 (35.7) 2.0 14.3 (3.8) where auc (0-48), c max , t max and ae represent area under the plasma concentration versus time plot, maximum plasma concentration, time to reach c max and amount excreted in urine over 48 hours. one triamterene and hydrochlorothiazide capsule is bioequivalent to a single-entity 25 mg hydrochlorothiazide tablet and 37.5 mg triamterene capsule used in the double-blind clinical trial below. (see clinical trials .) in a limited study involving 12 subjects, coadministration of triamterene and hydrochlorothiazide capsule with a high-fat meal resulted in: (1) an increase in the mean bioavailability of triamterene by about 67% (90% confidence interval = 0.99, 1.90), p-hydroxytriamterene sulfate by about 50% (90% confidence interval = 1.06, 1.77), hydrochlorothiazide by about 17% (90% confidence interval = 0.90, 1.34); (2) increases in the peak concentrations of triamterene and p-hydroxytriamterene; and (3) a delay of up to 2 hours in the absorption of the active constituents. clinical trials a placebo-controlled, double-blind trial was conducted to evaluate the efficacy of triamterene and hydrochlorothiazide capsules. this trial demonstrated that triamterene and hydrochlorothiazide capsules 37.5 mg/25 mg were effective in controlling blood pressure while reducing the incidence of hydrochlorothiazide-induced hypokalemia. this trial involved 636 patients with mild to moderate hypertension controlled by hydrochlorothiazide 25 mg daily and who had hypokalemia (serum potassium <3.5 meq/l) secondary to the hydrochlorothiazide. patients were randomly assigned to 4 weeks’ treatment with once-daily regimens of 25 mg hydrochlorothiazide plus placebo, or 25 mg hydrochlorothiazide combined with one of the following doses of triamterene: 25 mg, 37.5 mg, 50 mg or 75 mg. blood pressure and serum potassium were monitored at baseline and throughout the trial. all five treatment groups had similar mean blood pressure and serum potassium concentrations at baseline (mean systolic blood pressure range: 137±14 mmhg to 140±16 mmhg; mean diastolic blood pressure range: 86±9 mmhg to 88±8 mmhg; mean serum potassium range: 2.3 to 3.4 meq/l with the majority of patients having values between 3.1 and 3.4 meq/l). while all triamterene regimens reversed hypokalemia, at week 4 the 37.5 mg regimen proved optimal compared with the other tested regimens. on this regimen, 81% of the patients had a significant (p<0.05) reversal of hypokalemia vs. 59% of patients on the placebo/hydrochlorothiazide regimen. the mean serum potassium concentration on 37.5 mg triamterene went from 3.2±0.2 meq/l at baseline to 3.7±0.3 meq/l at week 4, a significantly greater (p<0.05) improvement than that achieved with placebo/hydrochlorothiazide (i.e., 3.2±0.2 meq/l at baseline and 3.5±0.4 meq/l at week 4). also, 51% of patients in the 37.5 mg triamterene group had an increase in serum potassium of ≥0.5 meq/l at week 4 vs. 33% in the placebo group. the 37.5 mg triamterene/25 mg hydrochlorothiazide regimen also maintained control of blood pressure; mean supine systolic blood pressure at week 4 was 138±21 mmhg while mean supine diastolic blood pressure was 87±13 mmhg.

ies of the mutagenic potential of the triamterene and hydrochlorothiazide combination, or of triamterene alone have not been performed. hydrochlorothiazide 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 1300 mcg/ml. positive test results were also obtained in the aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. impairment of fertility studies of the effects of the triamterene and hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted. hydrochlorothiazide 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.

systolic blood pressure range: 137±14 mmhg to 140±16 mmhg; mean diastolic blood pressure range: 86±9 mmhg to 88±8 mmhg; mean serum potassium range: 2.3 to 3.4 meq/l with the majority of patients having values between 3.1 and 3.4 meq/l). while all triamterene regimens reversed hypokalemia, at week 4 the 37.5 mg regimen proved optimal compared with the other tested regimens. on this regimen, 81% of the patients had a significant (p<0.05) reversal of hypokalemia vs. 59% of patients on the placebo/hydrochlorothiazide regimen. the mean serum potassium concentration on 37.5 mg triamterene went from 3.2±0.2 meq/l at baseline to 3.7±0.3 meq/l at week 4, a significantly greater (p<0.05) improvement than that achieved with placebo/hydrochlorothiazide (i.e., 3.2±0.2 meq/l at baseline and 3.5±0.4 meq/l at week 4). also, 51% of patients in the 37.5 mg triamterene group had an increase in serum potassium of ≥0.5 meq/l at week 4 vs. 33% in the placebo group. the 37.5 mg triamterene/25 mg hydrochlorothiazide regimen also maintained control of blood pressure; mean supine systolic blood pressure at week 4 was 138±21 mmhg while mean supine diastolic blood pressure was 87±13 mmhg.