dicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium (see warnings ). hydrochlorothiazide when given concurrently the following drugs may interact with thiazide diuretics. alcohol, barbiturates, or narcotics potentiation of orthostatic hypotension may occur. antidiabetic drugs (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required. other antihypertensive drugs additive effect or potentiation. cholestyramine and colestipol resins absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. corticosteroids, acth intensified electrolyte depletion, particularly hypokalemia. pressor amines (e.g., norepinephrine) possible decreased response to pressor amines but not sufficient to preclude their use. skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) possible increased responsiveness to the muscle relaxant. lithium generally should not be given with diuretics. diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. refer to the package insert for lithium preparations before use of such preparations with this combination product.

ated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked.

in ii receptor antagonist, cyclosporine or tacrolimus (see precautions: drug interactions ). warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ecg abnormalities. monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ecg. when abnormal, the ecg in hyperkalemia is characterized primarily by tall, peaked t waves or elevations from previous tracings. there may also be lowering of the r wave and increased depth of the s wave, widening and even disappearance of the p wave, progressive widening of the qrs complex, prolongation of the pr interval, and st depression. treatment of hyperkalemia if hyperkalemia occurs in patients taking amiloride and hydrochlorothiazide, the drug should be discontinued immediately. if the serum potassium level exceeds 6.5 meq per liter, active measures should be taken to reduce it. such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. if needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. patients with persistent hyperkalemia may require dialysis. diabetes mellitus in diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including amiloride hydrochloride, even in patients without evidence of diabetic nephropathy. therefore, amiloride and hydrochlorothiazide should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently. amiloride and hydrochlorothiazide should be discontinued at least 3 days before glucose tolerance testing. metabolic or respiratory acidosis antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes. if amiloride and hydrochlorothiazide is given to these patients, frequent monitoring of acid-base balance is necessary. shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.

f this product. hypochloremia usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. in actual salt depletion, appropriate replacement is the therapy of choice. hypokalemia may develop during thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, during concomitant use of corticosteroids or acth, or after prolonged therapy. however, this usually is prevented by the amiloride hydrochloride component of this combination drug product. interference with adequate oral electrolyte intake will also contribute to hypokalemia. hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. amiloride hydrochloride, a component of this combination product, has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone. increases in bun levels have been reported with amiloride hydrochloride and with hydrochlorothiazide. these increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. therefore, when amiloride and hydrochlorothiazide is given to such patients, careful monitoring of serum electrolyte and bun levels is important. in patients with preexisting severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretic therapy including amiloride hydrochloride and hydrochlorothiazide. in patients with renal disease, diuretics may precipitate azotemia. cumulative effects of the components of amiloride hydrochloride and hydrochlorothiazide may develop in patients with impaired renal function. if renal impairment becomes evident, amiloride and hydrochlorothiazide should be discontinued (see contraindications and warnings ).

rials have not demonstrated that combining amiloride and hydrochlorothiazide increases the risk of adverse reactions over those seen with the individual components. the adverse reactions for amiloride and hydrochlorothiazide listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence 1% or less. the incidence for group (1) was determined from clinical studies conducted in the united states (607 patients treated with amiloride and hydrochlorothiazide). the adverse effects listed in group (2) include reports from the same clinical studies and voluntary reports since marketing. the probability of a causal relationship exists between amiloride and hydrochlorothiazide and these adverse reactions, some of which have been reported only rarely. incidence >1% incidence ≤ 1% body as a whole headache reactions occurring in 3% to 8% of patients treated with amiloride hydrochloride and hydrochlorothiazide. (those reactions occurring in less than 3% of the patients are unmarked.) malaise weakness chest pain fatigue/tiredness back pain syncope cardiovascular arrhythmia tachycardia digitalis toxicity orthostatic hypotension angina pectoris digestive nausea/anorexia constipation diarrhea gi bleeding gastrointestinal pain gi disturbance abdominal pain appetite changes abdominal fullness hiccups thirst vomiting anorexia flatulence metabolic elevated serum gout potassium levels dehydration (> 5.5 meq per liter) see warnings . symptomatic hyponatremia see precautions . musculoskeletal leg ache muscle cramps/spasm joint pain nervous dizziness paresthesia/numbness stupor vertigo psychiatric none insomnia nervousness depression sleepiness mental confusion respiratory dyspnea none skin rash flushing pruritus diaphoresis erythema multiforme including stevens-johnson syndrome exfoliative dermatitis including toxic epidermal necrolysis alopecia special senses none bad taste visual disturbance nasal congestion urogenital none impotence nocturia dysuria incontinence renal dysfunction including renal failure gynecomastia other adverse reactions that have been reported with the individual components and within each category are listed in order of decreasing severity: amiloride body as a whole: painful extremities, neck/shoulder ache, fatigability; cardiovascular: palpitation; digestive: activation of probable preexisting peptic ulcer, abnormal liver function, jaundice, dyspepsia, heartburn; hematologic: aplastic anemia, neutropenia; integumentary: alopecia, itching, dry mouth; nervous system/psychiatric: encephalopathy, tremors, decreased libido; respiratory: shortness of breath, cough; special senses: increased intraocular pressure, tinnitus; urogenital: bladder spasms, polyuria, urinary frequency. hydrochlorothiazide digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation; hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; hypersensitivity: anaphylactic reactions, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, purpura; metabolic: electrolyte imbalance (see precautions ), hyperglycemia, glycosuria, hyperuricemia; nervous system/psychiatric: restlessness; special senses: transient blurred vision, xanthopsia; urogenital: interstitial nephritis (see warnings ). postmarketing experience 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.

dicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium (see warnings ). hydrochlorothiazide when given concurrently the following drugs may interact with thiazide diuretics. alcohol, barbiturates, or narcotics potentiation of orthostatic hypotension may occur. antidiabetic drugs (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required. other antihypertensive drugs additive effect or potentiation. cholestyramine and colestipol resins absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. corticosteroids, acth intensified electrolyte depletion, particularly hypokalemia. pressor amines (e.g., norepinephrine) possible decreased response to pressor amines but not sufficient to preclude their use. skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) possible increased responsiveness to the muscle relaxant. lithium generally should not be given with diuretics. diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. refer to the package insert for lithium preparations before use of such preparations with this combination product.

atogenicity studies with amiloride hydrochloride in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts. reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility. at approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred. hydrochlorothiazide teratogenic effects studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 mg and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. there are, however, no adequate and well controlled studies in pregnant women. nonteratogenic effects thiazides cross the placental barrier and appear in cord blood. there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

erving activity in patients receiving kaliuretic-diuretic agents. amiloride hydrochloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. amiloride hydrochloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. this mechanism accounts in large part for the potassium sparing action of amiloride. amiloride hydrochloride usually begins to act within 2 hours after an oral dose. its effect on electrolyte excretion reaches a peak between 6 to 10 hours and lasts about 24 hours. peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. effects on electrolytes increase with single doses of amiloride hydrochloride up to approximately 15 mg. amiloride hydrochloride is not metabolized by the liver but is excreted unchanged by the kidneys. about 50% of a 20 mg dose of amiloride hydrochloride is excreted in the urine and 40% in the stool within 72 hours. amiloride hydrochloride has little effect on glomerular filtration rate or renal blood flow. because amiloride hydrochloride is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops. hydrochlorothiazide the mechanism of the antihypertensive effect of thiazides is unknown. thiazides do not usually affect normal blood pressure. hydrochlorothiazide is a diuretic and antihypertensive. it affects the distal renal tubular mechanism of electrolyte reabsorption. hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. natriuresis may be accompanied by some loss of potassium and bicarbonate. after oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. when plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. at least 61% of the oral dose is eliminated unchanged within 24 hours. hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

dence 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 up to 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 1300 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.