TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide_capsule

CLINICAL PHARMACOLOGY
Triamterene and hydrochlorothiazide is a diuretic/antihypertensive drug product that combines natriuretic and antikaliuretic effects. Each component complements the action of the other. The hydrochlorothiazide component blocks the reabsorption of sodium and chloride ions, and thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. A portion of the additional sodium presented to the distal tubule is exchanged there for potassium and hydrogen ions. With continued use of hydrochlorothiazide and depletion of sodium, compensatory mechanisms tend to increase this exchange and may produce excessive loss of potassium, hydrogen, and chloride ions. Hydrochlorothiazide also decreases the excretion of calcium and uric acid, may increase the excretion of iodide, and may reduce glomerular filtration rate. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known. The triamterene component of triamterene 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 capsules are well absorbed. Upon administration of a single oral dose to fasted normal male volunteers, mean pharmacokinetic parameters were determined ( Table 1 Table 1. Mean Pharmacokinetic Parameters after Single Oral Dose in Fasted Male Volunteers AUC (0-48) max max max AUC (0-48) ng*h/mL (+/- SD) C max ng/mL (+/- SD) Median T max h Ae Mg (+/- SD) Triamterene 148. 4) Hydroxytriamterene sulfate 1,865 (471) 720 (364) 1. 1) Hydrochlorothiazide 834 (177) 135. 8) A capsule of triamterene and hydrochlorothiazide 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. 90), p-hydroxytriamterene sulfate by about 50% (90% confidence interval = 1. 77), hydrochlorothiazide by about 17% (90% confidence interval = 0. 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. 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 (25 mg hydrochlorothiazide/37. 5 mg triamterene) was 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. 4 mEq/L with the majority of patients having values between 3. 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 P.
Musculoskeletal
Muscle cramps.

INDICATIONS AND USAGE
This fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked. Triamterene and hydrochlorothiazide is indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone. Triamterene and hydrochlorothiazide is also indicated for those patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene and hydrochlorothiazide may be used alone or as an adjunct to other antihypertensive drugs, such as beta-blockers. Since triamterene and hydrochlorothiazide may enhance the action of these agents, dosage adjustments may be necessary. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there 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.
Hypokalemia
Hypokalemia is uncommon with triamterene and hydrochlorothiazide; but, should it develop, corrective measures should be taken such as potassium supplementation or increased intake of potassium-rich foods. Institute such measures cautiously with frequent determinations of serum potassium levels, especially in patients receiving digitalis or with a history of cardiac arrhythmias. If serious hypokalemia (serum potassium < 3.0 mEq/L) is demonstrated by repeat serum potassium determinations, triamterene and hydrochlorothiazide should be discontinued and potassium chloride supplementation initiated. Less serious hypokalemia should be evaluated with regard to other coexisting conditions and treated accordingly.

The usual dose of triamterene and hydrochlorothiazide capsules is one or two capsules given once daily, with appropriate monitoring of serum potassium and of the clinical effect (see WARNINGS, Hyperkalemia ).

Hyperkalemia
Triamterene and hydrochlorothiazide should not be used in patients with pre-existing elevated serum potassium.
Hyperkalemia
Abnormal elevation of serum potassium levels (>=5.5 mEq/liter) can occur with all potassium-sparing diuretic combinations, including triamterene and hydrochlorothiazide. Hyperkalemia is more likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment) and in the elderly or severely ill. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving triamterene and hydrochlorothiazide, when dosages are changed, or with any illness that may influence renal function.
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.
ADVERSE REACTIONS
Adverse effects are listed in decreasing order of severity. Anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, photosensitivity. Arrhythmia, postural hypotension. Diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, hypochloremia. Jaundice and/or liver enzyme abnormalities, pancreatitis, nausea and vomiting, diarrhea, constipation, abdominal pain. 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. Leukopenia, thrombocytopenia and purpura, megaloblastic anemia. Muscle cramps. Weakness, fatigue, dizziness, headache, dry mouth. Impotence, sialadenitis. Thiazides alone have been shown to cause the following additional adverse reactions: Paresthesias, vertigo. Xanthopsia, transient blurred vision. Allergic pneumonitis, pulmonary edema, respiratory distress. Necrotizing vasculitis, exacerbation of lupus. Aplastic anemia, agranulocytosis, hemolytic anemia. Thrombocytopenia and pancreatitis en dash rarely, in newborns whose mothers have received thiazides during pregnancy. Erythema multiforme, including Stevens-Johnson syndrome; exfoliative dermatitis, including toxic epidermal necrolysis. 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. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch.
Cardiovascular
Arrhythmia, postural hypotension.
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.
Central Nervous System
Weakness, fatigue, dizziness, headache, dry mouth.
Central Nervous System
Paresthesias, vertigo.
Respiratory
Allergic pneumonitis, pulmonary edema, respiratory distress.
Hematologic
Aplastic anemia, agranulocytosis, hemolytic anemia.
Skin
Erythema multiforme, including Stevens-Johnson syndrome; exfoliative dermatitis, including toxic epidermal necrolysis. 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. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS
Triamterene and hydrochlorothiazide should not be given to patients receiving other potassium-sparing agents such as spironolactone, amiloride, or other formulations containing triamterene. Concomitant potassium-containing salt substitutes should also not be used. Potassium supplementation should not be used with triamterene and hydrochlorothiazide except in severe cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary. Triamterene and hydrochlorothiazide is contraindicated in patients with anuria, acute and chronic renal insufficiency, or significant renal impairment. Hypersensitivity to either drug in the preparation or to other sulfonamide-derived drugs is a contraindication. Triamterene and hydrochlorothiazide should not be used in patients with pre-existing elevated serum potassium.
Hypersensitivity
Hypersensitivity to either drug in the preparation or to other sulfonamide-derived drugs is a contraindication.
Hypersensitivity
Anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, photosensitivity.

Usage in Pregnancy
The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there 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.
Pregnancy
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. 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. 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.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Neonate and Infancy
Thrombocytopenia and pancreatitis en dash rarely, in newborns whose mothers have received thiazides during pregnancy.

Antikaliuretic Therapy and Potassium Supplementation
Triamterene and hydrochlorothiazide should not be given to patients receiving other potassium-sparing agents such as spironolactone, amiloride, or other formulations containing triamterene. Concomitant potassium-containing salt substitutes should also not be used. Potassium supplementation should not be used with triamterene and hydrochlorothiazide except in severe cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary.
Drug Interactions
Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia. Concurrent use with chlorpropamide may increase the risk of severe hyponatremia. A possible interaction resulting in acute renal failure has been reported in a few patients on triamterene and hydrochlorothiazide when treated with indomethacin, a nonsteroidal anti-inflammatory agent. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene and hydrochlorothiazide. Lithium generally should not be given with diuretics because they reduce its renal clearance and increase the risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy with triamterene and hydrochlorothiazide. Thiazides have been shown to 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. 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 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 potassium up to 30 mEq/L of plasma or up to 65 mEq/L of whole blood when stored for more than 10 days); low-salt milk (may contain potassium up to 60 mEq/L); 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. Information for Patients Non-Melanoma Skin Cancer Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.
Drug/Laboratory Test Interactions
Triamterene and quinidine have similar fluorescence spectra; thus, triamterene and hydrochlorothiazide will interfere with the fluorescent measurement of quinidine.

Hydrochlorothiazide
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 capsules 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.
Hydrochlorothiazide
Hydrochlorothiazide was not genotoxic in in vitro Salmonella typhimurium in vivo Drosophila in vitro Aspergillus nidulans
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.
Triamterene and Hydrochlorothiazide
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