Attention, chocolate lovers: You may not be able to help yourselves. Swiss and British scientists have linked the widespread love of chocolate to a chemical "signature" that may be programmed into our metabolic systems.
Read more health news
Triamterene and Hydrochlorothiazide Capsules, USP 50 mg/25 mg
Rx only
DESCRIPTION
Triamterene is an antikaliuretic agent and hydrochlorothiazide is a diuretic/antihypertensive agent.
At 50°C, triamterene is practically insoluble in water (less than 0.1%). It is soluble in formic acid, sparingly soluble in methoxyethanol, and very slightly soluble in alcohol.
Triamterene is 2,4,7-triamino-6-phenylpteridine with a chemical formula of C12H11N7 and a molecular weight of 253.27.
The structural formula for triamterene is:
Hydrochlorothiazide is slightly soluble in water. It is soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide. It is sparingly soluble in methanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H -1,2, 4-benzothiadiazine-7-sulfonamide 1,1-dioxide with a chemical formula of C7H8ClN3O4S2 and a molecular weight of 297.73.
The structural formula for hydrochlorothiazide is:
Each capsule for oral administration contains 50 mg triamterene and 25 mg hydrochlorothiazide. Inactive ingredients include: FD & C Red #40, gelatin, lactose (monohydrate), magnesium stearate, povidone, starch (corn), and titanium dioxide.
Meets USP Dissolution Test 2.
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 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 1 hour, peaks at 2 to 3 hours and tapers off during the subsequent 7 to 9 hours.
The bioavailability of the triamterene and hydrochlorothiazide components from this capsule formulation is, in each case about 50% of that observed with an aqueous suspension of the components. (See PRECAUTIONS, Bioavailability).
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 capsules are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.
Triamterene and hydrochlorothiazide capsules are 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.
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.
CONTRAINDICATIONS
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.
Impaired Renal Function
Triamterene and hydrochlorothiazide is contraindicated in patients with anuria, acute and chronic renal insufficiency or significant renal impairment.
Hypersensitivity
Hypersensitivity to either drug in the preparation or to other sulfonamide-derived drugs is a contraindication.
Hyperkalemia
Triamterene and hydrochlorothiazide should not be used in patients with preexisting elevated serum potassium.
WARNINGS
Hyperkalemia
Abnormal elevation of serum potassium levels (greater than or equal to 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.
If hyperkalemia is suspected (warning signs include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because hyperkalemia may not be associated with ECG changes.
If hyperkalemia is present, triamterene 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.
PRECAUTIONS
Diabetes
Caution should be exercised when administering triamterene and hydrochlorothiazide to patients with diabetes, since thiazides may cause hyperglycemia, glycosuria and alter insulin requirements in diabetes. Also, diabetes mellitus may become manifest during thiazide administration.
Bioavailability
The bioavailability of the hydrochlorothiazide and triamterene components of triamterene and hydrochlorothiazide capsules is about 50% of the maximum obtainable with oral therapy. Theoretically, a patient transferred from therapy with hydrochlorothiazide with or without triamterene might show an increase in blood pressure, fluid retention, or change in serum potassium. Extensive clinical experience with triamterene and hydrochlorothiazide capsules, however, suggests that these conditions have not been commonly observed in clinical practice. (See CLINICAL PHARMACOLOGY.)
Impaired Hepatic Function
Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease. Potassium depletion induced by the thiazide may be important in this connection. Administer triamterene and hydrochlorothiazide cautiously and be alert for such early signs of impending coma as confusion, drowsiness and tremor; if mental confusion increases discontinue triamterene and hydrochlorothiazide for a few days. Attention must be given to other factors that may precipitate hepatic coma, such as blood in the gastrointestinal tract or preexisting potassium depletion.
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 less than 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.
Electrolyte Imbalance
Electrolyte imbalance, often encountered in such conditions as heart failure, renal disease or cirrhosis of the liver, may also be aggravated by diuretics and should be considered during triamterene and hydrochlorothiazide therapy when using high doses for prolonged periods or in patients on a salt-restricted diet. Serum determinations of electrolytes should be performed, and are particularly important if the patient is vomiting excessively or receiving fluids parenterally. Possible fluid and electrolyte imbalance may be indicated by such warning signs as: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal symptoms.
Hypochloremia
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. 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.
Renal Stones
Triamterene has been found in renal stones in association with the other usual calculus components. Triamterene and hydrochlorothiazide should be used with caution in patients with a history of renal stones.
Laboratory Tests
Drug Interactions
Drug/Laboratory Test Interactions
Triamterene and quinidine have similar fluorescence spectra; thus, triamterene and hydrochlorothiazide will interfere with the fluorescent measurement of quinidine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long term studies have not been conducted with triamterene and hydrochlorothiazide combination, or with triamterene alone.
Mutagenesis
Studies of the mutagenic potential of triamterene and hydrochlorothiazide combination, or of triamterene alone have not been performed.
Impairment of Fertility
Studies of the effects of triamterene and hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted.
Pregnancy: Category C
Teratogenic Effects
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.
ADVERSE REACTIONS
Adverse effects are uled in decreasing order of frequency; however, the most serious adverse effects are uled first regardless of frequency. The serious adverse effects associated with triamterene and hydrochlorothiazide capsules have commonly occurred in less than 0.1% of patients treated with this product.
Hypersensitivity: anaphylaxis, rash, urticaria, photosensitivity.
Cardiovascular: arrhythmia, postural hypotension.
Metabolic: diabetes mellitus, hyperkalemia, hyperglycemia, glycosuria, hyperuricemia, hypokalemia, hyponatremia, acidosis, 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.
OVERDOSAGE
Electrolyte imbalance is the major concern (See WARNINGS section). Symptoms reported include: polyuria, nausea, vomiting, weakness, lassitude, fever, flushed face, and hyperactive deep tendon reflexes. If hypotension occurs, it may be treated with pressor agents such as levarterenol to maintain blood pressure. Carefully evaluate the electrolyte pattern and fluid balance. Induce immediate evacuation of the stomach through emesis or gastric lavage. There is no specific antidote.
Reversible acute renal failure following ingestion of 50 tablets of a product containing a combination of 50 mg triamterene and 25 mg hydrochlorothiazide has been reported.
Although triamterene is largely protein-bound (approximately 67%), there may be some benefit to dialysis in cases of overdosage.
DOSAGE AND ADMINISTRATION
The usual dose of triamterene and hydrochlorothiazide capsules 50 mg/25 mg is one or two capsules given once daily, with appropriate monitoring of serum potassium and of the clinical effect. (See WARNINGS, Hyperkalemia.)
HOW SUPPLIED
Triamterene and hydrochlorothiazide capsules for oral administration are available as 50 mg/25 mg: opaque red cap/opaque red body, body and cap imprinted GG 580 in white ink, filled with yellow powder and supplied as:
NDC 0781-2715-01 bottles of 100
NDC 0781-2715-10 bottles of 1000
NDC 0781-2715-13 unit dose packages of 100
Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from light. Protect from moisture.
Dispense in a tight, light-resistant container.
Rev. 07-2006M
7086
Sandoz Inc.
Princeton, NJ 08540