TRIAMTERENE
and
HYDROCHLOROTHIAZIDE
CAPSULES, USP
37.5 mg/25 mg

Each triamterene and hydrochlorothiazide capsule for oral administration contains hydrochlorothiazide 25 mg and triamterene 37.5 mg. Hydrochlorothiazide is a diuretic/antihypertensive agent and triamterene is an antikaliuretic agent.

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 and its structural formula is:

Molecular Formula: C₇H₈ClN₃O₄S₂

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 and its structural formula is:

Molecular Formula: C₁₂H₁₁N₇

Inactive ingredients consist of colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, microcrystalline cellulose, pharmaceutical glaze, polyethylene glycol, polysorbate 80, propylene glycol, silicon dioxide, sodium bicarbonate, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide, yellow iron oxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, and FD&C Red #40 Aluminum Lake.

Triamterene and Hydrochlorothiazide Capsules, USP 37.5 mg/25 mg meet USP Dissolution Test 3.

The triamterene and hydrochlorothiazide capsule 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 capsules 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 of triamterene and hydrochlorothiazide capsules 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.

Triamterene and hydrochlorothiazide capsules are well absorbed.

Upon administration of a single oral dose to fasted normal male volunteers, the following mean pharmacokinetic parameters were determined:

where AUC(0–48), Cmax, Tmax and Ae represent area under the plasma concentration versus time plot, maximum plasma concentration, time to reach Cmax 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 capsules 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.

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 triamterene/25 mg hydrochlorothiazide) 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.

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 capsules may be used alone or as an adjunct to other antihypertensive drugs, such as beta-blockers. Since triamterene and hydrochlorothiazide capsules 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.

Triamterene and hydrochlorothiazide capsules 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 capsules 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 capsules are 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 capsules should not be used in patients with preexisting elevated serum potassium.

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 capsules are employed, frequent evaluations of acid/base balance and serum electrolytes are necessary.

Caution should be exercised when administering triamterene and hydrochlorothiazide capsules 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.

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 capsules cautiously and be alert for such early signs of impending coma as confusion, drowsiness and tremor; if mental confusion increases discontinue triamterene and hydrochlorothiazide capsules 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 is uncommon with triamterene and hydrochlorothiazide capsules; 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 capsules 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, 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.

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.

Triamterene has been found in renal stones in association with the other usual calculus components. Triamterene and hydrochlorothiazide capsules should be used with caution in patients with a history of renal stones.

Triamterene and quinidine have similar fluorescence spectra; thus, triamterene and hydrochlorothiazide will interfere with the fluorescent measurement of quinidine.

Long-term studies have not been conducted with the triamterene/hydrochlorothiazide combination, or with triamterene alone.

Studies of the mutagenic potential of the triamterene/ hydrochlorothiazide combination, or of triamterene alone have not been performed.

Studies of the effects of the triamterene/hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

Electrolyte imbalance is the major concern (see WARNINGS). 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 norepinephrine 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.

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.)

Triamterene and Hydrochlorothiazide Capsules, USP are available containing 37.5 mg triamterene and 25 mg hydrochlorothiazide in opaque olive and opaque rich yellow capsules imprinted in black ink with MYLAN over 2537 on both body and cap. They are available as follows:

NDC 0378-2537-01
bottles of 100 capsules

NDC 0378-2537-10
bottles of 1000 capsules