Triamterene and Hydrochlorothiazide: Package Insert and Label Information

TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide capsule
NuCare Pharmaceuticals,Inc.

DESCRIPTION

Each capsule of triamterene and hydrochlorothiazide for oral use, with opaque yellow cap and opaque white body, contains triamterene 37.5 mg and hydrochlorothiazide 25 mg, and is imprinted with 855. Hydrochlorothiazide is a diuretic/antihypertensive agent and triamterene is an antikaliuretic agent.

Hydrochlorothiazide, USP is very slightly soluble in water. It is freely soluble in sodium hydroxide solution, n-butylamine and dimethyl formamide. It is sparingly soluble in methanol. It is insoluble in ether, chloroform and dilute mineral acids.

Hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2 H-1, 2, 4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is:

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Triamterene, USP is soluble in formic acid. It is sparingly soluble in methoxyethanol. It is very slightly soluble in acetic acid, alcohol and dilute mineral acids. It is practically insoluble in water, benzene, ether, chloroform and dilute alkali hydroxides.

Triamterene, USP is 2, 4, 7-triamino-6-phenylpteridine and its structural formula is:

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Each triamterene and hydrochlorothiazide capsule, USP intended for oral administration contains 37.5 mg triamterene USP with 25 mg hydrochlorothiazide USP. In addition, each capsule contains the following inactive ingredients: citric acid monohydrate, colloidal silicon dioxide, croscarmellose sodium, gelatin, glycine, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and titanium dioxide. Each capsule is printed with black pharmaceutical ink which contains ferric oxide black, potassium hydroxide and shellac.

Capsules of triamterene and hydrochlorothiazide meet Drug Release Test 3 as published in the current USP monograph for Triamterene and Hydrochlorothiazide Capsules.

CLINICAL PHARMACOLOGY

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, mean pharmacokinetic parameters were determined (Table 1).

Table 1. Mean Pharmacokinetic Parameters after Single Oral Dose in Fasted Male Volunteers a
AUC (0-48) ng*h/mL SD) C max ng/mL SD) Median T max h Ae Mg SD)
Triamterene 148.7 (87.9) 46.4 (29.4) 1.1 2.7 (1.4)
Hydroxytriamterene sulfate 1,865 (471) 720 (364) 1.3 19.7 (6.1)
Hydrochlorothiazide 834 (177) 135.1 (35.7) 2 14.3 (3.8)

a 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.

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 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.

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 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 5 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.

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 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.

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 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.

Impaired Renal Function

Triamterene and hydrochlorothiazide capsules are 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 capsules should not be used in patients with pre-existing 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 capsules. 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 capsules, 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 capsules should be discontinued immediately and a thiazide alone should be substituted. If the serum potassium exceeds 6.5 mEq/L 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). 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 administration of triamterene and hydrochlorothiazide 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 capsules are 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 capsules are 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.

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