TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide_capsule

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, USP 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, USP are similar. Onset of diuresis with triamterene and hydrochlorothiazide capsules, USP 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, USP are well absorbed. Upon administration of a single oral dose to fasted normal male volunteers, mean pharmacokinetic parameters were determined (Table 1). Mean Pharmacokinetic Parameters after Single Oral Dose in Fasted Male Volunteers a AUC (0-48) C max Median max Ae Triamterene 148. 4) Hydroxytriamterene sulfate 1,865 (471) 720 (364) 1. 1) Hydrochlorothiazide 834 (177) 135. 8) a (0-48) max max max 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, USP 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, USP. This trial demonstrated that triamterene and hydrochlorothiazide capsules, USP (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. 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 increase in serum potassium of >=0. 5 mEq/L at Week 4 vs. 33% in the placebo group. 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, USP are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone. Triamterene and hydrochlorothiazide capsules, USP 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, USP may be used alone or as an adjunct to other antihypertensive drugs, such as beta-blockers. Since triamterene and hydrochlorothiazide capsules, USP may enhance the action of these agents, dosage adjustments may be necessary. Usage in Pregnancy: 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 capsules, USP; 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, USP 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, USP is 1 or 2 capsules given once daily, with appropriate monitoring of serum potassium and of the clinical effect (see WARNINGS, Hyperkalemia

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, USP. 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, USP, when dosages are changed, or with any illness that may influence renal function.
ADVERSE REACTIONS
Adverse effects are listed in decreasing order of severity. Hypersensitivity: Cardiovascular: Metabolic: Gastrointestinal: Renal: Hematologic: Musculoskeletal: Central Nervous System: Miscellaneous: Thiazides alone have been shown to cause the following additional adverse reactions: Central Nervous System: Ophthalmic: Respiratory: Other: Hematologic: Neonate and infancy: Skin: Postmarketing Experience: Non-Melanoma Skin Cancer:

Antikaliuretic Therapy and Potassium Supplementation: Potassium supplementation should not be used with triamterene and hydrochlorothiazide capsules, USP 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: Hypersensitivity: Hyperkalemia:

Triamterene and hydrochlorothiazide capsules, USP: The safe use of triamterene and hydrochlorothiazide capsules, USP in pregnancy has not been established since there are no adequate and well-controlled studies with triamterene and hydrochlorothiazide capsules, USP in pregnant women. Triamterene and hydrochlorothiazide capsules, USP should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Triamterene: Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Hydrochlorothiazide: There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 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.

Drug Interactions:
Angiotensin-Converting Enzyme Inhibitors: Oral Hypoglycemic Drugs: Nonsteroidal Anti-inflammatory Drugs: Lithium: Surgical Considerations: Other Considerations: 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 capsules, USP 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.
Drug/Laboratory Test Interactions:
Triamterene and quinidine have similar fluorescence spectra; thus, triamterene and hydrochlorothiazide capsules, USP will interfere with the fluorescent measurement of quinidine.

WARNINGS
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, USP. 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, USP, 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, USP 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 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, USP are used in diabetic patients. Metabolic or Respiratory Acidosis: Acute Myopia and Secondary Angle-Closure Glaucoma:.
Carcinogenesis,Mutagenesis, Impairment of Fertility:
Carcinogenesis: Hydrochlorothiazide: Mutagenesis: Hydrochlorothiazide: Salmonella typhimurium Drosophila Positive test results were also obtained in the Aspergillus nidulans Impairment of Fertility: Hydrochlorothiazide :
OVERDOSAGE
Electrolyte imbalance is the major concern (see WARNINGS 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.

REMEDYREPACK INC.

TRIAMTERENE AND HYDROCHLOROTHIAZIDE- triamterene and hydrochlorothiazide_capsule Product manual source documgent