Triamterene and Hydrochlorothiazide Actavis

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 Actavis (hydrochlorothiazide and triamterene) is indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.

Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) is also indicated for those patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked.

Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) may be used alone or as an adjunct to other antihypertensive drugs, such as beta-blockers. Since Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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.

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

Antikaliuretic Therapy and Potassium Supplementation: Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene). 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 Actavis (hydrochlorothiazide and triamterene), 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 Actavis (hydrochlorothiazide and triamterene) 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 administration of Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) is 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.

PRECAUTIONS

Diabetes

Caution should be exercised when administering Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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. 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 Actavis (hydrochlorothiazide and triamterene) cautiously and be alert for such early signs of impending coma as confusion, drowsiness, and tremor; if mental confusion increases discontinue Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) ; 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 Actavis (hydrochlorothiazide and triamterene) 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 therapy with Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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 Actavis (hydrochlorothiazide and triamterene) should be used with caution in patients with a history of renal stones.

Laboratory Tests

Serum Potassium: The normal adult range of serum potassium is 3.5 to 5.0 mEq per liter with 4.5 mEq often being used for a reference point. If hypokalemia should develop, corrective measures should be taken such as potassium supplementation or increased dietary intake of potassium-rich foods.

Institute such measures cautiously with frequent determinations of serum potassium levels. Potassium levels persistently above 6 mEq per liter require careful observation and treatment. Serum potassium levels do not necessarily indicate true body potassium concentration. A rise in plasma pH may cause a decrease in plasma potassium concentration and an increase in the intracellular potassium concentration. Discontinue corrective measures for hypokalemia immediately if laboratory determinations reveal an abnormal elevation of serum potassium.

Discontinue Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) and substitute a thiazide diuretic alone until potassium levels return to normal.

Serum Creatinine and BUN: Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) may produce an elevated blood urea nitrogen level, creatinine level or both. This apparently is secondary to a reversible reduction of glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia) rather than renal toxicity; levels usually return to normal when Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) is discontinued. If azotemia increases, discontinue Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene). Periodic BUN or serum creatinine determinations should be made, especially in elderly patients and in patients with suspected or confirmed renal insufficiency.

Serum PBI: Thiazide may decrease serum PBI levels without sign of thyroid disturbance.

Parathyroid Function: Thiazides should be discontinued before carrying out tests for parathyroid function. Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as bone resorption and peptic ulceration have not been seen.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term studies have not been conducted with Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) (the triamterene/hydrochlorothiazide combination), or with triamterene alone.

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 Actavis (hydrochlorothiazide and triamterene) 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.

Mutagenesis: Studies of the mutagenic potential of Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) (the triamterene/hydrochlorothiazide combination), or of triamterene alone have not been performed.

Hydrochlorothiazide: Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test, and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Impairment of Fertility: Studies of the effects of Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) (the triamterene/hydrochlorothiazide combination), or of triamterene alone on animal reproductive function have not been conducted.

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.

Pregnancy

Category C: Teratogenic Effects: Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) : Animal reproduction studies to determine the potential for fetal harm by Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) have not been conducted. However, a One Generation Study in the rat approximated composition of Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) 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, 3.1 and 6.2 times, respectively, the MRHD.

The safe use of Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) in pregnancy has not been established since there are no adequate and well-controlled studies with Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) in pregnant women. Triamterene and Hydrochlorothiazide Actavis (hydrochlorothiazide and triamterene) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Triamterene: 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: 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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects: 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.

Adverse effects are listed in decreasing order of severity.

Hypersensitivity: Anaphylaxis, rash, urticaria, subacute cutaneous lupus erythematosus-like reactions, photosensitivity.

Cardiovascular: Arrhythmia, postural hypotension.

Metabolic: Diabetes mellitus, hyperkalemia, hypokalemia, hyponatremia, acidosis, hypercalcemia, hyperglycemia, glycosuria, hyperuricemia, 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.

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

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.