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Triamterene 50mg/hydrochlorothiazide 25mg tablet: Peach-coloured, round, flat, bevel-edged tablet of 9mm diameter scored on one side.
Hydrochlorothiazide is a thiazide diuretic and acts to reduce the reabsorption of electrolytes from the renal tubules thereby increasing the excretion of sodium chloride, water and potassium to a less extent. A small reduction in carbonic anhydrase activity leads to some increase in sodium bicarbonate. The acid-base balance and pH of the urine are not altered appreciably.
Triamterene inhibits the reabsorption of sodium ions in exchange for potassium and hydrogen ions at the segment of the distal tubule under the control of adrenal mineralocorticoids. Triamterene acts directly on tubular transport and is independent of aldosterone.
By inhibiting the ion exchange mechanism of the distal tubule triamterene reduces the excess loss of potassium, hydrogen and chloride ions induced by hydrochlorothiazide.
Triamterene alone has little or no antihypertensive effect.
TRIZID is a combination of the above two diuretics which utilises their different but complimentary modes of action.
The natriuretic, diuretic and antihypertensive activity of hydrochlorothiazide is supplemented by the mild diuretic and potassium conserving action of triamterene. The combination reduces the risk of hypokalaemia and of acid-base imbalance seen sometimes with the use of hydrochlorothiazide alone. The onset of the diuretic action of TRIZID is within 1 hour, reaches a peak at 2-3 hours and tapers off during the subsequent 7-9 hours.
Hydrochlorothiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations occur between 60 and 120 minutes. Absorption is enhanced when given with food. Hydrochlorothiazide appears to preferentially bind to red blood cells. It also crosses the placental barrier and is excreted into breast milk. It is excreted unchanged into urine, 50% being recovered within the first 12 hours and 70% by 4 days. 11.4-24.5% of an oral dose may appear in the faeces. Reduced renal function may delay elimination. The serum half-life is estimated to be in the range of 3-4 hours with a biological half-life of 12 hours.
In treating hypertension, the antihypertensive effect takes 3-4 days to appear and may last up to several days after discontinuation of chronic therapy. Little is known about the effect of age or reduced hepatic function on the pharmacokinetics of hydrochlorothiazide.
Triamterene is rapidly absorbed from the gastrointestinal tract but to a variable extent (30-70% of the oral dose). The peak plasma concentration of triamterene is reached 2-4 hours after an oral dose and the half-life of the medicine in plasma ranges from 1.5-2 hours. Approximately 50% of the triamterene in plasma is protein bound.
Triamterene undergoes metabolism in the liver. Triamterene and its metabolites are then excreted renally utilising the processes of filtration and tubular secretion. The peak in triamterene renal excretion occurs 1-2 hours after dosing. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene, and 10% as free hydroxytriamterene and triamterene glucuronide. Hydroxytriamterene has diuretic activity.
Fixed-dose combination medicines are not indicated for initial therapy. Patients should be titrated on the individual medicine. If the fixed-combination represents the dosage so determined, its use may be more convenient in patient management. If during maintenance therapy dosage adjustment is necessary it is advisable to use the individual medicines.
TRIZID is to be administered orally, preferably after an adequate meal.
Oedema: The usual dosage is one tablet twice daily after meals. When dry weight is reached, one tablet daily will usually suffice. In some patients, one tablet every other day may be indicated.
Hypertension: The usual dosage is one tablet twice daily after meals. Dosage may be increased or decreased according to patients need. If two or more tablets per day are needed they should be given in divided doses. The maximum daily dose should not exceed four tablets as, at this dose, the incidence of adverse effects may increase.
TRIZID should not be used in patients with pre-existing elevated serum potassium, or in patients who develop hyperkalaemia while on the medicine.
TRIZID is contraindicated in patients with anuria, severe or progressive renal dysfunction, including oliguria and progressively increasing azotemia.
Severe or progressive hepatic dysfunction contraindicates further use of TRIZID.
TRIZID is contraindicated in patients who are hypersensitive to triamterene, hydrochlorothiazide, or other sulfonamide-derived medicines.
Potassium supplementation in the form of medication should not be used routinely in conjunction with TRIZID since hyperkalaemia may result. Abnormal elevation of serum potassium, although uncommon, is potentially the most serious electrolyte disturbance. Hyperkalaemia has been reported (overall incidence less than 8%) and in some cases has been associated with cardiac irregularities.
Hyperkalaemia is more likely to occur in patients who are seriously ill, have known renal impairment, or in elderly (incidence approximately 12%) or diabetic patients with confirmed or suspected renal insufficiency. Fatalities have been reported in such patients. All patients on TRIZID should be monitored carefully for clinical laboratory and electrocardiographic evidence of hyperkalemia and for acidosis.
Combination therapy with other potassium-conserving agents is potentially hazardous, since both can cause potassium retention and, in some cases, hyperkalemia. Such combination therapy should not be used routinely. If it is deemed essential the patient must be under close supervision and serum potassium levels determined frequently.
Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock and ECG abnormalities.
When abnormal, the ECG in hyperkalemia is characterised primarily by tall, peaked T waves or elevations from previous tracings.
There may also be lowering of the R wave and increased depth of the S wave, widening or disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression.
If hyperkalemia develops, discontinue TRIZID, substitute the thiazide alone and restrict dietary potassium intake. When indicated by the clinical situation, excess potassium may be removed by dialysis or oral or rectal administration of sodium polystyrene sulfonate. Infusion of glucose and insulin has also been used to treat hyperkalemia.
TRIZID should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Since triamterene has been found in renal stones, this should be taken into consideration before TRIZID is administered to patients who have a history of renal stones.
Use in Pregnancy: Thiazides cross the placental barrier and appear in cord blood. Triamterene has been shown to do the same in ewes and this may occur in humans. The use of TRIZID in women who are, or may become, pregnant requires that the anticipated benefits to the mother be weighed against possible risks to the fetus. Hazards include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occured in the adult.
Use in Nursing Mothers: Thiazides appear in breast milk and triamterene appears in cows milk. TRIZID should be discontinued or the patient should stop nursing.
Use in Children: The safety for use of TRIZID in children has not been established.
Careful checks should be kept for signs of fluid or electrolyte imbalance (hyperkalemia, hyponatremia, hypokalemia and hypochloremic alkalosis). Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.
Because of the potassium-sparing characteristics of triamterene, hypokalemia occurs less frequently with TRIZID than with thiazides alone. The effects of digitalis on the heart may be exaggerated in patients with hypokalemia and signs of digitalis intoxication may be seen at doses previously tolerated. Triamterene may cause a decreasing alkali reserve with the possibility of metabolic acidosis.
Thiazides can precipitate hepatic coma in patients with severe liver disease. Potassium depletion induced by the thiazide may be important in this connection. Administer TRIZID cautiously and be alert for such early signs of impending coma as confusion, drowsiness and tremor; if mental confusion increases discontinue TRIZID 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.
Any chloride deficit is generally mild and usually does not require specific treatment. A chloride deficit may be corrected by the use of ammonium chloride (except in patients with hepatic disease) and largely prevented by a near normal salt intake.
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.
Increases in urea nitrogen level and/or creatinine level have been reported. This apparently is secondary to a reversible reduction of glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia). Levels usually return to normal when TRIZID is discontinued. Careful monitoring of BUN or serum creatinine levels is important when administering TRIZID. If azotemia increases discontinue TRIZID ( see contraindications ).
Calcium excretion is decreased by thiazides. Pathological 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 renal lithiasis, bone resorption, and peptic ulceration have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function.
Hyperuricemia may occur or gout may be precipitated in certain patients receiving thiazide therapy.
Thiazides may cause hyperglycemia and glycosuria and may alter insulin requirements in diabetics.
Patients should be observed regularly for the possible occurrence of blood dyscrasias, liver damage, or other idiosyncratic reactions. There have been reports of blood dyscrasias in patients receiving triamterene.
Leukopenia, thrombocytopenia, agranulocytosis, and aplastic anemia have been reported with thiazides.
Cirrhotics with splenomegaly may have marked variations in their blood pictures - including thrombocyte and leukocyte levels - which are not related to medicine therapy. Since the triamterene component of TRIZID is a weak folic acid antagonist, it may contribute to the appearance of megaloblastosis in cases where folic acid stores are depleted. Periodic blood studies in these patients are recommended.
Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
The possibility of exacerbation or activation of systemic lupus erythmatosus has been reported.
Hydrochlorothiazide decreases arterial responsiveness to noradrenaline. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
The antihypertensive effect of TRIZID may be enhanced in the post-sympathectomy patient.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, or narcotics.
Thiazide medicines may increase the responsiveness to tubocurarine.
Lithium generally should not be given with diuretics because they reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Toxicology: Reproductive studies in rats and mice and a teratology study in rabbits showed no evidence of effects due to the administration of hydrochlorothiazide or triamterene.
The results of a reproductive study on three groups of 40 male and female rats given a 2:1 combination of triamterene and hydrochlorothiazide prior to mating and through two litters indicated that there was no significant difference between the parent rat mortality viability, live birth index, litter size, birth weight of the control, low dose (9mg/kg/day) and high dose group (12mg/kg/day). However, the dose given to the "high dose group" was reduced from 30mg/kg/day on day 5 to 15mg/kg/day, and on day 52 to 12mg/kg/day. This was said to be because of weight loss in this group.
Three rats were born with congenital abnormalities (hydrops): one from each of the groups.
The following adverse reactions have been associated with the use of thiazide diuretics and/or triamterene.
Gastrointestinal: Dry mouth, anorexia, gastric irritation, nausea, vomiting, cramps, diarrhea, constipation, jaundice (intra-hepatic cholestatic), pancreatitis, sialadenitis.
Note: Symptoms of nausea and vomiting can also indicate electrolyte imbalance ( see warnings and precautions ).
Central Nervous System: Dizziness, vertigo, paresthesia, headache, xanthopsia.
Dermatologic - Hypersensitivity: Purpura, photosensitivity, rash, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including penumonitis, anaphylactic reactions.
Hematologic: Leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia.
Cardiovascular: Orthostatic hypotension.
Renal: Triamterene (and its metabolite p-hydroxy-triamterene) have been found in renal stones in association with the usual components. Rare cases of interstitial nephritis have been reported.
Electrolyte Imbalance: ( see warnings and precautions ).
Miscellaneous: Hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, transient blurred vision.
Newborn, whose mothers had received thiazides during pregnancy, in rare instances have developed thrombocytopenia or pancreatitis.
Combination therapy with potassium supplements or other potassium-conserving agents is potentially hazardous since hyperkalemia may result.
Thiazides may cause hyperglycemia, and glycosuria and therefore alter insulin requirements in diabetics.
Hydrochlorothiazide decreases arterial responsiveness to noradrenaline but the diminution is insufficient to preclude the effectiveness of noradrenaline in therapy.
Alcohol, barbiturates and narcotics will potentiate the hypotensive effect of TRIZID.
Thiazides may enhance muscle relaxation induced by tubocurarine.
TRIZID may reduce the renal clearance of lithium thereby increasing the risk of lithium toxicity.
Electrolyte imbalance is the major concern ( see warnings and precautions section ). Symptoms reported include: Polyuria, nausea, 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.
Protect from light and moisture. Keep out of reach of children.
Prescription Medicine.
Bottles of 100 tablets
Chemistry, Hydrochlorothiazide:
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide1,1-dioxide. It has a molecular formula and weight of C7H8ClN3O4S2 and 297.73 respectively.
Chemistry, Triamterene:
Triamterene is 2,4,7-triamino-6-phenylpteridine. Its molecular formula and weight are C12H11N7 and 253.27 respectively.
Douglas Pharmaceuticals Ltd
P O Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
20 August 1999