AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE- amiloride hydrochloride and hydrochlorothiazide tablet
Mylan Pharmaceuticals Inc.
Amiloride hydrochloride and hydrochlorothiazide tablets, USP combine the potassium-conserving action of amiloride hydrochloride with the natriuretic action of hydrochlorothiazide.
Amiloride hydrochloride is designated chemically as 3,5-diamino-6-chloro-N -(diamino-methylene)pyrazinecarboxamide monohydrochloride, dihydrate. It has the following structural formula:
C6 H8 ClN7 O•HCl•2H2 O MW = 302.12
Hydrochlorothiazide is designated chemically as 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It has the following structural formula:
C7 H8 ClN3 O4 S2 MW = 297.74
It is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Each tablet, for oral administration, contains 5 mg of amiloride hydrochloride, USP (calculated on the anhydrous basis) and 50 mg of hydrochlorothiazide, USP. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, lactose monohydrate, magnesium stearate, pregelatinized starch (corn), and sodium lauryl sulfate.
Amiloride hydrochloride and hydrochlorothiazide tablets provide diuretic and antihypertensive activity (principally due to the hydrochlorothiazide component), while acting through the amiloride component to prevent the excessive potassium loss that may occur in patients receiving a thiazide diuretic. Due to its amiloride component, the urinary excretion of magnesium is less with amiloride and hydrochlorothiazide than with a thiazide or loop diuretic used alone (see PRECAUTIONS). The onset of the diuretic action of this product is within 1 to 2 hours and this action appears to be sustained for approximately 24 hours.
Amiloride hydrochloride is a potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. These effects have been partially additive to the effects of thiazide diuretics in some clinical studies. Amiloride hydrochloride has potassium-conserving activity in patients receiving kaliuretic-diuretic agents.
Amiloride hydrochloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone.
Amiloride hydrochloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. This mechanism accounts in large part for the potassium sparing action of amiloride.
Amiloride hydrochloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 to 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Effects on electrolytes increase with single doses of amiloride hydrochloride up to approximately 15 mg.
Amiloride hydrochloride is not metabolized by the liver but is excreted unchanged by the kidneys. About 50% of a 20 mg dose of amiloride hydrochloride is excreted in the urine and 40% in the stool within 72 hours. Amiloride hydrochloride has little effect on glomerular filtration rate or renal blood flow. Because amiloride hydrochloride is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome develops.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Amiloride hydrochloride and hydrochlorothiazide tablets are indicated in those patients with hypertension or with congestive heart failure who develop hypokalemia when thiazides or other kaliuretic diuretics are used alone, or in whom maintenance of normal serum potassium levels is considered to be clinically important, e.g., digitalized patients, or patients with significant cardiac arrhythmias.
The use of potassium-conserving agents is often unnecessary in patients receiving diuretics for uncomplicated essential hypertension when such patients have a normal diet.
Amiloride hydrochloride and hydrochlorothiazide tablets may be used alone or as an adjunct to other antihypertensive drugs, such as methyldopa or beta blockers. Since amiloride hydrochloride and hydrochlorothiazide enhances the action of these agents, dosage adjustments may be necessary to avoid an excessive fall in blood pressure and other unwanted side effects.
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.
Amiloride hydrochloride and hydrochlorothiazide tablets should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter).
Amiloride hydrochloride and hydrochlorothiazide should not be given to patients receiving other potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be used with this product except in severe and/or refractory 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.
Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of amiloride hydrochloride and hydrochlorothiazide. Patients with evidence of renal functional impairment (blood urea nitrogen [BUN] levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus should not receive the drug without careful, frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia.
Amiloride hydrochloride and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to this product, or to other sulfonamide-derived drugs.
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