AMURETIC

A pyrazine compound inhibiting sodium reabsorption through sodium channels in renal epithelial cells.

This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct.

Negative potential reduces secretion of potassium and hydrogen ions.

Amiloride is used in conjunction with diuretics to spare potassium loss. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p705).

For use as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or hypertension.

Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents.

It is an antihypertensive, potassium-sparing diuretic that was first approved for use in and helps to treat hypertension and congestive heart failure.

The drug is often used in conjunction with thiazide or loop diuretics.

Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride.

The risk is high in concurrent use of ACE inhibitors or spironolactone.

Patients are also advised not to use potassium-containing salt replacements.

Epithelial sodium channel subunit alpha Inhibitor

Epithelial sodium channel subunit beta Inhibitor Epithelial sodium channel subunit gamma Inhibitor + 1 more target.

Readily absorbed following oral administration.

Amiloride is not metabolized by the liver but is excreted unchanged by the kidneys.

HCl is not metabolized by the liver but is excreted unchanged by the kidneys.

About 50 percent of a 20 mg dose of amiloride HCl is excreted in the urine and 40 percent in the stool within 72 hours.

Plasma half-life varies from 6-9 hours.

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No data are available in regard to overdosage in humans.

The oral

LD of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36-85 mg/kg in rats, depending on the strain.

The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance.

Like other potassium-conserving agents, amiloride may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter) which, if uncorrected, is potentially fatal.

Hyperkalemia occurs commonly (about 10%) when amiloride is used without a kaliuretic diuretic.

This incidence is greater in patients with renal impairment, diabetes mellitus (with or without recognized renal insufficiency), and in the elderly.

When amiloride is used concomitantly with a thiazide diuretic in patients without these complications, the risk of hyperkalemia is reduced to about 1-2%.

It is thus essential to monitor serum potassium levels carefully in any patient receiving amiloride, particularly when it is first introduced, at the time of diuretic dosage adjustments, and during any illness that could affect renal function.

The risk of hyperkalemia may be increased when potassium-conserving agents, including amiloride HCl, are administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus.

Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities.

Monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ECG.

When abnormal, the ECG in hyperkalemia is characterized 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 and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression.

Treatment of hyperkalemia

If hyperkalemia occurs in patients taking amiloride HCl, the drug should be discontinued immediately.

If the serum potassium level exceeds 6.5 mEq per liter, active measures should be taken to reduce it.

Such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation.

If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema.

Patients with persistent hyperkalemia may require dialysis.

In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including amiloride HCl, even in patients without evidence of diabetic nephropathy.

Therefore, amiloride HCl should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently.

HCl should be discontinued at least 3 days before glucose tolerance testing.

Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes.

If amiloride

HCl is given to these patients, frequent monitoring of acid-base balance is necessary.

Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.

HCl should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter).

Antikaliuretic Therapy or Potassium Supplementation Amiloride

HCl 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 amiloride HCl 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 HCl.

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.

HCl is contraindicated in patients who are hypersensitive to this product.

HCl should be administered with food.

HCl, one 5 mg tablet daily, should be added to the usual antihypertensive or diuretic dosage of a kaliuretic diuretic.

The dosage may be increased to 10 mg per day, if necessary.

More than two 5 mg tablets of amiloride HCl daily usually are not needed, and there is little controlled experience with such doses.

If persistent hypokalemia is documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with careful monitoring of electrolytes.

In treating patients with congestive heart failure after an initial diuresis has been achieved, potassium loss may also decrease and the need for amiloride HCl should be re-evaluated.

Dosage adjustment may be necessary.

Maintenance therapy may be on an intermittent basis.

If it is necessary to use amiloride HCl alone See INDICATIONS, the starting dosage should be one 5 mg tablet daily.

This dosage may be increased to 10 mg per day, if necessary.

More than two 5 mg tablets usually are not needed, and there is little controlled experience with such doses.

Each yellow compressed tablet contains 5 mg of anhydrous Amiloride HCl and is debossed “Par 117”.

Store at controlled room temperature 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container as defined in the USP.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Teratogenicity studies with amiloride

HCl in rabbits and mice given and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts.

Reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility.

At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred.

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.

Studies in rats have shown that amiloride is excreted in milk in concentrations higher than those found in blood, but it is not known whether amiloride is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from amiloride HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of amiloride

HCI did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. See CONTRAINDICATIONS, Impaired Renal Function..