Like other potassium-conserving diuretic combinations, amiloride and hydrochlorothiazide may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter). In patients without renal impairment or diabetes mellitus, the risk of hyperkalemia with this combination product is about 1% to 2%. This risk is higher in patients with renal impairment or diabetes mellitus (even without recognized diabetic nephropathy). Since hyperkalemia, if uncorrected, is potentially fatal, it is essential to monitor serum potassium levels carefully in any patient receiving amiloride hydrochloride and hydrochlorothiazide, particularly when it is first introduced, at the time of dosage adjustments, and during any illness that could affect renal function.
The risk of hyperkalemia may be increased when potassium-conserving agents, including amiloride hydrochloride and hydrochlorothiazide, are administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus (see PRECAUTIONS: Drug Interactions). 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.
If hyperkalemia occurs in patients taking amiloride and hydrochlorothiazide, 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 hydrochloride, even in patients without evidence of diabetic nephropathy. Therefore, amiloride and hydrochlorothiazide should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently.
Amiloride and hydrochlorothiazide 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 and hydrochlorothiazide 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.
Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Patients should be observed for clinical signs of fluid or electrolyte imbalance: i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hyponatremia and hypochloremia may occur during the use of thiazides and other diuretics. Any chloride deficit during thiazide therapy is generally mild and may be lessened by the amiloride hydrochloride component of this product. Hypochloremia usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). 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.
Hypokalemia may develop during thiazide therapy, especially with brisk diuresis, when severe cirrhosis is present, during concomitant use of corticosteroids or ACTH, or after prolonged therapy. However, this usually is prevented by the amiloride hydrochloride component of this combination drug product.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Amiloride hydrochloride, a component of this combination product, has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone.
Increases in BUN levels have been reported with amiloride hydrochloride and with hydrochlorothiazide. These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when amiloride and hydrochlorothiazide is given to such patients, careful monitoring of serum electrolyte and BUN levels is important. In patients with preexisting severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretic therapy including amiloride hydrochloride and hydrochlorothiazide.
In patients with renal disease, diuretics may precipitate azotemia. Cumulative effects of the components of amiloride hydrochloride and hydrochlorothiazide may develop in patients with impaired renal function. If renal impairment becomes evident, amiloride and hydrochlorothiazide should be discontinued (see CONTRAINDICATIONS and WARNINGS).
In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when amiloride and hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Since indomethacin and potassium-sparing diuretics, including this product, may each be associated with increased serum potassium levels, the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently.
When amiloride hydrochloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, cyclosporine or tacrolimus, the risk of hyperkalemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium (see WARNINGS).
When given concurrently the following drugs may interact with thiazide diuretics.
Potentiation of orthostatic hypotension may occur.
Dosage adjustment of the antidiabetic drug may be required.
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