Tablets USP 50/5mg
Diuretic - Antihypertensive
PHARMACOLOGY: APO-AMILZIDE (hydrochlorothiazide and amiloride
hydrochloride) is a diuretic/antihypertensive combining the potent natriuretic
action of hydrochlorothiazide with the potassium conserving property of amiloride
hydrochloride. The mild diuretic and antihypertensive actions of amiloride
hydrochloride are additive to the natriuretic, diuretic and antihypertensive activity
of the thiazide while minimizing the loss of potassium and lessening the likelihood
of acid base imbalance. The onset of the diuretic action of APO-AMILZIDE is
within 1 to 2 hours and this action appears to be sustained for approximately
Hydrochlorothiazide : Hydrochlorothiazide is a diuretic and antihypertensive
agent. It affects the renal tubular mechanism of electrolyte reabsorption.
Hydrochlorothiazide increases excretion of sodium and chloride in approximately
equivalent amounts and may cause a simultaneous, usually minimal, loss of
bicarbonate. Natriuresis is usually accompanied by some loss of potassium.
The mechanism of the antihypertensive effect of thiazides may be related to
the excretion and redistribution of body sodium. Hydrochlorothiazide usually
does not decrease normal blood pressure. The onset of the diuretic action of
hydrochlorothiazide occurs in 2 hours and the peak action in about 4 hours.
Diuretic activity lasts about 6 to 12 hours. Hydrochlorothiazide is eliminated
rapidly by the kidney.
Amiloride Hydrochloride : Amiloride hydrochloride is an antikaliuretic drug with
mild natriuretic diuretic and antihypertensive activity. These activities may be
additive to the effects of thiazides or other saluretic diuretic agents. The principal
use of amiloride hydrochloride is to conserve potassium in selected patients
receiving kaliuretic-diuretic agents. The action is not related to the level of
aldosterone excretion. Amiloride hydrochloride is not an aldosterone antagonist.
The drug acts directly on the distal portion of the nephron. Amiloride hydrochloride
causes an increase in sodium excretion and a decrease in potassium and
hydrogen ion excretion. Chloride excretion may remain unchanged or increase
slowly with continued therapy. Approximately 50% of an oral dose is absorbed.
Amiloride hydrochloride usually begins to act within 2 hours after an oral dose. Its
effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts
about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and plasma half-
life varies from 6 to 9 hours. Amiloride hydrochloride is not metabolized by the
liver. About 50% of a 20mg dose amiloride hydrochloride is excreted unchanged
in the urine and 40% is excreted in the stool within 72 hours. In clinical studies
amiloride hydrochloride was found to have little effect on glomerular filtration
rate or renal blood flow. Bioavailability studies were performed using normal
human volunteers. The rate and extent of absorption after a single oral dose of
5mg amiloride and 50mg hydrochlorothiazide in the form of APO-AMILZIDE 5-50mg and Moduret 5-50mg was measured and compared. The results can be
summarized as follows:
|AUC 0-24 (ng-hr/ml)
|AUC 0-24 (ng-hr/ml)
|*SD - Standard Deviation
INDICATIONS AND CLINICAL USES: Fixed-dose combination drugs are not
indicated for initial therapy. Patients should be titrated on the individual drugs.
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 drugs. APO-AMILZIDE (hydrochlorothiazide and amiloride hydrochloride) is indicated
in the maintenance therapy of: patients with hepatic cirrhosis with ascities and
edema. Patients with edema of cardiac origin or with arterial hypertension
who are hypokalemic or in whom maintenance of normal potassium levels is
considered to be clinically important i.e., digitalized patients, patients in whom
adequate dietary intake of potassium is not feasible or patients with cardiac
arrhythmias. _: Amiloride hydrochloride used alone may provide satisfactory
diuresis with diminished potassium loss and with a reduced risk of metabolic
alkalosis. In resistant cases amiloride hydrochloride may be used with kaliuretic
diuretic agents to help produce satisfactory diuretics, while maintaining a more
balanced serum electrolyte pattern. As with all therapy for the ascites of hepatic
cirrhosis, gradual weight loss and avoidance of electrolyte imbalance are the
chief objectives (see PRECAUTIONS).
CONTRAINDICATIONS: Hyperkalemia : APO-AMILZIDE (hydrochlorothiazide
and amiloride hydrochloride) should not be used in the presence of elevated
serum potassium levels (see WARNINGS). Antikaliuretic Therapy or Potassium
Salts : Other antikaliuretic agents and potassium supplements are contraindicated
in patients receiving APO-AMILZIDE (such combination therapy is commonly
associated with rapid increases in plasma potassium levels). Impaired Renal
Function : Anuria, acute renal failure, severe or progressive renal disease and
diabetic nephropathy are contraindications to the use of APO-AMILZIDE (see
WARNINGS). Hypersensitivity : APO-AMILZIDE is contraindicated in patients
who are hypersensitive to either component or to other sulfonamide derived
WARNINGS : Hvperkalemia: Hyperkalemia, i.e. serum potassium levels over
5.5mEq per litre, has been observed in some patients who received amiloride
hydrochloride either alone or with diuretics. This has been noted particularly in
elderly patients, in diabetic patients, and in hospitalized patients with hepatic
cirrhosis or cardiac edema who had known renal impairment, were seriously
ill, or were receiving vigorous diuretic therapy. Since fatalities have occurred
in such patients, they should be monitored carefully for clinical, laboratory
and electrocardiographic (ECG) evidence of hyperkalemia and for acidoses.
Monitoring of the serum potassium level is important because hyperkalemia
is not always associated with an abnormal ECG. 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 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 APO-AMILZIDE (hydrochlorothiazide and amiloride hydrochloride), the drug should
be discontinued immediately. If the serum potassium level exceeds 6.5mEq per
litre, active measures should be taken to reduce it. Such measures include the
intravenous administration of sodium bicarbonate solution or oral or parenteral.
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. Diabetes Mellitus: In diabetic patients hyperkalemia has been commonly
reported with the use of amiloride hydrochloride, particularly if they have chronic
renal disease or pre-renal azotemia. Some deaths occurred in this last group
of patients. Therefore, if therapy with amiloride hydrochloride is considered
essential, the drug should be used with caution in diabetic or suspected diabetic
patients and only after first determining the status of renal function. Careful
monitoring of serum potassium levels is required throughout the therapy.
One patient with poorly controlled diabetes mellitus who became severely
hyperkalemia while on amiloride hydrochloride died following two repeated
intravenous glucose tolerance tests. Therefore, amiloride hydrochloride should
be discontinued at least 3 days before glucose tolerance testing. In diabetic
patients, insulin requirements may be increased, decreased or unchanged due to
the hydrochlorothiazide component. Diabetes mellitus which has been latent may
become manifest during administration of thiazide diuretics.
Metabolic or Respiratory Acidosis: Antikaliuretic therapy should be instituted only
with caution in patients in whom respiratory or metabolic acidosis may occur,
such as patients with cardiopulmonary disease or diabetes. If APO-AMILZIDE 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. Impaired Renal Function: Patients with impaired renal
function other than those listed under CONTRA-INDICATIONS and who have
BUN levels over 30mg per 100ml, serum creatinine levels over 1.5mg per 100ml,
or blood urea values over 60mg per 100ml, should not receive the drug without
careful, frequent monitoring of serum electrolyte, creatinine and BUN levels.
Potassium retention associated with the use of APO-AMILZIDE is accentuated
in the presence of renal impairment and may result in the rapid development of
hyperkalemia. Prolongation of amiloride hydrochloride excretion was observed in
patients with renal impairment.