Moduret (Amiloride / Hydrochlorothiazide)

MODURET®

MSD

Hydrochlorothiazide – Amiloride HCl

Diuretic – Antihypertensive

Action And Clinical Pharmacology: Moduret is a diuretic/antihypertensive combining the potent natriuretic action of hydrochlorothiazide with the potassium conserving property of amiloride. The mild diuretic and antihypertensive actions of amiloride 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 is within 1 to 2 hours and this action appears to be sustained for approximately 24 hours.

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 mimimal, 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: Amiloride 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 is to conserve potassium in selected patients receiving kaliuretic-diuretic agents. The action is not related to the level of aldosterone excretion. Amiloride is not an aldosterone antagonist. The drug acts directly on the distal portion of the nephron. Amiloride 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 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 is not metabolized by the liver. About 50% of a 20 mg dose of amiloride is excreted unchanged in the urine and 40% is excreted in the stool within 72 hours. In clinical studies amiloride was found to have litle effect on glomerular filtration rate or renal blood flow.

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.

Moduret is indicated in the maintenance therapy of patients with hepatic cirrhosis with ascites and edema. In those 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 e.g., digitalized patients, patients in whom adequate dietary intake of potassium is not feasible or patients with cardiac arrhythmias.

Hepatic Cirrhosis with Ascites and Edema: Amiloride used alone may provide satisfactory diuresis with diminished potassium loss and with a reduced risk of metabolic alkalosis. In resistant cases amiloride may be used with kaliuretic diuretic agents to help produce satisfactory diuresis, 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).

Contra-Indications: Hyperkalemia: Moduret should not be used in the presence of elevated serum potasssium levels (see Warnings).

Antikaliuretic Therapy or Potassium Salts: Other antikaliuretic agents and potassium supplements are contraindicated in patients receiving Moduret (such combination therapy is commonly associated with rapid increases in plasma potassium levels).

Impaired Renal Function: Anuria, acute renal failure, severe or progresssive renal disease, and diabetic nephropathy are contraindications to the use of Moduret (see Warnings).

Hypersensitivity: in patients who are hypersensitive to either component, or to other sulfonamide-derived drugs.

Manufacturers’ Warnings In Clinical States: Hyperkalemia: Hyperkalemia, i.e., serum potassium levels over 5.5 mEq/L, has been observed in some patients who received amiloride 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 acidosis. Monitoring of the serum potassium level is important because hyperkalemia is not always associated with an abnormal ECG.

Warning signs and 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 Moduret the drug should be discontinued immediately. If the serum potassium level exceeds 6.5 mEq/L, 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.

Diabetes Mellitus: In diabetic patients, hyperkalemia has been commonly reported with the use of amiloride, particularly if they have chronic renal disease or prerenal azotemia. Some deaths occurred in this last group of patients. Therefore, if therapy with amiloride 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 hyperkalemic while on amiloride died following 2 repeated i.v. glucose tolerance tests. Therefore, amiloride 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 Moduret is given to the 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 Contraindications and who have BUN levels over 30 mg/100 mL, serum creatinine levels over 1.5 mg/100 mL, or blood urea values over 60 mg/100 mL should not receive the drug without careful, frequent monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of Moduret 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.

Precautions: Electrolyte Imbalance and BUN Increases: Hyponatremia and hypochloremia may occur during the use of Moduret. Hypokalemia may also occur although the incidence is less than with thiazides alone. Any chloride deficit is usually mild and may be corrected by the use of ammonium chloride (except in patients with hepatic disease) and largely prevented by a near normal salt intake. Increases in BUN levels have been reported and have usually accompanied vigorous fluid elimination, especially when diuretic combinations were used in seriously ill patients, such as those who have hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, careful monitoring of serum electrolytes and BUN levels is important when using Moduret.

In patients with impaired renal function azotemia may be precipitated or increased by hydrochlorothiazide. Careful monitoring of such patients is therefore necessary. If increasing azotemia and oliguria occur during treatment Moduret should be discontinued.

Effects Related to Diuresis in Cirrhotic Patients: Patients with hepatic cirrhosis and ascites are intolerant of acute shifts in electrolyte balance and often have pre-existing hypokalemia as a result of associated secondary hyperaldosteronism. When oral diuretic therapy is used, these patients should be carefully monitored and diuresis should be gradual.

Hepatic encephalopathy, manifested by tremors, confusion, and coma, has been reported in association with amiloride therapy.

In cirrhotic patients receiving amiloride alone, jaundice associated with the underlying disease process has deepened in a few instances, but the relationship to the drug is uncertain.

Other Precautions: Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Calcium excretion is decreased by hydrochlorothiazide and magnesium excretion is increased.

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.

Patients should be observed regularly for the possible occurrence of liver dysfunction, idiosyncratic reactions, or blood dyscrasias.

Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bonchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with the thiazides.

Pregnancy: Because clinical experience is limited, Moduret is not recommended for use during pregnancy.

Teratologic studies with amiloride in rabbits and mice revealed no evidence of harm to the fetus. Reproduction studies in rats 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.

In rats a trace of drug crossed the placental barrier.

Thiazides cross the placental barrier and appear in the cord blood. Therefore, the use of Moduret when pregnancy is present or suspected requires that the benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia and possibly other side effects that have occurred in the adult.

Lactation: It is not known whether amiloride is excreted in human milk. In rats secretion of amiloride in milk has been demonstrated. Thiazides appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, if the use of Moduret is deemed essential, the patient should stop nursing.

Children: The safety for use of amiloride in children has not been established; therefore, Moduret is not recommended in the pediatric age group.

Drug Interactions: Hydrochlorothiazide potentiates the action of other antihypertensive drugs. Therefore, the dosage of these agents, especially the ganglion blockers, may need to be reduced when Moduret is added to the regimen.

Lithium should generally not be given to patients receiving diuretics, since the risk of lithium toxicity is very high in such patients.

Thiazide-containing drugs may increase the responsiveness to tubocurarine. The antihypertensive effect of the drug may be enhanced in the postsympathectomy patient.

Hydrochlorothiazide may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the effectiveness of the pressor agent for therapeutic use.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, or narcotics.

Adverse Reactions: While rare, the most serious adverse effect is symptomatic hyperkalemia. Other metabolic changes that occur are asymptomatic hyperkalemia, hypokalemia and hypochloremia.

The following incidence of other adverse reactions was determined from clinical trials (607 patients treated with Moduret.

Other adverse reactions that have been reported with the individual components are listed below:

Cardiovascular: necrotizing angiitis (vasculitis, cutaneous vasculitis).

Gastrointestinal: abnormal liver function, jaundice (intrahepatic cholestatic jaundice), activation of pre-existing peptic ulcer, cramping, gastric irritation, pancreatitis, dry mouth, sialadenitis.

Endocrine: glycosuria, hyperglycemia, hyperuricemia.

Hypersensitivity: urticaria, anaphylactic reactions.

Respiratory: respiratory distress including pneumonitis.

Special senses: photosensitivity, transient blurred vision, xanthopsia.

Hematologic: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia, neutropenia.

Others: restlessness, fever.

Symptoms And Treatment Of Overdose: Symptoms: No data are available in regard to overdosage in humans with Moduret or with the amiloride component.

The most common signs and symptoms to be expected from overdosage are dehydration and electrolyte imbalance. Serum electrolytes should be carefully monitored with special attention to potassium levels.

Cardiac arrhythmias may be caused by abnormal potassium levels. Digitalized patients are especially prone to arrhythmias.

Treatment: No specific information is available on the treatment of overdosage and no specific antidote is available. Treatment is symptomatic and supportive. Therapy with Moduret should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage.

It is not known whether the drug is dialyzable.

Dosage And Administration: Optimal dosage should be established by the individual titration of the components.

Maintenance doses may be lower than those required to initiate diuresis; therefore, reduction in the daily dosage should be attempted when the patient’s weight is stabilized. In cirrhotic patients, gradual weight reduction is especially desirable to reduce the likelihood of untoward reactions associated with diuretic therapy.

Hepatic Cirrhosis with Ascites and Edema: Maintenance: 1 tablet once daily. The dosage should not exceed 4 tablets a day in single or divided doses.

Edema of Cardiac Origin: Maintenance: 1 or 2 tablets given once daily or in divided doses. The dosage should not exceed 4 tablets a day. Therapy may be on an intermittent basis.

Hypertension: Maintenance: 1 or 2 tablets once daily or in divided doses. The dosage should not exceed 4 tablets a day.

Availability And Storage: Each peach colored, diamond-shaped, compressed tablet, scored on one side with code MSD 917, and tradename MODURET on other, contains: hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg. Also contains lactose. Gluten- and tartrazine-free. Bottles of 100 and 1 000. (Shown in Product Recognition Section)

MODURET® MSD Hydrochlorothiazide – Amiloride HCl Diuretic – Antihypertensive

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