Hyles

Hyles 25: Each tablet contains spironolactone 25 mg.
Hyles 100: Each tablet contains spironolactone 100 mg.

Pharmacodynamics: Mechanism of Action: Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule.
Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.
Spironolactone is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension. Through its action in antagonizing the effect of aldosterone, spironolactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.
Pharmacokinetics: Absorption: Absorption of spironolactone from the GI tract depends on the formulation in which it is administered. Currently available formulations of spironolactone are well absorbed from the GI tract and bioavailability of the drug exceeds 90% when compared to an optimally absorbed spironolactone solution in polyethylene glycol 400. Following a single oral dose of spironolactone, peak serum concentrations of the drug occur within 1-2 hours, and peak serum concentrations of its principal metabolites are attained within 2-4 hours. When spironolactone is administered concomitantly with food, peak serum concentrations and areas under the serum concentration-time curves (AUCs) of the drug and, to a lesser degree, its principal metabolites are increased substantially compared with the fasting state; however, the clinical importance of these findings is not known.
When administered alone, spironolactone has a gradual onset of diuretic action with the maximum effect being reached on the third day of therapy. The delay in onset may result from the time required for adequate concentrations of the drug or metabolites to accumulate. It has been suggested that a loading dose 2-3 times the usual daily dose be administered on the first day of therapy to overcome the delay in onset of action. After withdrawal of spironolactone, diuresis persists for 2 or 3 days. When a thiazide diuretic is used concomitantly with spironolactone, diuresis usually occurs on the first day of therapy.
Distribution: Spironolactone and canrenone, a major metabolite of the drug, are both more than 90% bound to plasma proteins. Spironolactone or its metabolites may cross the placenta. Canrenone is distributed into milk.
Metabolism: Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug.
Spironolactone undergoes deacetylation at its sulfur group to form 7α-thiospironolactone (7α- thiospirolactone), which then undergoes further metabolism. 7α-thiospironolactone is dethiolated to form canrenone and subsequently other non-sulfur-containing metabolites. 7α-Thiospironolactone also undergoes thiomethylation to form 7α-thiomethylspironolactone (7α-thiomethylspirolactone), which undergoes 6β-hydroxylation and subsequent metabolism to other sulfur-containing metabolites. Canrenone, 7α-thiospironolactone, and 7α-thiomethylspironolactone are pharmacologically active but substantially less so than the parent drug.
Excretion: Spironolactone metabolites are excreted principally in urine, but also in feces via biliary elimination.
Following a single oral dose in healthy adults, the half-life of spironolactone averaged 1.3-2 hours, and the half-life of 7α-thiomethylspironolactone average 2.8 hours. The half-life of canrenone reportedly ranges from 13-24 hours. In multiple-dose studies, the steady-state plasma elimination half-life of canrenone averaged 19.2 hours when 200 mg of spironolactone was administered daily as a single dose and averaged 12.5 hours when 200 mg of the drug was administered daily in 4 equally divided doses.

Edema: Spironolactone is used in the management of edema associated with excessive aldosterone excretion such as idiopathic edema and edema accompanying cirrhosis of the liver, nephrotic syndrome, and congestive heart failure, usually in conjunction with other diuretics.
Congestive heart failure: For the management of edema and sodium retention when patient is only partially responsive to, or is intolerant of, other therapeutic measures. Spironolactone is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate.
Cirrhosis of the liver accompanied by edema and/or ascites: For maintenance therapy together with bed rest and the restriction of fluid and sodium. Aldosterone levels may be exceptionally high in this condition.
Nephrotic syndrome: For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide on adequate response.
Essential hypertension: Usually in combination with other drugs, spironolactone is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate.
Spironolactone may be useful to decrease the potassium loss caused by other diuretics and potentiate the hypotensive effects of those agents or other more potent hypotensive agents.
Congestive heart failure: Low-dose (e.g., 25-50 mg daily) spironolactone therapy has been used in conjunction with angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and occasionally cardiac glycosides in patients with severe congestive heart failure (CHF) whose condition was inadequately controlled by therapy with an ACE inhibitor and a loop diuretic.
Primary aldosteronism: Spironolactone is used in the diagnosis of primary aldosteronism and used for the short-term preoperative treatment of primary aldosteronism and for long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who cannot undergo adrenalectomy or who decline surgery. The drug is also used for long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).
Hypokalemia: For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate. Spironolactone is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate.
Severe heart failure (New York Heart Association [NYHA] class III to IV): To increase survival and to reduce the need for hospitalization for heart failure when used in addition to standard therapy.

Recommended Doses: Edema Conditions: Usual dosage: 25 to 200 mg daily.
Initial dosage: 100 mg daily in either single or divided doses. When given as the sole agent for diuresis, continue for at least 5 days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses.
Concomitant therapy: If, after 5 days, an adequate diuretic response has not occurred, a second diuretic that acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of spironolactone when coadministered with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of spironolactone should remain unchanged when other diuretic therapy is added.
Essential Hypertension: Initial dosage: 50 to 100 mg daily in single or divided doses.
Dosage adjustment: Dosage should be adjusted according to the response of the patient.
Duration of therapy: Treatment should be continued for at least 2 weeks, because the maximum response may not occur before this time.
Concomitant therapy: May be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents.
Congestive Heart Failure: Spironolactone is indicated for the management of severe congestive heart failure in patients receiving an ACE inhibitor and a loop diuretic with or without a cardiac glycoside.
Initial dosage: 12.5 to 25 mg daily.
Dosage adjustment: the dosage of spironolactone has been increased to 50 mg daily after 8 weeks of therapy in patients who exhibited signs and symptoms of progressive heart failure and who had no hyperkalemia (serum potassium concentrations of 5.5 mEq/L). When hyperkalemia occurred, dosage of spironolactone was decreased to 25 mg every other day.
Primary Hyperaldosteronism: Usual dosage: 100 to 400 mg daily in preparation for surgery.
Maintenance dosage: For patients who are considered unsuitable for surgery, administer long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
Diagnosis: Long test: 400 mg daily for 3 to 4 weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.
Short test: 400 mg daily for 4 days. If serum potassium increases during spironolactone administration but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.
Hypokalemia: Usual dosage: 25 to 100 mg daily.
Severe heart failure (NYHA class III to IV): Initial dosage: 25 mg once daily if the patient's serum potassium is 5 mEq/L or less and the patient's serum creatinine is 2.5 mg/dL or less.
Dosage adjustment: Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate the 25 mg once daily dose may have their dosage reduced to 25 mg every other day.
Renal function impairment: Contraindicated in patients with anuria, acute renal insufficiency, and/or significant impairment of renal excretory function.
Mode of Administration: Spironolactone is administered orally. Although it has frequently been recommended that spironolactone be administered in 3 to 4 doses daily, more recent information suggests that 1 or 2 doses daily may be adequate.

Overdose: Overdosage of spironolactone would be expected to produce signs and symptoms that are mainly extensions of common adverse reactions such as drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, hyponatremia or hyperkalemia may occur, especially in patients with impaired renal function; hepatic coma may occur in patients with severe liver disease but a causal relationship of these effects to overdosage of spironolactone has not been established.
Treatment: In the event of overdosage, spironolactone should be discontinued and the patient should be carefully monitored. There is no specific antidote for spironolactone overdosage. In acute overdosage, the stomach should be emptied by inducing emesis or by gastric lavage. Supportive and symptomatic treatment should be initiated to maintain hydration, electrolyte balance, and vital functions. If severe hyperkalemia occurs (i.e., serum potassium concentration greater than 6.5 mEq/L), specific measures such as IV administration of calcium chloride solution, sodium bicarbonate, and/or oral or parenteral administration of glucose with a rapid-acting insulin preparation should be instituted to reduce serum potassium concentrations. If necessary, a cation exchange resin (e.g., sodium polystyrene sulfonate) may be administered orally or as a retention enema. Patients with persistent hyperkalemia may require dialysis.

Anuria;
Acute renal insufficiency;
Significant impairment of renal excretory function;
Hyperkalemia;
Impaired renal function or hepatic disease;
Patients with rapidly deteriorating renal function;
Patients whose serum creatinine or BUN concentration is more than twice normal.

Hyperkalemia: The most serious adverse effect of spironolactone therapy is hyperkalemia, which occurs most frequently in patients receiving potassium supplements concomitantly and in patients with renal insufficiency. Hyperkalemia can cause cardiac irregularities which may be fatal. Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinary be given in associated with spironolactone therapy. Excessive potassium intake may cause hyperkalemia in patients receiving spironolactone. If hyperkalemia is present, discontinue spironolactone immediately.
Fluid and Electrolyte Imbalance: 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 the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and GI disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fetal. Consequently, no potassium supplement should ordinarily be given with spironolactone.
Hyperchloremic Metabolic Acidosis: Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.
Hyponatremia: Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when spironolactone is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening.
Gynecomastia: Gynecomastia may develop in association with the use of spironolactone. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when spironolactone is discontinued. In rare instances, some breast enlargement may persist when spironolactone is discontinued.
Renal Effects: Spironolactone therapy may cause a transient elevation of serum urea nitrogen (BUN), especially in patients with preexisting renal impairment. Spironolactone may cause mild acidosis.
Hepatic function impairment: Spironolactone should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
GI Effects: Anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, and ulceration have occurred during spironolactone therapy.
Nervous System Effects: Headache, drowsiness, lethargy, ataxia, mental confusion, and fever have occurred during spironolactone therapy. In addition, severe fatigue and lassitude have been associated with the rapid and profound weight loss that occurs at the start of high-dose spironolactone therapy in patients with primary aldosteronism.
Dermatologic and Sensitivity Reactions: Maculopapular and erythematous rashes (sometimes accompanied by eosinophilia), anaphylactic reaction, vasculitis, and urticarial have been reported rarely in patients receiving spironolactone.
Mutagenicity and Carcinogenicity: Canrenone, a major metabolite of spironolactone, and canrenoic acid are the major metabolites of potassium canrenoate. In tests using bacteria or yeast and in an in vivo mammalian system, potassium canrenoate was not mutagenic; however, it did produce a mutagenic effect in several in vitro tests in mammalian cells following metabolic activation.
Spironolactone has been shown to be tumorigenic in chronic toxicity studies in rats. Studies in rats using spironolactone dosage 25-250 times the usual human dosage resulted in a dose-related increase in benign adenomas of the thyroid and testes, a dose-related increase in proliferative changes in the livers of male rats, and an increase in malignant mammary tumors in female rats. At dosages 250 times the usual human dosage, hepatocellular carcinoma, hepatocytomegaly, and hyperplastic nodules were reported in rats. At dosages greater than 20 mg/kg daily, a dose-related incidence of myelocytic leukemia was observed in rats receiving potassium canrenoate in their diet for one year. In rats receiving potassium canrenoate for 2 years, myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors were observed. In chronic toxicity studies in rats using spironolactone dosages up to 250 times the usual human dosage, an increased incidence of leukemia was not observed.

Pregnancy: Safe use of spironolactone during pregnancy has not been established. The drug should be used during pregnancy only when the potential benefits outweigh the possible risks to the fetus.
Lactation: Since canrenone, a metabolite of spironolactone, is distributed into milk, spironolactone should not be used in nursing woman. If use of spironolactone is deemed essential, nursing should be discontinued and an alternative method of infant feeding should be instituted.

CNS: Mental confusion, ataxia, headache, drowsiness, lethargy.
Endocrine: Gynecomastia, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone, but a cause and effect relationship has not been established.
GI: diarrhea and cramping, gastric bleeding, gastritis, nausea, ulceration, vomiting.
Hepatic: A very few cases of mixed cholestatic/hepatocellular toxicity, with 1 reported fatality, have been reported with spironolactone administration.
Hypersensitivity: anaphylactic reactions, fever, maculopapular or erythematous cutaneous eruptions, urticaria, vasculitis.
Miscellaneous: agranulocytosis, hyperkalemia, renal dysfunction (including renal failure).

Potassium-sparing Agents: Spironolactone should not be used concurrently with another potassium-sparing agent (e.g., amiloride, triamterene), since concomitant therapy with these drugs may increase the risk of hyperkalemia as compared with spironolactone alone.
Because indomethacin may increase serum potassium concentrations, indomethacin and spironolactone should be administered concomitantly with caution.
Potassium-sparing diuretics should also be used with caution and serum potassium should be determined frequently in patients receiving an ACE inhibitor (e.g., captopril).
Potassium-containing Preparations: Concomitant use of spironolactone and potassium supplements or other substances containing potassium (e.g., salt substitutes, low-salt milk) may increase the risk of hyperkalemia as compared with spironolactone therapy alone.
Antihypertensive and Hypotensive Agents: When used in conjunction with other diuretics or hypotensive agents, spironolactone may be additive with or may potentiate the action of these drugs. Therefore, dosage of these drugs, particularly ganglionic blocking agents, may need to be reduced by at least 50% when concomitant spironolactone therapy is instituted.
Cardiac Glycosides: Spironolactone has been shown to increase the half-life of digoxin, resulting in increased serum digoxin concentrations and subsequent cardiac glycoside toxicity.
Aspirin: Aspirin has been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals, possibly by reducing active renal tubular secretion of canrenone, the active metabolite of spironolactone. Patients receiving both drugs should be monitored for signs and symptoms of decreased clinical response to spironolactone.
Anticoagulants: When used in conjunction with spironolactone, the hypoprothrombinemic effect of anticoagulants (e.g., warfarin) may be decreased.
Lithium: Spironolactone may reduce lithium renal clearance and increase the risk of lithium toxicity.
Mitotane: Adrenolytic effects of mitotane may be blocked by spironolactone.
Alcohol, barbiturates, narcotics: Potentiation of orthostatic hypotension may occur.
NSAIDS: Effects of spironolactone maybe decreased. Coadministration has also been associated with severe hyperkalemia.
Corticosteroids, corticotropin (ACTH): Intensified electrolyte depletion particularly hypokalemia may occur.
Other Drugs: Spironolactone reportedly reduces vascular responsiveness to norepinephrine and regional or general anesthesia should be used with caution in patients receiving spironolactone.

Store below 30°C. Protect from light.

Diuretics

C03DA01 - spironolactone ; Belongs to the class of aldosterone antagonists. Used as potassium-sparing diuretics.

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