Spire

Each film-coated tablet contains: Spironolactone BP 20 mg or 50 mg.

Pharmacotherapeutic group: Potassium-sparing agents. ATC code: C03DA01.
Pharmacology: Pharmacodynamics: Mechanism of action: Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action, maximum response being usually attained after 2 to 3 days treatment. Combination of Spironolactone with a conventional, more proximally acting diuretic usually enhances diuresis without excessive potassium loss.
Severe Heart Failure: RALES was a multinational, double-blind study in 1663 patients with an ejection fraction of ≤35%, a history of NYHA Class IV heart failure within 6 months, and Class III-IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18%-40%). Spironolactone reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure by 31% compared to placebo (p <0.001; 95% confidence interval 18%-42%).
Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias or myocardial infarction) by 30% (p<0.001 95% confidence interval 18%-41%). Changes in NYHA class were more favorable with spironolactone: in the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (p<0.001).
Paediatric population: There is a lack of substantive information from clinical studies on spironolactone in children. This is a result of several factors: the few trials that have been performed in the paediatric population, the use of spironolactone in combination with other agents, the small numbers of patients evaluated in each trial and the different indications studied. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.
Pharmacokinetics: Spironolactone is well absorbed from the gastrointestinal tract, with a bioavailability of about 90%. It is about 90% bound to plasma proteins. Spironolactone is metabolized extensively to a number of metabolites including canrenone and 7α-thiomethylspironolactone, both of which are pharmacologically active. The major metabolite may be 7α-thiomethylspironolactone, although it is uncertain to what extent the actions of spironolactone are dependent on the parent compound or its metabolites.
Spironolactone is excreted mainly in the urine and also in the feces, in the form of metabolites. Spironolactone or its metabolites may cross the placental barrier and canrenone is distributed into breast milk.

Spironolactone, a steroid with a structure resembling that of the natural adrenocortical hormone aldosterone, acts on the distal portion of the renal tubule as a competitive antagonist of aldosterone. It acts as a potassium-sparing diuretic, increasing sodium and water excretion and reducing potassium excretion.
Spironolactone is reported to have a relatively slow onset of action, requiring 2 or 3 days for maximum effect, and a similarly slow diminishment of action over 2 or 3 days on stopping.
Spironolactone is used in the management of heart failure, both to treat refractory oedema and in lower doses as an adjunct to standard therapy. It is also used for refractory oedema associated with cirrhosis of the liver or the nephrotic syndrome, and in ascites associated with malignancy. It is frequently given with the thiazides, furosemide, or similar diuretics, where it adds to their natriuretic but diminishes their kaliuretic effects, hence conserving potassium in those at risk from hypokalemia.
It has been used in the treatment of essential hypertension (in lower doses than for edema), but in the UK is no longer recommended for use in either essential hypertension or idiopathic edema; doubts have been expressed over its safety during long term administration.
Spironolactone is also used in the diagnosis and treatment of primary hyperaldosteronism. Other conditions in which spironolactone has been tried on the basis of its anti-androgenic properties include hirsutism, particularly in the polycystic ovary syndrome.

In the treatment of edema, spironolactone is usually given in an initial oral dose of 100 mg daily, subsequently adjusted as necessary; some patients may require doses of up to 400 mg daily. In hepatic cirrhosis with ascites and edema, patients with a urinary sodium/potassium ratio greater than 1 may be given an initial dose of spironolactone 100 mg daily while patients with a ratio of less than 1 may be given initial doses of 200 to 400 mg daily.
Spironolactone is given in doses of 400 mg daily in the presumptive diagnosis of primary hyperaldosteronism; in doses of 100 to 400 mg daily for the preoperative management of hyperaldosteronism; and in the lowest effective dosage for long-term maintenance therapy in the absence of surgery.
Suggested doses of spironolactone for children range from 1 to 3 mg/kg daily, in divided doses.

Acute overdosage may be manifested by drowsiness, mental confusion, nausea, vomiting, dizziness, diarrhoea or maculopapular or erythematous rash. Dehydration may occur. Hyponatraemia or hyperkalaemia may be induced but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electro-cardiographic changes are the earliest specific signs of potassium disturbance. No specific antidote has been identified. Spironolactone use should be discontinued. Improvement may be expected after withdrawal of the drug. General supportive measures including replacement of fluids and electrolytes may be indicated. For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin, or oral ion-exchange resins.

Spironolactone should not be used in patients with hyperkalemia or severe renal impairment. It should be used with care in patients who are at increased risk of developing hyperkalemia; such patients include the elderly those with diabetes mellitus and those with some degree of renal or hepatic impairment. It should also be given with care to patients likely to develop acidosis. Serum electrolytes and blood-urea-nitrogen should be measured periodically.

Spironolactone may give rise to headache and drowsiness, and gastrointestinal disturbances, including cramp and diarrhoea. Ataxia, mental confusion, and skin rashes have been reported as adverse effects. Gynaecomastia is not uncommon and in rare cases breast enlargement may persist. Other endocrine disorders include hirsutism, deepening of the voice, menstrual irregularities, and impotence. Transient increases in blood-urea-nitrogen concentrations may occur and mild acidosis has been reported. Spironolactone has been shown to cause tumours in rats. Spironolactone may cause hyponatremia and hyperkalemia.

There is an increased risk of hyperkalemia if spironolactone is given with potassium supplements or with other potassium-sparing diuretics. Hyperkalemia may occur as well in patients also given ACE inhibitors, angiotensin II receptor antagonists NSAIDs, ciclosporin, or trilostane. In patients given spironolactone with NSAIDs or ciclosporin the risk of nephrotoxicity may also be increased. Diuretics may reduce the excretion of lithium and increase the risk of lithium toxicity.
Hyponatremia may occur in patients taking a potassium-sparing diuretic with a thiazide; this risk may be increased in patients given chlorpropamide. Spironolactone may reduce the ulcer-healing properties of carbenoxolone. As with other diuretics, spironolactone may enhance the effects of other antihypertensive drugs and may reduce vascular responses to noradrenaline.

Store at temperatures not exceeding 30°C.
Shelf-life: 36 months.

Diuretics

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

Rx