Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Nova Laboratories Ireland Limited, 3<sup>rd</sup> Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
Pharmacotherapeutic group: diuretics, aldosterone antagonists and other potassium-sparing agents
ATC code: C03DA01
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.
RALES was a multinational, double-blind study in 1 663 patients with an ejection fraction of ≤35%, a history of New York Heart Association (NYHA) Class IV heart failure within 6 months, and Class III-IV heartfailure 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 dose 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 favourable 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).
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 dose recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.
Spironolactone is well absorbed orally and is principally metabolised to active metabolites: sulfur containing metabolites (80%) and partly canrenone (20%). Although the plasma half-life of spironolactone itself is short (1.3 hours) the half-lives of active metabolites are longer (ranging from 2.8 to 11.2 hours).
There are no pharmacokinetic data available in respect of use in paediatric population. The dose recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.
Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18- month study using doses of about 50, 150 and 500 mg/kg/day (about 1x, 4x, and 12x, respectively, the maximum human recommended daily dose of 400 mg/day based on body surface area), there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In 24-month studies in which rats were administered doses of about 10, 30, 100, and 150 mg/kg/day of spironolactone (about 0.2x, 0.7x, and 2x, respectively, the maximum recommended daily dose of 400 mg/day based on body surface area), the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumours in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant increase in benign uterine endometrial stromal polyps in females. A dose related (above 30 mg/kg/day) incidence of myelocytic leukaemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of 1 year. In 2-year studies in the rats, oral administration of potassium canrenoate was associated with myelocytic leukaemia and hepatic, thyroid, testicular and mammary tumours.
Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and positive for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others.
In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg/kg/day of spironolactone (about 0.4x and 1x, respectively, the maximum human recommended daily dose of 400 mg/day based on body surface area), there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. Spironolactone was devoid of teratogenic effects in mice. Rabbits receiving spironolactone showed reduced conception rate, increased resorption rate, and lower numbers of live births. No embryotoxic effects were seen in rats administered high doses, but limited, dose-related hyprolactinemia and decreased ventral prostate and seminal vesicle weights in males, and increasing luteinizing hormone secretion and ovarian and uterine weights in females were reported. Feminization of the external genitalia of male fetuses was reported in another study in rats. When injected into female rats (100 mg/kg/day for 7 days, i.p.) (about 2x the maximum human recommended daily dose of 400 mg/day based on body surface area), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a 2-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Spironolactone (100 mg/kg/day) (about 1x, the maximum human recommended daily dose of 400 mg/day based on body surface area), administered i.p. to female mice during a 2- week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg (about 2x, the maximum human recommended daily dose of 400 mg/day based on body surface area) also increased the latency period to mating.
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