Source: Marketing Authorisation Holder Revision Year: 2022 Publisher: Alphapharm Pty Ltd trading as Viatris, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000, www.viatris.com.au, Phone: 1800 274 276
Spironolactone is a specific pharmacological 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. It has both diuretic and antihypertensive activity. It may be given alone or in combination with other diuretic agents which act more proximally in the renal tubule.
Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Oedematous states in which secondary aldosteronism is usually involved include congestive cardiac failure, hepatic cirrhosis, and the nephrotic syndrome. Spironolactone provides effective therapy for the oedema and ascites in those conditions by competing with aldosterone for receptor sites.
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.
Spironolactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss by antagonising the effect of aldosterone. It has not been demonstrated to elevate serum uric acid, to precipitate gout or to alter carbohydrate metabolism.
Spironolactone has moderate anti-androgenic activity in humans by inhibition of the interaction between dihydrotestosterone and the intracellular androgen receptor. It also inhibits several steps in ovarian steroidogenesis, resulting in lowered plasma levels of testosterone and some other weak androgenic steroids. Through this activity, spironolactone is effective in the treatment of female hirsutism.
No data available.
In humans, the bioavailability of spironolactone from orally administered tablets is greater than 90% when compared with an optimally absorbed solution (spironolactone in polyethylene glycol 400).
Food may increase the bioavailability of spironolactone; the clinical relevance of this effect is uncertain.
Both spironolactone and canrenone are more than 90% bound to plasma proteins.
Approximately 25 to 30% of the dose administered is converted to canrenone. Sulfur containing products are the predominant metabolites and together with spironolactone are thought to be primarily responsible for the therapeutic effects of the drug. Canrenone attains peak serum levels at 2 to 4 hours following single oral administration. Canrenone plasma concentrations decline in two distinct phases, being rapid in the first 12 hours and slower from 12 to 96 hours. The log-linear phase half-life of canrenone, following multiple doses of spironolactone, is between 13 and 24 hours.
The metabolites of spironolactone are excreted primarily in urine, but also in bile.
In animal studies, spironolactone was devoid of teratogenic effects in mice and rabbits at oral doses up to 20mg/kg/day, and in rats at dietary doses up to 50 mg/kg/day. However, increased resorption rate was seen at 20 mg/kg/day in rabbits, and the incidence of stillbirths was increased in rats dosed at 50 mg/kg/day. Subcutaneous administration of spironolactone (approximately 50 to 100 mg/kg/day) to rats during late pregnancy caused endocrine dysfunction in both sexes of offspring 70 to 80 days after birth (hypoprolactinaemia and decreased ventral prostate and seminal vesical weights in males; increased luteinising hormone secretion and ovarian and uterine weights in females). Feminisation of the external genitalia of male foetuses was reported in another study in rats at oral doses of approximately 200 mg/kg/day. Subcutaneous administration of spironolactone to neonatal female mice caused histological changes in the cervicovaginal epithelium that were similar to those caused by diethylstilboestrol (a drug which causes vaginal neoplasia in adulthood following in utero exposure).
The risk of demasculinisation of the male foetus will only occur from about 6 weeks post conception onwards, hence if inadvertent spironolactone administration is stopped at an early stage, the risk to the male foetus is small.
Spironolactone has been shown to be tumorigenic in chronic toxicity studies performed in rats. It should be used only for approved indications. Unnecessary use of this drug should be avoided.
In chronic toxicity studies of spironolactone in rats, changes were observed in the endocrine organs and the liver. In one study using dietary doses of 50, 150 and 500 mg/kg/day there was a statistically significant doserelated increase in benign adenomas of thyroid follicular cells and testicular interstitial cells. In female rats there was a statistically significant increase in malignant mammary tumours at the middle dose only. In male rats, there was a dose- related increase in proliferative changes in the liver which included hyperplastic nodules and hepatocellular carcinomas at the middle and high doses.
In a two-year oral carcinogenicity study in which rats were administered spironolactone 10, 30, 100 and 150 mg/kg/day, the range of proliferative effects observed was consistent with earlier studies. There were statistically significant increases at higher doses in hepatocellular adenomas and testicular interstitial cell tumours in males, and in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant increase in benign uterine endometrial polyps in females. There was an increase in hepatocellular carcinomas in males at 150 mg/kg, but this was not statistically significant. There was no significant increase in the incidence of mammary tumours.
The significance of these findings with respect to clinical use is not known.
Spironolactone was not mutagenic in the Ames test using five strains of Salmonella typhimurium with or without metabolic activation.
A dose-related (above 20 mg/kg/day) incidence of myelocytic leukaemia was observed in rats fed daily doses of potassium canrenoate for a period of one year. Canrenone and canrenoic acid are the major metabolites of potassium canrenoate. Spironolactone is also metabolised to canrenone. In long-term (2 year) oral carcinogenicity studies of potassium canrenoate in the rat, myelocytic leukaemia, and hepatic, thyroid, testicular and mammary tumours were observed. Potassium canrenoate did not produce a mutagenic effect in tests using bacteria or yeast. It did produce a positive mutagenic effect in several in vitro tests in mammalian cells following metabolism activation. In an in vivo mammalian system, potassium canrenoate was not mutagenic. An increased incidence of leukaemia was not observed in chronic rat toxicity or carcinogenicity studies conducted with spironolactone at doses up to 500 mg/kg/day. The recommended human dose of spironolactone is 1.4 to 5.7 mg/kg/day.
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