Spironolactone

Non-steroidal anti-inflammatory medicinal products such as acetylsalicylic acid, indomethacin and mefenamic acid may attenuate the natriuretic efficacy of diuretics due to the inhibition of intra-renal synthesis of prostaglandins and have been shown to attenuate the diuretic effect of spironolactone.

Since impaired hepatic function may result in reduced elimination of spironolactone and its metabolites, patients with impaired hepatic function should be started on the lowest dose and titrated slowly. Patients should be monitored for dose related adverse reactions.

Patients with mild renal impairment (glomerular filtration rate (GFR) 60 – 90 ml/min) should be started on the lowest dose. Serum potassium levels and renal function should be monitored closely.

Concomitant administration with cardiac glycosides may necessitate adjustment of the doses of these medicinal products.

Spironolactone has been shown to increase the half-life of digoxin. Spironolactone has been reported to increase serum digoxin concentration and to interfere with certain serum digoxin assays. In patients receiving digoxin and spironolactone the digoxin response should be monitored by means other than serum digoxin concentrations, unless the digoxin assay used has been proven not to be affected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin, patients should be carefully monitored for evidence of enhanced or reduced digoxin effect.

Potentiation of the effect of other diuretics and antihypertensive medicinal products occurs and their dose may need to be reduced by about 50% when spironolactone is added to the treatment regime, and then adjusted as necessary.

Dilution hyponatraemia may occur in combination with other diuretics.

Concomitant use of spironolactone with other potassium sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory medicinal products, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin or other medicinal products or conditions known to cause hyperkalaemia, potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalaemia.

Concomitant use of medicinal products known to cause hyperkalaemia (such as lisinopril, valsartan, indomethacin) with spironolactone may result in severe hyperkalaemia. In addition, concomitant use of trimethoprim/sulfamethoxazole (co-trimoxazole) with spironolactone may result in clinically relevant hyperkalaemia.

Since ACE inhibitors decrease aldosterone production, they should not routinely be used with spironolactone, particularly in patients with marked renal impairment.

Studies in animals suggest spironolactone may impair fertility.

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Use with abiraterone is not recommended.

Hyperkalaemic metabolic acidosis has been reported in patients given spironolactone concurrently with ammonium chloride or colestyramine.

Concurrent use with carbenoxolone or lithium salts should be avoided.

Spironolactone may reduce mitotane plasma levels in adrenocortical carcinoma patients treated with mitotane and should not be used concomitantly with mitotane.

Spironolactone reduces vascular responsiveness to noradrenaline.

Spironolactone enhances the metabolism of antipyrine.

Caution should be exercised in the management of patients subjected to regional or general anaesthesia while they are being treated with spironolactone.

There are no studies of spironolactone in pregnant women. Studies in animals have shown reproductive toxicity. Spironolactone is not recommended during pregnancy and in women of childbearing potential not using contraception.

Canrenone is excreted in human milk. Spironolactone should not be used during breast-feeding.

Fertility

Studies in animals suggest spironolactone may impair fertility.

Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Summary of the safety profile

The most frequent adverse reactions of spironolactone include: hyperkalaemia, reported in 17.5% of patients, particularly in patients with renal impairment or if receiving ACE-inhibitors or angiotensin II antagonists concomitantly; gynaecomastia and breast pain, reported in 9% of males.

The following undesirable effects have been observed in clinical trials and reported during treatment with spironolactone with the following frequencies: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data). The table presented below is according to the MedDRA system organ classification and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Tabulated list of adverse reactions:

^* Gynaecomastia may develop in association with the use of spironolactone. Development appears to be related to both dose level and duration of therapy and is normally reversible when the medicinal product is discontinued. In rare instances some breast enlargement may persist.
^** In clinical trials, breast pain was reported more commonly in males than in females.
^*** Arrhythmia, chest pain, nausea, diarrhoea, paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electrocardiographic changes are the earliest specific signs of potassium disturbance.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be similar to adults.