Spironolactone Side Effects: Potentially Permanent Side Effects Explained

Which side effects last, and which the label just monitors

Spironolactone and its active metabolites block aldosterone at the sodium-potassium exchange site in the distal convoluted tubule, so more sodium and water are excreted while potassium is retained [1]. The label also notes that the drug has antiandrogenic and progestational effects in animals [1].

Most of the entries in the label's adverse-reactions section come from voluntary reports in a population of uncertain size, so the label says frequency cannot be estimated reliably [1]. That applies to the menstrual changes, libido changes, blood count changes, liver toxicity and skin reactions listed there [1].

Gynecomastia: usually reversible, but not always

Gynecomastia is the most common adverse reaction with Aldactone [1]. In RALES, a heart failure trial in which men took a mean 26 mg once daily, about 9% of the male subjects developed it; the label says the risk increases with dose and that onset varies from 1 to 2 months to over a year [1]. The label adds that gynecomastia is usually reversible [1].

A review of gynecomastia names spironolactone among the medications that can cause male breast enlargement, notes that enlargement from a medication can resolve when the drug is stopped, and describes surgery as an option when gynecomastia does not resolve spontaneously or with medical therapy [2].

The 9% figure comes from heart failure treatment at a mean 26 mg/day [1]. Off-label acne dosing is higher: SAFA used 50 mg/day for 6 weeks then 100 mg/day to week 24 [3], and a crossover trial covered in a 2017 systematic review used 200 mg/day [4].

Pregnancy: the fetal risk the label warns about

The label states that, based on its mechanism and animal findings, spironolactone may affect sex differentiation of the male during embryogenesis [1]. In rat studies, feminization of male fetuses was seen at 200 mg/kg/day given between gestation days 13 and 21, and offspring exposed at 50 and 100 mg/kg/day showed dose-dependent changes in reproductive tract weights (smaller ventral prostate and seminal vesicles in males, enlarged ovaries and uteri in females) that persisted into adulthood [1].

Human data are limited. Published case reports and case series did not demonstrate an association with major malformations or other adverse pregnancy outcomes [1]. The label's instruction is to avoid spironolactone in pregnant women or to advise a pregnant woman of the potential risk to a male fetus [1]. Pregnancy is not among the label's three contraindications, which are hyperkalemia, Addison's disease and concomitant eplerenone [1].

Potassium and kidney function: what the label asks you to monitor

Hyperkalemia is the label's central warning, and it names what raises the risk: impaired renal function, potassium supplements, potassium-containing salt substitutes, and drugs that increase potassium such as ACE inhibitors and angiotensin receptor blockers [1]. It directs that serum potassium be checked within 1 week of starting or titrating the dose and regularly thereafter, with more frequent monitoring possible when other potassium-raising drugs are used or kidney function is impaired. If hyperkalemia occurs, the label says to decrease the dose or discontinue the drug and treat the hyperkalemia [1].

Low blood pressure and worsening renal function are the next warning: excessive diuresis, particularly in salt-depleted patients or those taking ACE inhibitors or ARBs, with nephrotoxic drugs such as aminoglycosides, cisplatin and NSAIDs adding risk; the label says to monitor volume status and renal function periodically [1]. Renal dysfunction, including renal failure, appears in the voluntary-report adverse reactions list, which gives no frequency and no outcome data [1].

In healthy young women, abnormal potassium values have been uncommon. A retrospective study of 974 healthy young women taking spironolactone for acne found 13 abnormal potassium values among 1802 measurements, 0.72%, against a baseline rate of 0.76% in 1165 comparison women; 6 of the 13 repeat values were normal [5]. That study excluded women with heart or kidney disease and those taking drugs acting on the renin-angiotensin system, and its authors concluded that routine potassium monitoring has low usefulness in this group [5]. The label still directs potassium monitoring [1].

Menstrual, breast and libido effects in women

The label lists irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain, and decreased libido among reproductive adverse reactions reported voluntarily, with frequency not estimable [1].

In the SAFA trial, 410 women with facial acne persisting at least 6 months were randomized to spironolactone or placebo; there were no serious adverse reactions, adverse reactions were otherwise similar between groups, and headache was more frequent with spironolactone (20.4% versus 12.0%) [3].

A systematic review of 10 randomized trials and 21 case series found menstrual side effects were significantly more common at 200 mg/day and significantly less frequent with a combined oral contraceptive [4]. In a single-center, uncontrolled series of 403 women, menstrual adverse effects were less common among those using combined oral contraception (odds ratio 0.23, 95% CI 0.11 to 0.50), and mean drug survival was 470.7 days [6].

Liver, blood and skin reactions on the label

A very few cases of mixed cholestatic/hepatocellular liver toxicity, with one reported fatality, are listed with spironolactone, along with leukopenia including agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, alopecia, pruritus, anaphylaxis and vasculitis [1]. All of these come from voluntary reports, so the label assigns no frequency [1].

The rat-tumorigenicity boxed warning, and which label carries it

The current Aldactone label has no boxed warning [1]. Some older-format generic and repackager labels still carry boxed text stating that spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats and that it should be used only for labeled conditions [7]. An older generic spironolactone label also lists breast carcinoma among reported reactions in patients taking the drug, with no cause-and-effect relationship established [7].

Bottom line

Gynecomastia is the side effect most likely to be asked about: the label calls it usually reversible, reports it in about 9% of men at a mean 26 mg/day in heart failure, and describes dose-dependent risk with onset from 1 to 2 months to over a year [1][2]. Hyperkalemia, low blood pressure and worsening kidney function are managed by monitoring [1]. For pregnancy, the label's concern is the male fetus, based on animal data [1].