Spironolactone Side Effects: Incidence Rates Across Clinical Trials

What incidence data exist for spironolactone?

The Aldactone label states that its adverse-reaction list comes from clinical trials and voluntary postmarketing reports from a population of uncertain size, so frequency cannot be reliably estimated and causality cannot always be established [1]. That covers nearly the whole list: menstrual irregularity, breast and nipple pain, headache, nausea, and the serious skin and blood reactions [1].

The acne literature is thinner than its citation count suggests. A systematic review found 10 randomized trials and 21 case series of oral spironolactone in adult women, judged every trial at high risk of bias, and rated the quality of evidence low or very low for every outcome [6].

SAFA: the largest randomized acne trial

SAFA randomized 410 women aged 18 or older with facial acne persisting at least 6 months to spironolactone 50 mg/day to week 6 then 100 mg/day to week 24 (201 women) or placebo (209 women), continuing their usual topical treatment [2].

Headache was reported by 20.4% of the spironolactone group and 12.0% of the placebo group. The trial reported no serious adverse reactions, and adverse reactions were otherwise similar between the groups [2].

Hyperkalemia: the best-measured risk

The label states that spironolactone can cause hyperkalemia, that the risk is increased by impaired renal function, potassium supplements, potassium-containing salt substitutes, and drugs that raise potassium such as ACE inhibitors and angiotensin receptor blockers, and that serum potassium should be checked within 1 week of starting or changing the dose and regularly afterward [1]. If hyperkalemia occurs, the label directs a dose reduction or discontinuation with treatment of the hyperkalemia [1].

The dermatology figure comes from 974 healthy young women taking spironolactone for acne at two US tertiary centers: 13 abnormal potassium values among 1802 measurements, a rate of 0.72%, compared with a 0.76% baseline rate in 1165 healthy young women who included users and nonusers [3]. Six of the 13 abnormal values repeated normal [3].

Those women had no cardiovascular disease, no renal failure, and no drugs acting on the renin-angiotensin-aldosterone system, so the 0.72% applies to that group [3]. The systematic review also pooled serum potassium results and supported the position that routine potassium monitoring is not required in this population [6]. Hyperkalemia is a contraindication to spironolactone, alongside Addison disease and concomitant eplerenone [1].

Gynecomastia and breast symptoms

Gynecomastia is the label's most common adverse reaction. In RALES, patients with heart failure taking a mean 26 mg once daily, about 9% of the men developed gynecomastia; the risk rises with dose, onset varied from 1 to 2 months to over a year, and the effect is usually reversible [1]. The label also states that spironolactone binds the androgen receptor, which it describes as the basis of its anti-androgen effects [1].

A review of gynecomastia names spironolactone among the drugs that can cause it and notes that medication-related gynecomastia can resolve when the drug is stopped [7].

Breast and nipple pain is listed among the label's reproductive reactions [1].

Menstrual irregularity

Irregular menses or amenorrhea, and postmenopausal bleeding, are listed among the label's reproductive reactions [1].

The systematic review found menstrual side effects significantly more common with a 200 mg daily dose and significantly less frequent when a combined oral contraceptive was used alongside [6]. In a single-center series of 403 adult women treated between 2008 and 2019, menstrual adverse effects were less common among those using combined oral contraception, odds ratio 0.23 (95% CI 0.11 to 0.50) [9].

Headache, stomach and nerve effects

Headache, drowsiness, dizziness, lethargy, mental confusion and ataxia all appear in the label's nervous-system list [1]. Headache is the one with a trial figure: 20.4% versus 12.0% in SAFA [2].

Digestive reactions in the label include gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea and vomiting [1].

The label also lists leukopenia including agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, anaphylaxis, vasculitis, renal dysfunction including renal failure, and a very few cases of mixed cholestatic/hepatocellular liver toxicity with one reported fatality [1].

How long women stay on it

A retrospective series of 403 adult women treated for acne at one academic center found a mean drug survival of 470.7 days; 75.5% of patients with available data had reduction or clearance of facial acne at first follow-up, and the study was uncontrolled [9].

In 80 pediatric patients (median age 19, range 14 to 20) treated at a median dose of 100 mg daily, the authors described limited side effects over a median 7 months of treatment (range 3 to 45 months) [10]. In an earlier series of 85 women treated with 50 to 100 mg/day, 57.5% reported no adverse effects [8].

What the label says to watch

The label calls for more frequent potassium monitoring when spironolactone is given with other potassium-raising drugs or in impaired renal function [1]. It also calls for periodic monitoring of volume status and renal function, because excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking ACE inhibitors or angiotensin receptor blockers [1].