Spironolactone Side Effects: Severity Distribution by Patient Phenotype

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What the acne trial showed

SAFA randomized 410 women aged 18 or older with facial acne persisting at least 6 months: 201 to spironolactone 50 mg/day to week 6 then 100 mg/day to week 24, and 209 to placebo, with usual topical treatment continued [3]. No serious adverse reactions were reported with spironolactone [3]. Headache was more common on spironolactone, 20.4% versus 12.0%; other adverse reactions were similar [3].

In a systematic review of acne trials, menstrual side effects were significantly more common at 200 mg/day, and a combined oral contraceptive reduced their frequency [4]. In a case 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) [5].

Potassium: healthy women versus higher-risk patients

Among 974 healthy young women taking spironolactone for acne, 13 of 1,802 potassium measurements were abnormal, 0.72%, against a 0.76% baseline rate in 1,165 comparison women [1]. That study excluded women with cardiovascular disease, renal failure, or drugs acting on the renin-angiotensin-aldosterone system, so the low rate describes a selected healthy population [1].

The label says hyperkalemia 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 [2]. It also names NSAIDs, heparin and trimethoprim as drugs that can raise potassium [2].

Kidney and liver disease

The label says patients with renal impairment are at increased risk of hyperkalemia [2]. In patients with cirrhosis and ascites, the label warns that sudden fluid and electrolyte shifts can precipitate impaired neurological function, worsening hepatic encephalopathy and coma, and says to start treatment for edema in a hospital setting [2].

Gynecomastia and other labeled reactions

In RALES, patients with heart failure on a mean 26 mg/day, about 9% of the men developed gynecomastia; risk rises with dose, onset varies from 1 to 2 months to over a year, and it is usually reversible [2]. These figures come from different groups, women treated for acne in SAFA and men with heart failure in RALES, so they are not directly comparable [3][2]. The label says many of its other listed reactions were reported voluntarily from a population of uncertain size, so their frequency cannot be reliably estimated [2].