Spironolactone Side Effects: Rare but Serious Adverse Events

Which serious reactions does the Aldactone label actually list?

Spironolactone is an aldosterone antagonist. It binds competitively at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule, so more sodium and water are excreted while potassium is retained [1]. Hyperkalemia is the first warning in the label, which also lists serious blood, skin, liver and immune reactions [1].

The current label puts four items under warnings and precautions: hyperkalemia; hypotension and worsening renal function; electrolyte and metabolic abnormalities; and gynecomastia [1]. The blood, skin, liver and immune reactions are in the adverse reactions section. The label says these were identified in clinical trials or from voluntary reports from a population of uncertain size, so frequency cannot be estimated reliably and a causal relationship cannot be established [1].

Hyperkalemia

Risk goes up with impaired renal function, potassium supplementation, potassium-containing salt substitutes, and drugs that raise potassium such as ACE inhibitors and angiotensin receptor blockers [1]. The label directs serum potassium to be checked within 1 week of starting or titrating Aldactone and regularly thereafter, with more frequent checks when it is given with other potassium-raising drugs or in patients with impaired renal function; if hyperkalemia occurs, the label says to decrease the dose or discontinue and treat the hyperkalemia [1]. It also directs checking potassium when ACE inhibitor or ARB therapy is altered, and discontinuing potassium supplements in heart failure patients who start the drug [1].

The label contraindicates spironolactone in hyperkalemia, Addison's disease, and with concomitant eplerenone [1]. For heart failure it directs starting at 25 mg once daily in patients with serum potassium at or below 5.0 mEq/L and eGFR above 50 mL/min/1.73 m2, and considering 25 mg every other day when eGFR is 30 to 50 [1].

In healthier users the picture is different. A retrospective study of 974 healthy young women taking spironolactone for acne found 13 abnormal potassium values in 1802 measurements, a rate of 0.72%, against a baseline rate of 0.76% in 1165 comparison women; 6 of the 13 abnormal values were normal on repeat testing [4]. That study excluded women with heart or kidney disease and those taking drugs that affect the renin-angiotensin-aldosterone system, and its authors concluded routine potassium monitoring had low usefulness in this group [4]. The label itself still directs potassium monitoring [1].

Hypotension and worsening kidney function

The label states that excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking ACE inhibitors and ARBs, and that renal function can also worsen with nephrotoxic drugs such as aminoglycosides, cisplatin and NSAIDs [1]. It directs monitoring of volume status and renal function periodically [1].

In hepatic impairment with cirrhosis and ascites, the label states that spironolactone can cause sudden alterations of fluid and electrolyte balance that may precipitate impaired neurological function, worsening hepatic encephalopathy and coma, and that treatment in that group should start in a hospital [1].

Reported reactions: blood, skin, liver and immune

The adverse reactions section lists leukopenia, including agranulocytosis, and thrombocytopenia; hypersensitivity reactions including fever, urticaria, maculopapular or erythematous eruptions, anaphylactic reactions and vasculitis; skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, alopecia and pruritus; renal dysfunction including renal failure; and, in the liver, a very few cases of mixed cholestatic/hepatocellular toxicity with one reported fatality [1].

Report counts do not translate into risk figures. The FDA states that reports in its adverse event database can be duplicated or incomplete, that the existence of a report does not establish that the drug caused the event, and that the data cannot be used to estimate how often an event occurs [5].

Does spironolactone carry a boxed warning?

Not on the current Aldactone label. The latest label supplement, S-080, was approved on 14 November 2025 and the DailyMed version is effective 28 November 2025; it has no boxed warning [6][1]. Some older spironolactone labels carry boxed text about tumors observed in rat studies [2].

Acne, hirsutism and female pattern hair loss are not labeled indications. The labeled uses are NYHA Class III-IV heart failure with reduced ejection fraction, add-on therapy for hypertension, edema in cirrhosis or nephrotic syndrome, and primary hyperaldosteronism [1].

Pregnancy

The label states that, based on its mechanism of action and animal findings, spironolactone may affect sex differentiation of the male during embryogenesis, and that rat studies report feminization of male fetuses and endocrine dysfunction in females exposed in utero [1]. Limited human data from published case reports and case series did not demonstrate an association with major malformations or other adverse pregnancy outcomes [1]. The label directs avoiding spironolactone in pregnant women or advising a pregnant woman of the potential risk to a male fetus [1]. Pregnancy is not listed in the contraindications section, which names hyperkalemia, Addison's disease and concomitant eplerenone [1].

What the acne trial shows about serious events

The largest randomized evidence in acne is the SAFA trial: 410 women aged 18 or older with facial acne persisting at least 6 months, randomized to spironolactone 50 mg/day for 6 weeks then 100 mg/day to week 24 (201 women) or placebo (209 women) [3]. No serious adverse reactions were reported, and adverse reactions were otherwise similar between groups apart from headache, which occurred in 20.4% of the spironolactone group versus 12.0% of the placebo group [3]. A single 24-week trial of that size cannot describe how often the uncommon label reactions occur.

What the label directs prescribers to monitor

Serum potassium within 1 week of initiation or titration and regularly afterward; volume status and renal function periodically; and serum electrolytes, uric acid and blood glucose periodically [1]. Gynecomastia is the most common adverse reaction overall, affecting about 9% of men in RALES at a mean dose of 26 mg/day, rising with dose and usually reversible [1].