Spironolactone Side Effects: Delayed-Onset Adverse Events You Need to Know

Which side effects actually show up late?

Gynecomastia has a documented onset range of 1 to 2 months to over a year [1]. The label also lists menstrual and breast symptoms and warns about kidney and electrolyte effects, but it does not state when most of these begin [1].

The label's adverse reactions come from clinical trials and from voluntary postmarketing reports from populations of uncertain size, so frequencies cannot be estimated reliably [1].

Gynecomastia and breast symptoms

Gynecomastia is the label's most common adverse reaction [1]. In RALES, men with heart failure treated with a mean dose of 26 mg once daily, about 9% developed it; the risk rises with dose, and it is usually reversible [1].

RALES enrolled 1,663 patients with severe heart failure: 822 were assigned 25 mg of spironolactone daily and 841 were assigned placebo [3]. Gynecomastia or breast pain was reported in 10% of men taking spironolactone compared with 1% of men on placebo (P<0.001) [3]. A review of gynaecomastia lists spironolactone among the medications that can cause breast enlargement, which can resolve when the drug is stopped [4].

In women, the label lists breast and nipple pain among reproductive adverse reactions [1]. In the SAFA acne trial of 410 women, there were no serious adverse reactions, adverse reactions were otherwise similar between groups, and headache was reported by 20.4% on spironolactone versus 12.0% on placebo [2].

Potassium: the check the label schedules

The Aldactone label says to monitor serum potassium within 1 week of starting or titrating spironolactone and regularly thereafter. If hyperkalemia occurs, it says to decrease the dose or discontinue the drug and treat the hyperkalemia [1]. Risk is increased by impaired kidney function, potassium supplements, potassium-containing salt substitutes, ACE inhibitors and angiotensin receptor blockers; NSAIDs, heparin, low molecular weight heparin and trimethoprim are also named as drugs that can raise potassium [1]. Spironolactone is contraindicated in hyperkalemia, Addison's disease, and with concomitant eplerenone [1].

A retrospective study of 974 healthy young women taking spironolactone for acne found 13 abnormal potassium values in 1,802 measurements (0.72%), essentially the same as the 0.76% baseline rate in 1,165 comparison women [5]. Six of the 13 abnormal values were normal on repeat testing [5]. Women with cardiovascular disease, renal failure, or drugs affecting the renin-angiotensin-aldosterone system were excluded [5]. The Aldactone label itself still calls for potassium monitoring [1].

Menstrual changes and breast pain

Irregular menses or amenorrhea, postmenopausal bleeding, and breast and nipple pain are all listed among the label's reproductive adverse reactions, drawn from voluntary reports [1].

A systematic review of oral spironolactone for acne in adult women identified 10 randomized trials and 21 case series; all trials were at high risk of bias and the evidence was rated low or very low quality [6]. One crossover trial found 200 mg daily statistically superior to placebo for inflamed lesions, and the review found menstrual side effects were significantly more common with the 200 mg daily dose, with frequency significantly reduced by concomitant combined oral contraceptive use [6].

In a single-center, uncontrolled case series of 403 adult women treated for acne, menstrual adverse effects were less common among those using a combined oral contraceptive (odds ratio 0.23, 95% CI 0.11 to 0.50), and mean drug survival was 470.7 days [7].

Kidney function, blood pressure and electrolytes

The label warns that excessive diuresis can cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking ACE inhibitors or angiotensin receptor blockers, and that nephrotoxic drugs such as aminoglycosides, cisplatin and NSAIDs add to the risk [1]. It advises monitoring volume status and renal function periodically [1].

Beyond potassium, spironolactone can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis and hyperglycemia, and asymptomatic hyperuricemia with rare gout [1]. Renal dysfunction, including renal failure, is listed among the reported adverse reactions [1].

Other reactions the label lists

The label also lists, from voluntary reports, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), alopecia and pruritus; leukopenia including agranulocytosis and thrombocytopenia; mixed cholestatic and hepatocellular liver toxicity with one reported fatality; anaphylaxis and vasculitis [1].

On pregnancy, the label says to avoid spironolactone because of its anti-androgenic properties and rat data showing feminization of male fetuses, while noting that limited human case reports did not show an association with major malformations [1].

Interactions that affect risk

Drugs that raise potassium, including ACE inhibitors and angiotensin receptor blockers, increase the risk of hyperkalemia with spironolactone [1]. The label reports that spironolactone reduces renal lithium clearance and increases the risk of lithium toxicity, and calls for periodic lithium-level monitoring [1]. NSAIDs can reduce the diuretic, natriuretic and antihypertensive effect [1]. Acetylsalicylic acid may reduce spironolactone's efficacy [1]. Cholestyramine has been associated with hyperkalemic metabolic acidosis when given with spironolactone [1]. Spironolactone and its metabolites interfere with digoxin radioimmunoassays and increase apparent digoxin exposure, and the label says to use an assay that does not interact [1]. The label says concomitant abiraterone is not recommended and mitotane should be avoided [1].

What longer-term use looks like in the data

An 8-year follow-up survey of 91 women treated with spironolactone for acne, covering 200 person-years of exposure, reported no serious illness attributed to the drug; side effects were reported by 59% and led to stopping treatment in 15%, with diuretic effects and menstrual irregularities the most common [8].