Spironolactone Month-by-Month: What to Expect in the First 3 Months

The trial that actually measured this window

One randomized trial gives a clean read on the first three months: SAFA, a pragmatic double-blind UK trial. It enrolled 410 women aged 18 and over with facial acne persisting for at least 6 months and judged to potentially warrant oral antibiotic treatment. Participants stayed on their usual topical treatment and were randomized to spironolactone (201 women) or placebo (209), starting at 50 mg daily to week 6 and increasing to 100 mg daily to week 24 [1].

Skin outcomes were reported at 12 weeks and 24 weeks, and the primary endpoint at week 12 was a quality-of-life score, the Acne-Specific Quality of Life symptom subscale [1]. Acne is not a labeled use of spironolactone; the labeled indications are heart failure, add-on treatment of hypertension, edema in cirrhosis or nephrotic syndrome, and primary hyperaldosteronism [2].

Month 1 (weeks 1 to 4): monitoring and side effects

What is documented for the opening weeks is the monitoring and the side effects. The label says to check serum potassium within 1 week of starting spironolactone or changing the dose, and regularly thereafter [2].

How often that check catches a problem in this group: in a study of 974 healthy young women taking spironolactone for acne, 13 of 1,802 potassium measurements were abnormal, a rate of 0.72%, compared with a 0.76% baseline rate in 1,165 comparison women; six of the 13 repeat tests were normal [3]. Women with cardiovascular disease or kidney failure, and those taking medications that affect the renin-angiotensin-aldosterone system, were excluded from that analysis [3]. The Aldactone label itself still says to monitor potassium, and it names impaired kidney function, potassium supplements, potassium-containing salt substitutes, ACE inhibitors and ARBs as raising the risk [2].

The label lists nausea, vomiting, diarrhea and cramping, dizziness, headache, drowsiness, lethargy, leg cramps, breast and nipple pain, and irregular menses or amenorrhea [2]. It describes these as reactions reported voluntarily, from a population of uncertain size, so frequency cannot be estimated reliably [2]. SAFA reported headache in 20.4% of the spironolactone group and 12.0% of the placebo group over the trial; there were no serious adverse reactions and other adverse reactions were similar between groups [1].

Month 2 (weeks 5 to 8): the week-6 dose step

In SAFA, week 6 is where the dose doubled from 50 mg to 100 mg daily [1].

Acne can fluctuate around menstruation: in one survey of adult women attending a dermatology clinic, 65% said their acne was worse with their period; of those, 56% said the worst week was the one before menstruation, 17% during it, 3% after it, and 24% reported worsening throughout the cycle [4].

In the review of spironolactone for adult female acne, menstrual side effects were more common at 200 mg daily, and their frequency was reduced by concomitant use of a combined oral contraceptive; all 10 randomized trials were at high risk of bias and the evidence quality was low or very low [5]. In a case series of 403 adult women, menstrual adverse effects were also less common among those using combined oral contraception (odds ratio 0.23, 95% CI 0.11 to 0.50) [6].

On breast symptoms, the label names gynecomastia as the most common adverse reaction overall: in RALES, a heart failure trial using a mean 26 mg daily, about 9% of men developed it, with risk rising with dose and onset ranging from 1 to 2 months to over a year, usually reversible [2]. Breast and nipple pain is listed separately among the label's reproductive adverse reactions [2].

Month 3 (weeks 9 to 12): the first hard number

At week 12 in SAFA, Investigator's Global Assessment success occurred in 18.5% of women on spironolactone versus 5.6% on placebo, an adjusted odds ratio of 5.18 (95% CI 2.18 to 12.28). The quality-of-life symptom subscale difference was 1.27 points (95% CI 0.07 to 2.46), a confidence interval that only just excludes zero [1].

Longer, uncontrolled data paint a friendlier picture of what happens with continued use. In the 403-woman case series, 75.5% of those with facial data, 84.0% with chest data and 80.2% with back data had reduction or complete clearance at their first follow-up visit; mean drug survival was 470.7 days. That was a single academic center and uncontrolled, so it cannot tell you what would have happened without the drug [6].

What changes between month 3 and month 6

The SAFA differences were larger at week 24. The quality-of-life symptom subscale difference had grown to 3.77 points (95% CI 2.50 to 5.03), and 81.9% of women on spironolactone rated themselves improved versus 63.3% on placebo [1].

The 2017 systematic review found only one crossover trial that showed a clear win over placebo, at 200 mg daily for inflamed lesions; evidence for doses of 100 mg daily or less was of limited quality [5].

What the label says to watch for in these months

• Hyperkalemia. Risk rises with impaired kidney function, potassium supplements, potassium-containing salt substitutes, ACE inhibitors and ARBs. The label says that if hyperkalemia occurs, the dose should be decreased or spironolactone discontinued and the hyperkalemia treated [2].
• Hypotension and worsening kidney function, particularly with excessive diuresis, salt depletion, or ACE inhibitor or ARB use. NSAIDs, aminoglycosides and cisplatin add kidney risk [2]. NSAIDs can also blunt the diuretic and antihypertensive effect of spironolactone [2].
• Pregnancy. Because of anti-androgenic effects and rat data showing feminization of male fetuses, the label says to avoid spironolactone in pregnant women or advise a pregnant woman of the potential risk to a male fetus; limited human case reports did not show an association with major malformations [2].
• Food timing. The label says spironolactone can be taken with or without food but should be taken consistently with respect to food; food increased bioavailability by about 95% [2].
• Contraindications. Hyperkalemia, Addison's disease, and concomitant use of eplerenone [2].