Drug products: Aldactone®, Spironolacton AL, Spironolactone Accord, Spironolactone Orion, Spironolakton Pfizer, Spironolakton Takeda
ATC code: C03DA01
The indications for spironolactone are treatment of hypertension and as an add-on in severe cardiac failure. Some studies show that the anti-hypertensive effect of spironolactone is similar in men and women. However, other studies have shown better effect in post-menopausal women.
Spironolactone reduces the risk of morbidity and death in patients with severe cardiac failure. The effect is equal in men and women.
Spironolactone can block the androgen receptor and induce hormonal side effects in both men and women. Men using spironolactone have an increased risk of gynecomastia with high doses and long-term treatment. If this happens, a change to eplerenone or a lowered dose is recommended.
No studies with a clinically relevant sex analysis regarding the pharmacokinetics of spironolactone have been found. Effective reduction in blood pressure could be obtained also with lower doses (25-50 mg/day) of spironolactone. A lower dose may reduce the problem with sex steroid-related adverse effects , in particular the dose-dependent side effect gynecomastia in men [2, 3].
Studies analyzing sex differences in blood pressure reduction after spironolactone treatment report contradictory results. The effect of spironolactone on blood pressure was evaluated among hypertensive patients in the ASCOT-BPLA trial (1091 men, 320 women), a large-scale, randomized, controlled study. Overall, similar reductions in blood pressure (BP) were observed in men and women. However, there were modest but significantly greater reduction in diastolic BP among women compared with men. This difference did not differ after adjustment for pre-spironolactone BP levels .In a post-hoc analysis of the APIRANT trial (37 men, 18 women), treatment with 25 mg spironolactone once daily or placebo for 8 weeks in patients with resistant hypertension, resulted in similar reductions in systolic and diastolic BP in men and women .One study on primary-care hypertensive patients (45 men, 45 women) treated with potassium kanrenoate (the active metabolite of spironolactone), reported that the drug was twice as effective in reducing systolic BP in women compared to men after 2 months of treatment. A subgroup analysis of the results showed that the larger effect was obtained in postmenopausal women, suggesting a role of aldosterone in these patients .
The favorable effect of spironolactone on heart failure related mortality appears to be similar for both men and women [7, 8].
Because of its non-selective binding to the mineralocorticoid receptor, spironolactone can antagonize the androgen receptor causing a variety of sexual adverse events in both men and women . Clinical trials have reported gynecomastia as a commonly sex hormone-related adverse event in men [3, 4, 8]. In the RALES study, examining the effect of 25 mg spironolactone on symptomatic heart failure patients (1217 men, 446 women), 10% of men taking spironolactone complained of gynecomastia and/or breast pain, as compared with 1% of men in the placebo group . Also in the ASCOT trial (1091 men, 320 women), analyzing the effect of 25-50 mg spironolactone on blood pressure, gynecomastia or breast discomfort was recorded as an adverse event in 6% of spironolactone treated patients (all men), resulting in discontinuation in 3.7%. However, as the study was not focused on adverse events of spironolactone, the authors suggested gynecomastia could be more common .
The risk of gynecomastia should not be an argument against the use of spironolactone in men with severe heart failure, since spironolactone reduces the risk of both morbidity and death [k1] . If gynecomastia occurs, switching to eplerenone might be an option.
Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).
Treatment and 6-month outcome were compared among men and women in a prospective cross-sectional Italian study in heart failure patients (1127 men, 1000 women) admitted to hospital. Women were less frequently treated with spironolactone compared with men in-hospital. At discharge, spironolactone was less frequently prescribed to women. A possible explanation to this might be that spironolactone is not used in patients with preserved left ventricular function, which included many of the women in this study . Spironolactone is more used in women with hypertension but apparently not in heart failure.
Date of litterature search: 2019-03-04
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson