What are the common side effects of spironolactone?

Spironolactone is a mineralocorticoid antagonist that acts on the distal tubule in the nephrons of the kidney, specifically upon aldosterone-dependent sodium-potassium exchange sites.¹ Via competitive binding on the aldosterone receptors, spironolactone causes water and sodium loss, while conserving potassium.^2–6 It is recommended for the treatment of hypertension, heart failure, edema, and ascites.¹

The manufacturer’s prescribing information offers an extensive list of adverse reactions that have been reported in patients taking spironolactone. They do not provide information on the frequency of these side effects, nor can they ascertain the reliability of the reported side effects having a causal relationship with the use of the drug because the list is a summary of passive reporting systems, clinical trials, and post-marketing reports.¹ Some of the clinical trials are described further below.

Spironolactone also has an affinity for progesterone and androgen receptors, raising the levels of these hormones in some patients who are receiving this drug. This accounts for some of the side effects of spironolactone, such as menstrual irregularities in women and gynecomastia in men.^3,7

To ascertain the safety and frequency of patient-reported side effects of spironolactone, Shaw and White conducted a mail-in survey of women who had taken spironolactone (50 – 200 mg/day) for acne, an off-label use, for up to eight years in a Chicago dermatology practice.⁸ Of 173 surveys mailed, 91 were completed. At least one side effect was reported by 59% of respondents. The frequency of reported side effects among these women was: diuresis (29%), menstrual irregularities (22%), fatigue (17%), headache (14%), dizziness (12%), lightheadedness (11%), breast tenderness (17%), and decreased libido (15%). Although the side effects were not serious, 15% of women surveyed stopped taking the drug because of them. The actual rates of side effects may be different than reported because of the low survey response rate (43%) and lack of a control group, but this survey suggests some basis for relative frequencies of potential adverse effects. 

As mentioned, gynecomastia is consistently reported as a side effect of spironolactone use.^1,9–13 The incidence of gynecomastia ranged from 4% to 14% depending on the population studied.

Nishizaka et al conducted an open-label study on a cohort of 76 patients with resistant hypertension.¹¹ They found that 14% of the men developed gynecomastia when taking between 12.5 – 50 mg/day of spironolactone.

Jeunemaitre et al used a computerized database (ARTEMIS) of clinical metrics at two Paris hypertension clinics to follow 182 patients taking spironolactone monotherapy.¹⁰ They reported that 91 (13%) of 699 male patients taking spironolactone developed gynecomastia. These researchers concluded the gynecomastia was reversible and dose-related. Patients taking 50 mg or less per day yielded an incidence rate of 6.9%, whereas daily doses of 150 mg or higher yielded an incidence rate of 52.2%.

Chapman et al evaluated 1,790 patients from the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm randomized trial who received spironolactone for any reason.¹² The median dose of spironolactone was 25 mg during the period of observation. Gynecomastia or breast discomfort was recorded in 114 (6%) of the male patients. This compared with a rate of 0.6% of gynecomastia or breast discomfort among study participants who did not take spironolactone.

De Souza et al conducted a prospective trial of 175 patients with resistant hypertension who were receiving spironolactone in doses ranging from 25 to 100 mg/day.¹³ Gynecomastia or breast discomfort occurred in 4% of all patients, including one woman with breast discomfort. In the same study, one man discontinued spironolactone because of reduced libido.

Erectile dysfunction (ED) has also been reported among men taking spironolactone.^1,14 It is thought to be a consequence of the drug’s blocking of the progesterone receptors. A case report described a 49-year old man who reported ED while taking spironolactone.¹⁵ He discontinued the drug and was subsequently able to achieve and maintain an erection.

Spironolactone administration has been reported to induce irregular menses, amenorrhea, and postmenopausal bleeding.¹ Hughes et al surveyed 47 women taking spironolactone for hirsutism or acne (200 mg/day for 1 – 45 months) of whom 33 (72%) reported disturbances in the menstrual cycle.¹⁶ In another survey of women aged 16 to 40 years who were taking spironolactone (≤100 mg/day) for hypertension or edema that resulted from kidney disease, six out of nine women reported amenorrhea.¹⁷ In each case, discontinuation of the drug resulted in resumption of menses within two months.  

The potassium-sparing action of spironolactone increases the risk of the serious but uncommon side effect of hyperkalemia.^{1,3,11–13,17,18} This is particularly true for patients with reduced kidney function and patients who are also taking other drugs that affect the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Manufacturer’s prescribing information recommend that serum potassium levels should be monitored regularly during spironolactone therapy.¹ Hyperkalemia is defined as elevation of the serum potassium level, but the cut-off of serious hyperkalemia varies in different studies (generally between 5 – 6 mmol/L). Reported rates of hyperkalemia among patients taking spironolactone range from 1.1%,¹³ 1.6%,¹⁸ 2.6%,¹¹ 4%,¹² and 12%.¹⁹

Gastric hemorrhage, gastritis, diarrhea, nausea, and vomiting have all been reported as side effects of spironolactone.¹ Gulmez et al conducted a case-control study in Denmark to estimate the risk of upper gastrointestinal bleeding (UGIB) in spironolactone users.²⁰ Among 3,652 cases of UGIB from 1995 to 2006, the use of spironolactone significantly increased the risk of UGB compared to age- and gender-matched controls (odds ratio 2.7, 95% confidence interval [CI] [2.2 – 3.2]).

Because of the known endocrine effects of spironolactone, the possibility that use of this drug might increase the risk of certain endocrine cancers has been considered.^1,21,22 Using a primary care database, the Clinical Practice Research Datalink, MacKenzie et al conducted a matched cohort study that compared cancer rates in the United Kingdom of 74,272 patients exposed to spironolactone matched 1:2 with unexposed controls.²² In this study, there was no evidence of an increased risk of any cancer associated with spironolactone use, but spironolactone use was associated with a significantly lower risk of prostate cancer (hazard ratio 0.69, 95% CI [0.60 – 0.80], p<0.001).

Other less common but more serious case reports from the manufacturer include Stevens-Johnson syndrome, toxic epidermal necrolysis, and agranulocytosis.¹

^References

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