Spironolactone Side Effects
Spironolactone causes menstrual irregularities in 15-40% of women (most commonly metrorrhagia with shortened cycles), breast tenderness in 3-5%, hyperkalemia in 2-5%, and gynecomastia in up to 10% of men, with most side effects being dose-dependent and manageable through dose adjustment or concurrent hormonal contraception. 1
Common Side Effects by Frequency
Menstrual Irregularities (15-40%)
- Menstrual irregularities are the most common side effect, occurring in 40.6% of patients in clinical trials compared to 0% with placebo (RR 10.89). 1
- The specific pattern is typically metrorrhagia with shortened 14-day cycles, which while not medically dangerous, can be intolerable to patients. 2, 3
- This side effect is strongly dose-dependent, with a relative risk of 4.12 (95% CI 3.27-5.19) at 200mg/day compared to lower doses. 2
- Concurrent use of combined oral contraceptives (COCs) or hormonal IUDs substantially reduces menstrual irregularities and is specifically recommended by the American Academy of Dermatology. 1, 2
Breast-Related Effects (3-10%)
- Breast tenderness occurs in 3-5% of women and up to 10% of men compared to placebo. 1, 4
- Gynecomastia (breast enlargement) affects 1.8-6% of patients, is dose-dependent, and may necessitate switching to eplerenone in men. 1, 4, 5
- Breast and nipple pain can occur in both sexes. 6
Electrolyte Disturbances (2-5%)
- Hyperkalemia occurs in 2-5% of patients and is the most potentially serious side effect, especially in elderly patients and those with renal impairment. 4, 6, 5
- Hyponatremia and hypovolemia can also occur. 6
Other Common Effects
- Diuresis, fatigue, headache, and dizziness are frequently reported. 1
- Gastritis and gastrointestinal symptoms (nausea, vomiting, diarrhea, cramping) occur in approximately 2% of patients. 6, 5
- Decreased libido and sexual dysfunction can occur. 7, 6
High-Risk Populations Requiring Monitoring
Potassium Monitoring is Essential For:
- Older patients, those with hypertension, diabetes mellitus, or chronic kidney disease. 1
- Patients taking ACE inhibitors, ARBs, NSAIDs, or digoxin, as these medications increase hyperkalemia risk. 1, 4
- Monitor potassium before starting treatment, at 1 and 4 weeks after initiation, and after any dose increase. 4
- If potassium rises to >5.5 mmol/L, halve the dose; if ≥6.0 mmol/L, stop immediately and treat hyperkalemia. 4
Renal Function Monitoring
- Worsening renal function can occur, particularly in patients with pre-existing kidney disease. 4, 6
- In patients who developed hyperkalemia, average creatinine clearance decreased from 64.6 ml/min to 50.3 ml/min. 5
- Spironolactone is substantially excreted by the kidney, making elderly patients at higher risk for adverse reactions. 6
Pregnancy and Reproductive Considerations
Absolute Contraindication in Pregnancy
- Spironolactone should not be used in pregnancy due to its anti-androgenic properties. 1, 6
- Animal studies show feminization of male fetuses at high doses, and spironolactone crosses the placenta. 1, 6
- Human data include one case of ambiguous genitalia in a newborn whose mother used spironolactone until week 5 of gestation. 1
- Concurrent COC use is strongly recommended both to prevent pregnancy and to minimize menstrual irregularities. 1
Lactation
- Spironolactone is not present in breast milk, but the active metabolite canrenone is present in low amounts expected to be clinically inconsequential. 6
Hepatic Impairment Risks
- Spironolactone can cause sudden alterations of fluid and electrolyte balance, precipitating impaired neurological function, worsening hepatic encephalopathy, and coma in patients with cirrhosis and ascites. 6
- In patients with cirrhosis, initiate spironolactone in the hospital and start with the lowest dose, titrating slowly. 6
Cancer Risk: Reassuring Long-Term Data
- Despite FDA warnings based on rat studies at 150 times human doses, large cohort studies of 4.5 million individuals show no increased risk of breast (RR 1.04), ovarian (1.52), bladder (0.89), kidney (0.96), gastric (1.02), or esophageal cancer (1.09). 1
- Spironolactone use is associated with decreased prostate cancer risk (RR 0.79) based on very low certainty evidence. 1
- Long-term studies up to 8 years show no serious illnesses attributable to spironolactone use. 7, 8
Rare but Serious Side Effects
- Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome have been reported. 6
- Leukopenia (including agranulocytosis) and thrombocytopenia can occur. 6
- Anaphylactic reactions, vasculitis, and urticaria are possible hypersensitivity reactions. 6, 3
- Very rare cases of mixed cholestatic/hepatocellular toxicity with one reported fatality. 6
Practical Dosing to Minimize Side Effects
- Start with 100mg daily (or 50mg twice daily on cycle days 4-21) to balance efficacy with tolerability. 2, 7, 3
- Lower doses (75-100mg daily) are as effective as higher doses (150-300mg daily) but with substantially fewer side effects. 2, 7
- The median effective dose in large studies is 25-50mg for cardiovascular indications. 5, 9
- Avoid high-potassium diets during treatment. 1