Spironolactone Side Effects
Spironolactone causes menstrual irregularities in 15-40% of women, breast tenderness in 3-5%, hyperkalemia in 5%, and gastrointestinal symptoms in 2%, with most side effects being dose-dependent and manageable through dose adjustment or concurrent hormonal contraception. 1
Most Common Side Effects
Menstrual Irregularities (Most Frequent)
- Occur in 15-30% of patients according to the American Academy of Dermatology, though rates as high as 40.6% have been reported in clinical trials (compared to 0% with placebo; RR 10.89). 1, 2
- The specific pattern is typically metrorrhagia with shortened cycles (often 14-day cycles), which while not medically dangerous, can be intolerable to patients. 2, 3
- Strongly dose-dependent: relative risk of 4.12 at 200mg/day compared to lower doses. 2
- Mitigation strategy: Concomitant use of combined oral contraceptives (COCs) or hormonal IUDs substantially reduces menstrual irregularities. 1, 2
Breast-Related Effects
- Breast tenderness and enlargement occur in 3-5% of women. 1, 4
- Gynecomastia occurs in men at a rate of 1.8%, is dose-dependent, and may necessitate switching to eplerenone. 5, 6
- Breast and nipple pain reported in FDA labeling. 7
Diuretic Effects
- Diuresis is common and expected given the mechanism of action. 1
- Can lead to hypovolemia and electrolyte disturbances. 7
Neurological Symptoms
- Fatigue, headache (2%), and dizziness (3-4%) are commonly reported. 1, 4
- Lethargy, mental confusion, ataxia, and drowsiness listed in FDA labeling. 7
Gastrointestinal Effects
- Gastritis occurs in approximately 2% of patients. 6
- Nausea (2-4%), gastric bleeding, ulceration, diarrhea, cramping, and vomiting reported. 4, 7
Sexual Function
- Decreased libido and inability to achieve or maintain erection in men. 4, 7
- Irregular menses or amenorrhea in women. 7
Serious Side Effects Requiring Monitoring
Hyperkalemia (Most Serious)
- Occurs in approximately 5.3% of patients in real-world practice. 6
- Risk factors include: older age, renal impairment (creatinine clearance decreases from ~65 to ~50 ml/min at onset), diabetes, chronic kidney disease, hypertension, and concomitant use of ACE inhibitors, ARBs, NSAIDs, or digoxin. 1, 5, 6
- Monitoring protocol: Check potassium before starting, at 1 and 4 weeks after initiation, and after any dose increase. 5
- Management: If K+ >5.5 mmol/L, halve the dose; if K+ ≥6.0 mmol/L, stop immediately and treat hyperkalemia. 5
- Patients should avoid high-potassium diets. 1
Renal Function Deterioration
- Worsening renal function can occur, particularly in patients with pre-existing kidney disease. 5
- Spironolactone is substantially excreted by the kidney, increasing risk in elderly patients. 7
Hepatic Effects
- Can cause sudden alterations in fluid and electrolyte balance, precipitating hepatic encephalopathy and coma in patients with cirrhosis and ascites. 5, 7
- Very rare cases of mixed cholestatic/hepatocellular toxicity with one reported fatality. 7
Rare but Serious Reactions
Hypersensitivity
- Fever, urticaria, maculopapular or erythematous eruptions, anaphylactic reactions, vasculitis. 7
- Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome reported. 7
Hematologic
- Leukopenia (including agranulocytosis) and thrombocytopenia. 7
Dermatologic
- Alopecia (scalp hair loss) reported. 7, 3
- Chloasma (hyperpigmentation) is a previously rare complication that tends to occur late in treatment. 8
Pregnancy and Reproductive Considerations
Pregnancy Risk
- Spironolactone is pregnancy category C and should not be used in pregnancy. 1, 7
- Crosses the placenta and may cause feminization of male fetuses based on animal studies at high doses. 1, 4, 7
- Limited human data: 5 cases with normal male genital development, 1 case of ambiguous genitalia when exposed until week 5 of gestation. 1
- Patients must be counseled to avoid pregnancy; concurrent COC use is often indicated. 1, 4
Lactation
- Spironolactone not present in breast milk, but active metabolite (canrenone) is present in low, likely clinically inconsequential amounts. 7
Cancer Risk (Long-Term Safety)
Tumorigenicity Warning
- FDA warning based on rat studies exposed to 150 times human doses showing tumors in thyroid, testes, and liver. 1, 7
Human Evidence (Reassuring)
- Systematic review of 7 studies with 4.5 million individuals showed 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) based on low to very low certainty evidence. 1
- Decreased prostate cancer risk (RR 0.79) compared to non-users based on very low certainty evidence. 1
- Long-term studies up to 8 years show no serious illnesses attributable to spironolactone. 4, 9
Practical Management Strategies
Dose Optimization
- Start with 100mg daily (or 50mg twice daily on cycle days 4-21) to balance efficacy with tolerability. 2, 4, 3
- Lower doses (75-100mg daily) are as effective as higher doses (150-300mg daily) but with substantially fewer side effects. 2, 4
- In one study, 68% of women on 100mg twice daily required dose reduction due to side effects, primarily metrorrhagia. 3
Monitoring Schedule
- Regular review during the initial 3 months of treatment is advised, as side effects tend to occur early. 8
- Potassium and renal function monitoring essential in high-risk patients. 1, 5