Spironolactone
Brand names: Aldactone (Pfizer, tablets); CaroSpir (CMP Pharma, oral suspension)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| NYHA Class III–IV heart failure with reduced ejection fraction — to increase survival, manage edema, and reduce the need for HF hospitalisation | Adults | Per FDA label, usually administered in conjunction with other heart failure therapies | FDA Approved (Aldactone & CaroSpir) |
| Hypertension — to lower BP and reduce risk of fatal and non-fatal cardiovascular events | Adults not adequately controlled on other agents | Per FDA label, indicated as add-on therapy (not first-line) | FDA Approved (Aldactone & CaroSpir) |
| Edema in cirrhosis when not responsive to fluid and sodium restriction | Adults | Monotherapy or with other diuretics; particularly useful when other diuretics have caused hypokalemia | FDA Approved (Aldactone & CaroSpir) |
| Edema in nephrotic syndrome when other diuretics produce inadequate response (Aldactone tablets only — not CaroSpir) | Adults | Monotherapy or with other diuretics | FDA Approved (Aldactone) |
| Primary hyperaldosteronism — short-term preoperative treatment; long-term maintenance for adenomas in non-surgical candidates and for bilateral adrenal hyperplasia (Aldactone tablets only — not CaroSpir) | Adults | Monotherapy or as part of broader endocrine management | FDA Approved (Aldactone) |
Spironolactone occupies a unique position among diuretics. Mechanistically it is an aldosterone antagonist that promotes natriuresis while retaining potassium — an electrolyte profile precisely opposite to that of loop and thiazide diuretics. Clinically it has earned its place in heart-failure care less for its diuretic potency than for the survival benefit demonstrated in RALES (Pitt, NEJM 1999), in which spironolactone reduced all-cause mortality by 30% and cardiac hospitalisation by 30% in patients with NYHA Class III–IV heart failure and reduced ejection fraction. The 2022 ACC/AHA/HFSA Heart Failure Guideline gives mineralocorticoid receptor antagonists a Class 1, Level A-NR recommendation as one of the four pillars of guideline-directed medical therapy for HFrEF.
The 2025 FDA label positions spironolactone for hypertension specifically as add-on therapy in patients not adequately controlled on other agents — a meaningful update from older labelling that listed it as a more general antihypertensive option. This positioning reflects current evidence (notably the PATHWAY-2 trial) showing spironolactone’s particular value in resistant hypertension rather than as initial monotherapy. The agent also remains the established medical management of primary hyperaldosteronism, both as preoperative preparation and as long-term therapy for patients who are not surgical candidates.
Note that the FDA-approved indications differ between the two formulations. Aldactone tablets (Pfizer) and generic spironolactone tablets are approved for all four indication groups: HFrEF, hypertension as add-on, edema (cirrhotic and nephrotic), and primary hyperaldosteronism. CaroSpir oral suspension (CMP Pharma) is approved only for HFrEF, hypertension as add-on, and cirrhotic edema. CaroSpir is not indicated for nephrotic-syndrome edema or for primary hyperaldosteronism, and per FDA label is not therapeutically equivalent to tablets — clinically meaningful when switching between formulations.
Resistant hypertension — fourth-line agent after thiazide, ACEi/ARB, and CCB based on PATHWAY-2 (Williams, Lancet 2015), which showed spironolactone superior to bisoprolol and doxazosin in BP reduction. (Evidence: strong)
Heart failure with preserved ejection fraction (HFpEF) — TOPCAT (Pitt, NEJM 2014) showed regional variability with apparent benefit in the Americas cohort but not overall; current guidelines provide a Class 2b recommendation. (Evidence: moderate)
Acne and hirsutism in women — antiandrogenic effect; widely used dermatologically at 50–200 mg/day. (Evidence: moderate)
Female pattern hair loss (androgenetic alopecia) — at 100–200 mg/day. (Evidence: moderate)
Gender-affirming hormone therapy in transgender women — anti-androgen as part of feminising regimens; typical doses 100–200 mg/day. (Evidence: established clinical practice)
PCOS-associated hyperandrogenism — for hirsutism and acne refractory to combined oral contraceptives. (Evidence: moderate)
Refractory ascites in cirrhosis — first-line diuretic with stepwise addition of furosemide (commonly used at higher doses than the 25–200 mg labelled range). (Evidence: established clinical practice)
Dosing
Spironolactone dosing differs sharply across its four FDA-approved indications, reflecting the distinct mechanisms by which it provides benefit in each setting. The heart-failure dosing schedule is conservative because the goal is mortality benefit through neurohormonal blockade rather than diuresis, and because hyperkalemia is the dose-limiting toxicity. Higher doses are used in primary hyperaldosteronism and edema, where greater natriuretic effect is needed. Per FDA label, spironolactone may be taken with or without food but should be taken consistently with respect to meals, because food increases bioavailability by approximately 95.4%. The doses below refer to Aldactone tablets and generic spironolactone tablets; CaroSpir oral suspension uses different (lower) doses because it is not therapeutically equivalent to tablets — see the CaroSpir-specific note below.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| NYHA Class III–IV HFrEF (eligible patients only) | 25 mg PO once daily if K ≤ 5.0 mEq/L AND eGFR > 50 mL/min/1.73 m² | May increase to 50 mg PO once daily if tolerated and clinically indicated. If hyperkalemia develops on 25 mg/day, reduce to 25 mg every other day | 50 mg/day per the FDA-cited HF schedule (RALES mean dose at study end was 26 mg) | Per FDA label, in patients with eGFR 30–50 mL/min/1.73 m², consider initiating at 25 mg every other day due to hyperkalemia risk. Discontinue oral potassium supplements when initiating spironolactone in HF Check K and creatinine within 1 week of initiation, then per Warnings & Precautions schedule |
| Essential hypertension (add-on therapy) | 25–100 mg PO daily in single or divided doses | Titrate at two-week intervals based on BP response | Per FDA label, doses above 100 mg/day generally do not provide additional BP reductions | Per the 2025 FDA label, spironolactone is indicated as add-on therapy in patients not adequately controlled on other antihypertensive agents — not first-line PATHWAY-2 used 25–50 mg for resistant hypertension |
| Edema (cirrhosis or nephrotic syndrome) | 100 mg PO daily in single or divided doses (range 25–200 mg daily) — initiate in hospital setting in cirrhosis | When given as the sole diuretic agent, administer for at least 5 days before increasing dose to obtain desired effect per FDA label | 200 mg/day per the FDA-labelled range for edema | Per FDA label, in cirrhosis: initiate in hospital and titrate slowly because sudden electrolyte/fluid shifts may precipitate hepatic encephalopathy. Often combined with a loop diuretic at a 100:40 spironolactone:furosemide ratio in cirrhotic ascites per AASLD practice guidance Reduced clearance in cirrhosis means slow upward titration is essential |
| Primary hyperaldosteronism — preoperative | 100–400 mg PO daily | Titrate to BP and potassium response while preparing for adrenalectomy | 400 mg/day per the FDA-labelled range | Higher doses can produce profound antiandrogenic effects (gynecomastia, menstrual irregularity); plan for surgical correction in adenoma cases Confirm diagnosis with aldosterone-to-renin ratio and confirmatory testing first |
| Primary hyperaldosteronism — long-term maintenance (non-surgical adenoma; bilateral hyperplasia) | Use the lowest effective dose | Individualise based on BP, potassium, and tolerability | As needed (lower long-term doses preferred to limit antiandrogenic effects) | Eplerenone is an alternative for patients with intolerable antiandrogenic side effects — but note: concomitant eplerenone with spironolactone is contraindicated per the FDA label |
| Older adults (≥ 65 y) | Start at the lower end of the dose range for the given indication | Cautious titration with attention to renal function and potassium | As above | Per FDA label, spironolactone is substantially excreted by the kidney; risk of adverse reactions may be greater in patients with impaired renal function. Monitor renal function Hyperkalemia risk is particularly elevated in elderly patients on RAAS blockade |
| Pediatric patients | Per FDA label, safety and effectiveness in pediatric patients have not been established. Off-label paediatric use does occur (especially for HF, edema, and primary hyperaldosteronism) but with limited supporting evidence | If used off-label, monitor potassium and renal function carefully Some references cite weight-based regimens (1–3 mg/kg/day); confirm with paediatric specialty resources | ||
Per the FDA CaroSpir label, the oral suspension is not therapeutically equivalent to spironolactone tablets and uses different (lower) doses. CaroSpir hypertension dosing is 20 mg (4 mL) to 75 mg (15 mL) daily, with doses above 75 mg generally not providing additional BP reductions. In patients with eGFR 30–50 mL/min/1.73 m², initial dose is 10 mg (2 mL). Per the FDA label, in patients requiring a dose greater than 100 mg, use another formulation of spironolactone — doses of CaroSpir suspension greater than 100 mg may result in spironolactone concentrations higher than expected. Do not switch between tablet and suspension on a 1:1 mg basis without prescriber review. Refer to the CaroSpir prescribing information for full dosing detail.
The 25–50 mg/day used in HFrEF is roughly an order of magnitude lower than the 100–400 mg/day used in primary hyperaldosteronism or edema. The reason: in HF the goal is neurohormonal blockade, not natriuresis. RALES demonstrated mortality benefit at a mean dose of just 26 mg/day, where mineralocorticoid receptor blockade in cardiac, vascular, and renal tissue prevents adverse remodeling, fibrosis, and arrhythmia — at a dose low enough that the diuretic effect is modest. The dose-limiting toxicity is hyperkalemia, not insufficient diuresis. This is why eligibility criteria centre on baseline potassium (≤ 5.0 mEq/L) and eGFR (> 50 mL/min/1.73 m²) — replicating the RALES inclusion criteria. Patients excluded from RALES (creatinine > 2.5 mg/dL or recent 25% rise) should not be initiated on spironolactone outside of careful specialist-led monitoring.
Per the FDA label, food increases the bioavailability of spironolactone by approximately 95.4% (AUC). Patients should establish a routine pattern of taking the dose with regard to meals — taking it with food on some days and without on others creates substantial day-to-day variability in exposure. The practical recommendation is to take spironolactone at the same time each day, with breakfast or with the same meal, rather than to insist on either fasted or fed administration. The dose can be split across the day (twice daily) at higher edema or hyperaldosteronism doses, but once-daily morning dosing is standard for HF and add-on hypertension.
Pharmacology
Mechanism of Action
Spironolactone and its active metabolites are specific pharmacologic antagonists of aldosterone, acting primarily through competitive binding at the aldosterone-dependent sodium–potassium exchange site in the distal convoluted tubule. Per the FDA label, by competitively blocking the mineralocorticoid receptor, spironolactone causes increased excretion of sodium and water while potassium is retained. The drug functions as a potassium-sparing diuretic in edematous states and as an antihypertensive agent through the same receptor-blocking mechanism. In heart failure, the mortality benefit observed in RALES is attributed not to the modest diuretic effect at low doses but to broader mineralocorticoid receptor blockade in cardiac, vascular, and renal tissues — preventing aldosterone-mediated fibrosis, adverse remodeling, sympathetic activation, and arrhythmogenesis.
Spironolactone is also a mechanism-based androgen-receptor antagonist and a weak inhibitor of androgen biosynthesis — which underpins its widespread off-label use in dermatology and gender-affirming care, but also explains its principal class-typical adverse effects: gynecomastia, breast tenderness, decreased libido, erectile dysfunction in men, and menstrual irregularities in women. This antiandrogenic activity is dose-dependent and is the major reason eplerenone (a more selective MRA) is sometimes preferred when these effects are intolerable.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Per FDA label, mean Tmax for spironolactone is 2.6 h and for the active metabolite canrenone 4.3 h. Food increases the bioavailability of unmetabolised spironolactone by approximately 95.4% (AUC). Cmax and AUC are dose-proportional within the labeled range | The substantial food effect means patients should take spironolactone consistently with respect to meals to keep exposure stable. The relatively long Tmax for canrenone explains why diuretic onset is gradual — diuresis builds over several days rather than within hours |
| Distribution | Per FDA label, spironolactone and its metabolites are more than 90% bound to plasma proteins | High protein binding limits the unbound fraction available for renal filtration; the therapeutic effect comes from receptor occupancy in the distal nephron rather than tubular concentration. Ascites and hypoalbuminaemia in cirrhosis can alter free-fraction pharmacokinetics |
| Metabolism | Per FDA label, spironolactone is rapidly and extensively metabolised. Metabolites fall into two categories: those in which the sulfur of the parent molecule is removed (e.g., canrenone) and those in which sulfur is retained (e.g., TMS — 7-α-thiomethyl-spirolactone — and HTMS — 6-β-hydroxy-7-α-thiomethyl-spirolactone). All three metabolites are pharmacologically active and contribute to the therapeutic effect | The active-metabolite-dominant pharmacology has two clinical implications: (1) onset is slow because the metabolites must accumulate to steady state, and (2) the apparent half-life of effect (16+ hours) is much longer than the 1.4-hour parent compound half-life would suggest. Once-daily dosing is therefore appropriate for the HF and HTN indications |
| Elimination | Per FDA label, mean half-life of spironolactone is 1.4 h. Mean half-life of metabolites: canrenone 16.5 h, TMS 13.8 h, HTMS 15 h. Metabolites are excreted primarily in urine and secondarily in bile. The terminal half-life of spironolactone is increased in cirrhotic patients with ascites | Steady-state pharmacology is reached over several days; conversely, the effect persists for several days after discontinuation. In cirrhosis the prolonged half-life and reduced clearance argue for lower starting doses and slow titration |
Side Effects
The side-effect profile of spironolactone is dominated by two distinct mechanisms: mineralocorticoid receptor blockade (responsible for hyperkalemia, hyponatremia, hypotension, AKI) and androgen receptor antagonism / progesterone receptor agonism (responsible for gynecomastia, breast tenderness, menstrual irregularity, erectile dysfunction). Per the FDA label, the most common adverse reaction is gynecomastia, which in RALES occurred in approximately 9% of male subjects on a mean dose of 26 mg/day. Adverse-event frequencies for most other reactions are not estimable per the label because they derive from voluntary postmarketing reports.
| Adverse Effect | Incidence (FDA PI) | Clinical Note |
|---|---|---|
| Gynecomastia (in male HF patients on low-dose therapy) | ~9% in RALES at mean dose 26 mg/day per FDA PI | Per FDA label, risk increases in a dose-dependent manner; onset varies widely from 1–2 months to over a year. Per FDA label, gynecomastia is usually reversible after discontinuation, although established large breasts may not regress fully without surgical management |
| System / Adverse Effect | Frequency | Clinical Note |
|---|---|---|
| Reproductive / endocrine — decreased libido, erectile dysfunction (in men); irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain (in women) | Postmarketing | Reflect antiandrogenic and progesteronic activity; dose-dependent. Frequency is higher at the higher doses used for primary hyperaldosteronism, edema, or off-label dermatological indications than at HF doses |
| Metabolism — hyperkalemia, hyponatremia, hypovolemia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, hyperglycemia, asymptomatic hyperuricemia | Postmarketing | Per FDA label, hyperkalemia is the dose-limiting toxicity in HF; risk increased by impaired renal function, K supplementation, or concomitant ACEi / ARB / NSAID / heparin / trimethoprim. Per FDA label, gout may rarely be precipitated |
| Digestive — gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting | Postmarketing | Take with food to reduce GI symptoms (also improves bioavailability per label) |
| Nervous system / psychiatric — lethargy, mental confusion, ataxia, dizziness, headache, drowsiness | Postmarketing | Confusion or lethargy may signal hyponatremia or hyperkalemia — check electrolytes |
| Musculoskeletal — leg cramps | Postmarketing | Often related to electrolyte disturbance; check magnesium and potassium |
| System / Adverse Effect | Frequency | Clinical Note |
|---|---|---|
| Hematologic — leukopenia (including agranulocytosis), thrombocytopenia | Postmarketing | Obtain CBC if symptoms suggestive (fever, infection, bruising, bleeding) |
| Hypersensitivity — fever, urticaria, maculopapular or erythematous cutaneous eruption, anaphylactic reaction, vasculitis | Postmarketing | Discontinue at first sign of severe hypersensitivity |
| Liver / biliary — mixed cholestatic / hepatocellular toxicity | Postmarketing — one fatality reported per FDA label | Per FDA label, very rare; check LFTs if persistent fatigue, jaundice, or RUQ discomfort. Most cases reversible with discontinuation |
| Renal — renal dysfunction including renal failure | Postmarketing | Often reversible with volume repletion and drug discontinuation; risk increased with concomitant ACEi/ARB/NSAID |
| Adverse Effect | Risk Setting | Typical Onset | Required Action |
|---|---|---|---|
| Severe hyperkalemia (K > 6.0 mEq/L) — risk of arrhythmia, cardiac arrest | Greatest in CKD, diabetes, RAAS blockade, NSAID use, K supplementation per FDA label | Days to weeks | Hold drug; treat hyperkalemia per protocol (calcium, insulin/dextrose, beta-agonist, K-binder, dialysis if severe); review concurrent K-elevating drugs and supplements |
| Symptomatic hypotension and acute kidney injury | Salt-depleted patients, dual RAAS blockade, intercurrent illness with vomiting/diarrhea per FDA label | Days | Hold drug; assess volume status and creatinine; resume at lower dose; review concurrent ACEi/ARB/NSAID |
| Hepatic encephalopathy / impaired neurological function in cirrhosis | Per FDA label, sudden alterations in fluid and electrolyte balance can precipitate impaired neurological function and coma | Hours to days | Suspend or discontinue; reduce dose; treat precipitants of encephalopathy |
| Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), DRESS | Postmarketing reports per FDA label | Days to weeks after initiation | Discontinue immediately at first sign; hospital-level supportive care; never rechallenge |
| Anaphylaxis / vasculitis | Postmarketing per FDA label | Variable | Discontinue; standard anaphylaxis treatment; document allergy |
| Mixed cholestatic / hepatocellular toxicity (one fatality reported per FDA label) | Rare; postmarketing | Approximately one month after initiation in published case reports | Discontinue if confirmed; supportive care; LFTs typically normalise after withdrawal |
The single most important safety challenge with spironolactone in heart failure is real-world hyperkalemia, which has been more frequent in clinical practice than in RALES. Practical mitigation strategies that preserve mortality benefit while reducing risk include: (1) confirming pre-treatment K ≤ 5.0 mEq/L and eGFR > 50 mL/min/1.73 m² (or starting at 25 mg every other day if eGFR 30–50); (2) discontinuing oral potassium supplements and salt substitutes containing potassium when initiating spironolactone; (3) measuring potassium and creatinine within one week of initiation or any titration, then regularly thereafter; (4) reviewing — and where possible avoiding — concurrent NSAIDs, trimethoprim, heparin, and excessive RAAS-inhibitor doses; (5) holding the dose during acute illness with vomiting, diarrhea, or dehydration; and (6) considering newer potassium binders (patiromer, sodium zirconium cyclosilicate) when persistent hyperkalemia threatens guideline-directed medical therapy.
Drug Interactions
Spironolactone’s interaction profile is dominated by additive hyperkalemia with virtually any drug that elevates serum potassium — a long list that includes the very RAAS inhibitors with which spironolactone is co-prescribed in heart failure. Several interactions are unique to spironolactone among diuretics: interference with digoxin radioimmunoassays, the abiraterone interaction (PSA elevation), and the mitotane interaction (avoidance recommended). Patients started on spironolactone in heart failure should generally have their oral potassium supplementation discontinued, per the FDA label.
Monitoring
- Serum Potassium Baseline; within 1 week of initiation or titration; regularly thereafter — more frequently with concurrent K-elevating drugs or renal impairmentRoutine Per FDA label, monitor serum potassium within 1 week of initiation or titration of ALDACTONE and regularly thereafter. Eligibility for HF initiation: K ≤ 5.0 mEq/L. If hyperkalemia develops on 25 mg/day, reduce to 25 mg every other day. Hold or discontinue if K > 5.5 mEq/L pending workup.
- Renal Function (creatinine / eGFR / BUN) Baseline; within 1–2 weeks of initiation or dose change; routinely thereafterRoutine Per FDA label, monitor volume status and renal function periodically. Eligibility for HF initiation: eGFR > 50 mL/min/1.73 m² for full dose; eGFR 30–50 → consider 25 mg every other day; eGFR < 30 → generally avoid. Pay close attention if also on ACEi/ARB or NSAID.
- Other Electrolytes (Na, Mg, Ca, Cl, HCO₃) Baseline and periodically; more frequently in cirrhosis or high-dose therapyRoutine Per FDA label, monitor serum electrolytes, uric acid, and blood glucose periodically. Hyponatremia is common at higher doses, particularly in cirrhotic and elderly patients. Hypochloremic alkalosis may emerge at edema doses.
- Blood Pressure At each visit; orthostatic measurements in symptomatic patientsRoutine Per FDA label, dose-response for hypertension is not well characterised; doses above 100 mg/day generally do not provide additional BP reductions. Titrate at 2-week intervals because steady-state pharmacology takes several days to develop.
- Daily Body Weight (in HF / cirrhosis edema) Daily during dose titration and acute decongestionRoutine Aim for ~0.5 kg/day in cirrhotic patients without peripheral edema (to avoid intravascular volume contraction precipitating AKI or encephalopathy); up to 1 kg/day in patients with peripheral edema.
- Glucose and Uric Acid Baseline; periodically — particularly in diabetes or gout historyTrigger-based Per FDA label, asymptomatic hyperuricemia can occur and rarely gout is precipitated; monitor blood glucose periodically. Effects are generally smaller in magnitude than with thiazides.
- Lithium Levels (if on lithium) Within 5–7 days of starting or stopping spironolactone; routinely thereafterTrigger-based Per FDA label, spironolactone reduces renal clearance of lithium with high risk of lithium toxicity; monitor lithium levels periodically when co-administered.
- Digoxin Assay Selection (if on digoxin) At every digoxin level drawTrigger-based Per FDA label, in patients taking concomitant digoxin, use an assay that does not interact with spironolactone — historic radioimmunoassays falsely elevated apparent digoxin levels.
- Gynecomastia / Breast / Menstrual Symptoms Each visit; ask directly — patients may not volunteerTrigger-based Per FDA label, gynecomastia is dose-dependent with onset 1–2 months to over a year. Reduce dose or switch to eplerenone if intolerable; reassure that effects are usually reversible after discontinuation.
- Liver Function and Mental Status (in cirrhosis) Baseline and during dose changes; alert for any behavioural changeTrigger-based Per FDA label, sudden alterations in fluid and electrolyte balance can precipitate impaired neurological function and coma in patients with cirrhosis and ascites; consider suspending or discontinuing if encephalopathy develops.
- CBC / LFTs Baseline; whenever clinically suspiciousTrigger-based Postmarketing reports per FDA label include leukopenia (incl. agranulocytosis), thrombocytopenia, anemia, and rare mixed cholestatic / hepatocellular hepatotoxicity (one fatality). Obtain labs if symptoms suggestive.
Contraindications & Cautions
Absolute Contraindications (per FDA label)
The 2025 FDA Aldactone label formally lists three contraindications:
- Hyperkalemia — defer until potassium is corrected and the underlying cause addressed
- Addison’s disease — mineralocorticoid antagonism in a state of mineralocorticoid deficiency is dangerous
- Concomitant use of eplerenone — dual mineralocorticoid receptor blockade with no incremental benefit and additive hyperkalemia risk
Although not formally listed as a labelled contraindication, known severe hypersensitivity to spironolactone is a sensible additional contraindication given postmarketing reports of anaphylactic reactions, vasculitis, SJS/TEN, and DRESS.
Relative Contraindications (Specialist Input Recommended)
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²) — high hyperkalemia risk; per FDA label, generally avoid initiation in HF outside of specialist supervision
- Pregnancy — per FDA label, avoid in pregnancy or counsel about potential risk to a male fetus due to anti-androgenic properties; animal data show feminisation of male fetuses
- Decompensated cirrhosis with prior hepatic encephalopathy — per FDA label, initiate diuresis in hospital with slow titration
- Concomitant use with abiraterone — per FDA label, not recommended due to androgen-receptor-binding effect on PSA monitoring
- Concomitant use with mitotane — per FDA label, avoid due to reduced mitotane plasma levels
- Patients under 18 years of age — per FDA label, safety and efficacy in pediatric patients have not been established
Use with Caution
- Concurrent ACE inhibitors / ARBs — per FDA label, additive hyperkalemia risk; combination is therapeutic in HFrEF and should not be avoided per se but requires monitoring
- Concurrent NSAIDs — per FDA label, may reduce diuretic, natriuretic, and antihypertensive effect; additive hyperkalemia and AKI risk
- Concurrent trimethoprim or trimethoprim-sulfamethoxazole — per FDA label, additive hyperkalemia risk via ENaC inhibition
- Concurrent heparin / LMWH — per FDA label, additive hyperkalemia risk via aldosterone suppression
- Diabetes mellitus — increased hyperkalemia risk due to combined hyporeninemic-hypoaldosteronism
- Older adults — per FDA label, more likely to have decreased renal function; monitor renal function closely
- Lactation — per FDA label, canrenone is detected in breast milk in low amounts expected to be clinically inconsequential; weigh maternal need against unknown long-term infant effects
- Patients receiving digoxin — per FDA label, use a non-interacting digoxin assay
Per the 2025 FDA label, spironolactone does not carry an FDA boxed warning. The Warnings/Precautions section identifies four principal risks: (1) Hyperkalemia — increased by impaired renal function or concomitant K supplements / ACEi / ARB / NSAID / heparin / trimethoprim; (2) Hypotension and worsening renal function — particularly in salt-depleted patients or those on RAAS inhibitors; (3) Electrolyte and metabolic abnormalities — hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, hyperglycemia, and rare gout; (4) Gynecomastia — approximately 9% of male HF patients in RALES at a mean dose of 26 mg/day, dose-dependent and usually reversible.
Patient Counselling
Purpose of Therapy
Spironolactone is an “aldosterone blocker” — it works differently from most water tablets. Unlike most diuretics, which lower potassium, spironolactone tends to raise it. In heart failure, even at low doses, it has been shown to help patients live longer and stay out of hospital. It is also used to treat high blood pressure (usually as an add-on to other medicines), to reduce fluid build-up in liver disease and certain kidney conditions, and to treat a hormonal condition called primary hyperaldosteronism. The medicine takes several days to reach full effect because it has long-acting active byproducts in the body.
How to Take
Take spironolactone consistently with respect to food — taking it with food increases how much is absorbed by roughly twofold, so taking it with meals on some days but not others creates day-to-day variation. The simplest plan is to take it at the same time each day, ideally with breakfast or with the same meal. Most people take it once a day in the morning; some doses may be split into morning and afternoon. Do not stop the medicine suddenly without speaking to the prescriber, especially in heart failure where stopping can lead to fluid build-up. If a dose is missed, take it as soon as remembered unless it is close to the next scheduled dose; never double up. Important: if the prescription is changed between Aldactone tablets and CaroSpir oral suspension, the dose number is not the same — each formulation has its own dosing scale, so always confirm the new dose with the prescriber rather than matching mg-for-mg.
Sources & References
- Pfizer Inc. ALDACTONE® (spironolactone) tablets, for oral use — Prescribing Information. Reference ID: 5695854. Revised November 2025. accessdata.fda.gov/drugsatfda_docs/label/2025/012151s080lbl.pdfThe current FDA-approved label for the original tablet formulation — primary source for the four FDA-approved indications (HFrEF NYHA III–IV, hypertension as add-on, edema in cirrhosis or nephrotic syndrome, primary hyperaldosteronism), dosing, pharmacokinetics including the food effect, contraindications (hyperkalemia, Addison’s, eplerenone), Warnings/Precautions, drug interactions including the unique abiraterone and mitotane interactions, and the RALES gynecomastia rate of approximately 9% at mean dose 26 mg/day.
- CMP Pharma, Inc. CAROSPIR® (spironolactone) oral suspension — Prescribing Information. FDA approved August 4, 2017 (NDA 209478). accessdata.fda.gov/drugsatfda_docs/label/2017/209478s000lbl.pdfFDA-approved label for the only FDA-approved oral suspension of spironolactone. Indications are narrower than the tablet (HFrEF NYHA III–IV, hypertension as add-on, cirrhotic edema only — not nephrotic syndrome, not primary hyperaldosteronism). Per the label, CaroSpir is not therapeutically equivalent to tablets; doses greater than 100 mg may produce concentrations higher than expected, and another formulation should be used at higher doses.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063Class 1, Level A-NR recommendation for mineralocorticoid receptor antagonists (spironolactone or eplerenone) in HFrEF as one of the four pillars of guideline-directed medical therapy. Specifies eligibility criteria mirroring the RALES inclusion criteria.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065Modern hypertension guidance; spironolactone is recommended as a fourth-line agent for resistant hypertension after thiazide, ACEi/ARB, and CCB.
- Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure (RALES). N Engl J Med. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001The landmark trial — 1663 patients with NYHA III–IV HF and EF ≤ 35% randomised to spironolactone (mean dose 26 mg) or placebo on background loop diuretic and ACE inhibitor. Terminated early after mean 24 months for 30% reduction in all-cause mortality (95% CI 18–40%, p < 0.001) and 30% reduction in cardiac hospitalisation. The basis of the FDA HFrEF indication and of the modern eligibility criteria.
- Williams B, MacDonald TM, Morant S, et al; British Hypertension Society’s PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2). Lancet. 2015;386(10008):2059-2068. doi:10.1016/S0140-6736(15)00257-3PATHWAY-2 demonstrated spironolactone (25–50 mg) is superior to bisoprolol and doxazosin for resistant hypertension on background ACEi/ARB + CCB + thiazide; the foundation for current guideline preference for spironolactone as fourth-line therapy.
- Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction (TOPCAT). N Engl J Med. 2014;370(15):1383-1392. doi:10.1056/NEJMoa1313731TOPCAT did not meet its primary endpoint overall but showed apparent benefit in the Americas cohort; concerns about regional protocol-adherence drove a Class 2b guideline recommendation for spironolactone in HFpEF.
- Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ. 2011;343:d5228. doi:10.1136/bmj.d5228Population-based nested case-control study quantifying the markedly increased risk of hospitalisation for hyperkalemia when TMP-SMX is added to spironolactone in elderly patients — the basis for the cautious co-prescribing guidance.
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