Spironolactone

Registered South African indications:

• Essential hypertension
• Primary hyperaldosteronism
• Establishing a diagnosis of primary hyperaldosteronism
• Congestive heart failure
• Severe heart failure (NYHA class III-IV)
• Conditions in which secondary hyperaldosteronism may be present, including liver cirrhosis accompanied by oedema and/or ascites, nephrotic syndrome, and other oedematous conditions
• Diuretic-induced hypokalaemia/hypomagnesaemia

Contraindications

South African recommendations

• Hypersensitivity to spironolactone or to any of the excipients
• Acute renal insufficiency
• Rapidly progressing impairment of renal function
• Anuria
• Hyperkalaemia
• Concomitant use of eplerenone
• Addison’s disease

Recommendations in other jurisdictions

• Acute renal insufficiency
• Significant renal compromise
• Anuria
• Addison's disease
• Hyperkalaemia
• Hypersensitivity to spironolactone or to any of the excipients
• Concomitant use of eplerenone or other potassium sparing diuretics
• Paediatric patients with moderate to severe renal impairment
• Concurrent administration with other potassium-conserving diuretics and potassium supplements
• Porphyria

Cautions

• Pregnancy
• Breastfeeding
• Hepatic impairment
• Elderly
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Essential hypertension

• Oral (tab): 50-100mg/day, as a single dose or in divided doses; Difficult or severe cases: Titrate gradually at intervals of 2 weeks up to 200mg/day; Continue treatment for ≥2 weeks to ensure an adequate response to therapy; Dose should be adjusted as needed

Establishing a diagnosis of primary hyperaldosteronism
Long test

• Oral (tab): 400mg/day, as a single dose or in divided doses; Treatment duration: 3-4 weeks

---

Correction of hypokalaemia and of hypertension provides presumptive evidence or the diagnosis of primary hyperaldosteronism

---

Short test

• Oral (tab): 400mg/day, as a single dose or in divided doses; Treatment duration: 4 days

---

If serum potassium increases during spironolactone administration, but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered

---

Spironolactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets

---

Primary hyperaldosteronism
- For short-term preoperative treatment after diagnosis of hyperaldosteronism has been established by more definitive testing procedures

• Oral (tab): 100-400mg/day, as a single dose or in divided doses in preparation for surgery

---

For patients who are considered unsuitable candidates for surgery, spironolactone may be employed for long term maintenance therapy at the lowest effective dosage determined for the individual patient

---

Congestive heart failure (Additional agent(s) may be required)
- As monotherapy or in combination with standard therapy

• Oral (tab): Initial: 100mg/day, as a single dose or in divided doses; Range for dosing: 25-200mg/day; Maintenance dose should be individually determined

Severe heart failure (NYHA class III-IV) (Additional agent(s) required)
- In combination with standard therapy

• Oral (tab): Initial: 25mg, dly if serum potassium is ≤5.0mmol/l and serum creatinine is ≤220µmol/l; If tolerant to 25mg/day: Increase to 50mg/day, as clinically indicated; If not tolerant to 25mg/day: Reduce dose to 25mg, every other day

Conditions in which secondary hyperaldosteronism may be present (Additional agent(s) may be required)
 - As monotherapy or in combination with standard therapy in liver cirrhosis accompanied by oedema and/or ascites

• Oral (tab): If urinary Na⁺/K⁺ ratio is >1.0: 100mg/day, as a single dose or in divided doses; If the ratio is <1.0: 200-400mg/day, as a single dose or in divided doses; Maintenance dose should be individually determined

- As monotherapy or in combination with standard therapy in nephrotic syndrome

• Oral (tab): 100-200mg/day, as a single dose or in divided doses

---

Spironolactone has not been shown to affect the basic pathological process, and its use is advised only if other therapy is ineffective

---

Diuretic-induced hypokalaemia/hypomagnesaemia
- As adjunctive therapy

• Oral (tab): 25-100mg/day, as a single dose or in divided doses

---

Spironolactone may be useful in treating diuretic-induced hypokalaemia and/or hypomagnesaemia when oral potassium and/or magnesium supplements are considered inappropriate

---

Indications and dosages registered in other jurisdictions

Congestive cardiac failure with oedema

• Oral (tab): Initial: 100mg/day, as a single dose or in divided doses; Range for dosing: 25-200mg/day; Maintenance dose should be individually determined

Severe heart failure (New York Heart Association Class III-IV) (Additional agent(s) required)
- In conjunction with standard therapy

• Oral (tab): Initial: 25mg, dly if serum potassium is ≤5.0mEq/l and serum creatinine is <2.5mg/dL; If tolerant to 25mg/day: Increase to 50mg/day, as clinically indicated; If not tolerant to 25mg/day: Reduce dose to 25mg, every other day

Hepatic cirrhosis with ascites and oedema

• Oral (tab): If urinary Na⁺/K⁺ ratio is >1.0: 100mg/day; If the ratio is <1.0: 200-400mg/day; Maintenance dose should be individually determined

Malignant ascites

• Oral (tab): 100-200mg/day; Severe cases: Titrate gradually up to 400mg/day; Maintenance dosage should be individually determined once oedema is controlled

Nephrotic syndrome

• Oral (tab): 100-200mg/day 

---

Spironolactone has not been shown to be anti-inflammatory, or to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective

---

Diagnosis of primary aldosteronism
Long test

• Oral (tab): 400mg/day; Treatment duration: 3-4 weeks

---

Correction of hypokalaemia and of hypertension provides presumptive evidence or the diagnosis of primary hyperaldosteronism

---

Short test

• Oral (tab): 400mg/day; Treatment duration: 4 days

---

If serum potassium increases during spironolactone administration, but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered

---

Spironolactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets

---

Primary hyperaldosteronism
- For treatment after diagnosis of hyperaldosteronism has been established by more definitive testing procedures

• Oral (tab): 100-400mg/day, in preparation for surgery

---

For patients who are considered unsuitable candidates for surgery, spironolactone may be employed for long term maintenance therapy at the lowest effective dosage determined for the individual patient

Paed. forms avail. in SA and covered in this monograph: tab

Paed. dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Essential hypertension
Establishing a diagnosis of primary hyperaldosteronism
Primary hyperaldosteronism
- Short-term preoperative treatment
Congestive heart failure (Additional agent(s) may be required)
- As monotherapy or in combination with standard therapy
Severe heart failure (NYHA class III-IV) (Additional agent(s) required)
- In combination with standard therapy
Conditions in which secondary hyperaldosteronism may be present (Additional agent(s) may be required)
- As monotherapy or in combination with standard therapy in liver cirrhosis accompanied by oedema and/or ascites
- As monotherapy or in combination with standard therapy in nephrotic syndrome
- As monotherapy or in combination with standard therapy in other oedematous conditions
Diuretic-induced hypokalaemia/hypomagnesaemia
- As adjunctive therapy

• Oral (tab): Initial: 3mg/kg body weight, in divided doses; Dosage should be adjusted on the basis of response and tolerance

---

Spironolactone is insoluble in water but the tablets may be crushed and given in suspension if necessary

---

Indications and dosages registered in other jurisdictions

Children should only be treated under guidance of a paediatric specialist

Congestive cardiac failure with oedema
Severe heart failure (New York Heart Association Class III-IV) (Additional agent(s) required)
- In conjunction with standard therapy
Hepatic cirrhosis with ascites and oedema
Malignant ascites
Nephrotic syndrome
Diagnosis of primary aldosteronism
Primary hyperaldosteronism
- For treatment after diagnosis of hyperaldosteronism has been established by more definitive testing procedures

• Oral (tab): Initial: 1-3mg/kg body weight, in divided doses; Dosage should be adjusted on the basis of response and tolerance

---

There is limited paediatric data available

Pregnancy

• Caution
• There are very limited data on the use of spironolactone during pregnancy in humans
• Experimental animal studies have shown reproductive toxicity associated with the anti-androgenic effect of spironolactone. Spironolactone should not be used during pregnancy
• Diuretics can lead to reduced perfusion of the placenta and thus to impairment of intrauterine growth and are therefore not recommended for the standard therapy for hypertension and oedema during pregnancy

Breastfeeding

• Caution; not recommended
• Canrenone, the principal and active metabolite of spironolactone, appears in small quantities in human breast milk. Spironolactone should not be used during breastfeeding. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from spironolactone-therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the women

Renal Impairment

• Contraindicated

Hepatic Impairment

• Caution; no dose adjustment recommended 

Elderly

• Caution; no dose adjustment recommended 

Porphyria Information

• Porphyrinogenic (P)

Drugs in Sport

• Prohibited - At all times

Central Nervous System Disorders

• Drowsiness
• Headache
• Ataxia
• Coma
• Fatigue
• Confusion
• Weakness
• Lethargy
• Paraesthesia
• Paralysis
• Paraplegia
• Dizziness

Cardiovascular Disorders

• Vasculitis
• Hypotension

Gastrointestinal Disorders

• Diarrhoea
• Indigestion
• Nausea and vomiting
• Gastric inflammation
• Gastric ulcers
• Intestinal haemorrhage
• Cramps

Hepatobiliary Disorders

• Hepatitis
• Transient hepatic coma

Genitourinary Disorders

• Elevated serum creatinine levels
• Acute renal failure

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hyponatraemia
• Impotence
• Gynecomastia
• Hirsutism 
• Irregular menses
• Electrolyte imbalance
• Hyponatraemia
• Diabetes mellitus
• Acidoses
• Dehydration
• Porphyria
• Increase in nitrogen levels in the blood and urine
• Hyperuricemia

Musculoskeletal Disorders

• Muscle spasms
• Leg cramps
• Systemic lupus erythematosus
• Osteomalacia

Skin and Subcutaneous Tissue Disorders

• Maculopapular or erythematous cutaneous eruptions
• Eczema
• Rash
• Urticaria
• Erythema
• Chloasma
• Pruritus
• Exanthema
• Alopecia
• Erythema annulare centrifugum
• Hypertrichosis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis 
• Drug rash with eosinophilia and systemic symptoms 
• Pemphigoid

Immune, Blood and Lymphatic System Disorders

• Breast cancer
• Thrombocytopenia
• Eosinophilia
• Leukopenia 
• Hypersensitivity

Sensory Disorders

• Deepening voice

• Eplerenone
• Other potassium-sparing diuretics/ conserving diuretics
• Potassium supplements
• Agents that increase serum potassium
• Angiotensin-converting enzyme inhibitors
• Ciclosporin
• Heparin or low molecular weight heparin 
• Non-steroidal anti-inflammatory drugs
• Anticoagulants
• Noradrenaline
• Antihypertensive agents
• Lithium 
• Digoxin
• Central nervous system depressants
• Cholestyramine
• Corticosteroids
• Liquorice  

Renal function

Spironolactone is a specific antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule. Spironolactone binds to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone's primary function is to retain sodium and excrete potassium in the kidneys.

Tablet 25mg

• Aldactone (Pfizer) originator
• Sandoz Spironolactone (Sandoz)
• Spiractin (Pharmacare)

Tablet 100mg

• Aldactone (Pfizer) originator
• Spiractin (Pharmacare)