Spironolactone (Aldactone) is a mineralocorticoid antagonist and a diuretic drug. It also acts as an antiandrogen and is therefore used in acne and hirsutism in females.

Spironolactone Uses:

• Edema:

  • Management of edema in liver cirrhosis when not responsive to fluid and sodium restriction.
  • Tablet only:
    • Management of edema for nephrotic syndrome when unresponsive to the treatment of underlying disease, restriction of fluid and sodium intake, and use of other diuretics; may be useful for the treatment of edema when other diuretics have caused hypokalemia.

• Heart failure:

  • To increase survival, manage edema and reduce hospitalization for heart failure in patients with New York Heart Association (NYHA) class III to IV and reduced ejection fraction;
  • usually administered in conjunction with other heart failure therapies
  • Guideline recommendations:
    • The American College of Cardiology/American Heart Association (ACC/AHA) 2013 heart failure guidelines recommend the use of aldosterone antagonists, along with other guideline-directed medical therapies, to reduce morbidity and mortality in patients with heart failure (NYHA class III to IV) with left ventricular ejection fraction (LVEF) 35% or less.

• Hypertension:

  • Management of hypertension unresponsive to other therapies.
  • Note: for the initial treatment of hypertension, it is not recommended.

• Primary hyperaldosteronism (tablet only):

  • Short-term preoperative treatment of primary hyperaldosteronism;
  • in long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas/malignancies who are not candidates for surgery;
  • long-term maintenance therapy for bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

• Off Label Use of Spironolactone in Adults:

  • Acne vulgaris in females;
  • Heart failure (NYHA class II; LVEF ≤35%);
  • Heart failure (post-myocardial infarction; LVEF ≤40%):;
  • Hirsutism;
  • Hormone therapy for transgender females (male-to-female)

Spironolactone Dose in Adults

Note:

• Suspension is NOT therapeutically equivalent to tablets. In patients who need >100 mg/dose, use tablets (using >100 mg/dose of suspension may result in spironolactone concentration higher than expected).

Spironolactone Dose in the treatment of Edema:

• Note: When used as the sole agent for diuresis, administer ≥5 days before increasing dose to obtain the desired effect.

• Tablet:

  • Oral: Initial: 100 mg daily in single or divided doses;
  • dosage range: 25 to 200 mg daily in single or divided doses.

• Suspension:

  • Oral: Initial: 75 mg daily in single or divided doses.
  • Titrate slowly.

Spironolactone Dose in the treatment of Heart failure:

• Tablet:

  • Severe (NYHA class III to IV):

    • Oral: Initial: 12.5 to 25 mg once a day;
    • maximum: 50 mg/day.
    • If 25 mg once a day dose is not tolerated, may reduce to 25 mg every other day.

  • NYHA class II; LVEF ≤35% (off-label):

    • Oral: 12.5 to 25 mg once daily;
    • maximum: 50 mg/day.

Spironolactone Dose in the treatment of Post myocardial infarction; LVEF ≤40% (off-label):

• Oral: 12.5 to 25 mg once daily;
• maximum: 50 mg/day.

Note: Withhold treatment if potassium >5.5 mEq/L or renal function worsens; Hold doses until potassium is <5 mEq/L and consider restarting with a reduced dose after confirming the resolution of hyperkalemia/renal insufficiency for at least 72 hours.

• Suspension:

  • Serum potassium ≤5 mEq/L:
    • Initial: 20 mg once daily.
    • May titrate to 37.5 mg once daily or decrease to 20 mg every other day as clinically indicated.

Dose as an alternative agent in the treatment of Hypertension: Oral: Initial:

• Tablet:

  • 25 to 50 mg daily in 1 or 2 divided doses; may titrate every 2 weeks as needed based on patient response up to 100 mg daily.

• Suspension:

  • 20 to 100 mg daily in 1 or 2 divided doses;
  • may titrate at 2-week intervals.

Note: Doses >75 mg/day generally do not provide additional reductions in blood pressure.

Spironolactone Dose in the treatment of Primary aldosteronism: Oral: Tablet:

• Manufacturer's labeling:

  • Maintenance until surgical correction: 100 to 400 mg once a day.

• Alternate recommendations:

  • Treatment of bilateral adrenal hypersecretion, or unilateral hypersecretion in patients unwilling or unable to undergo surgery:
  • Initial: 12.5 to 25 mg once daily;
  • gradually titrate upward if necessary, to the lowest effective dose (maximum: 100 mg/day).

Spironolactone Dose in the treatment of Acne vulgaris in females) (off-label):

• Oral: 50 to 200 mg once daily.

Spironolactone Dose in the treatment of Ascites, due to cirrhosis (off-label dose):

• Initial: 100 mg once a day;
• Titrate every 3 to 5 days as clinically indicated (usual maximum: 400 mg once a day);
• spironolactone to furosemide dosing ratio of 100 mg (spironolactone) to 40 mg (furosemide) should be maintained (AASLD [Runyon 2012]).

Spironolactone Dose in the treatment of Hirsutism (off-label):

• Females:

  • Oral: Usual therapeutic dose: 100 to 200 mg/day in 2 divided doses;
  • assess response at 6-month intervals before adjusting the dose, adding additional agents, or switching to alternative therapy (Endocrine Society [Martin 2018])

Spironolactone Dose in the treatment of Hormone therapy for transgender females (male-to-female) (adjunct) (off-label):

• Initial: 25 mg twice daily orally in combination with other appropriate agents;
• increase each week based on response and tolerability to a usual dose of 100 to 300 mg/day.
• Adjust dose with a goal of suppressing serum testosterone levels into the normal range for females (ie, <50 ng/dL).
• Maximum: 200 mg twice daily.

Spironolactone Dose in Childrens

Note:

• Although spironolactone is commercially available in a suspension, it is NOT therapeutically equivalent to the tablets;
• commercially available suspension results in 15% to 37% higher serum concentration compared to the tablet;
• pediatric dosing is based on experience with tablets and extemporaneously compounded suspension.
• Multiple concentrations of oral suspension exist; use extra precaution and prescribe in mg (not mL).

Spironolactone Dose in the treatment of Bronchopulmonary dysplasia (BPD):

Limited data available; efficacy results variable. Although the benefits of diuretic therapy in the management of BPD are variable (eg, the optimal duration of therapy, impact on pulmonary endpoints), diuretics continue to be used in clinical practice..

• Infants:

  • Oral: 1.5 mg/kg/dose every 12 hours.

Spironolactone Dose in the treatment of Edema (diuresis):

• Oral: Initial: 1 to 3 mg/kg/day divided every 6 to 24 hours;
• titrate as needed;
• The reported maximum daily dose range: 4 to 6 mg/kg/day in divided doses every 6 to 12 hours or 400 mg/day, whichever is less.

Spironolactone Dose in the treatment of Hypertension:

• Oral: Initial: 1 mg/kg per day divided into once or twice a day dose;
• titrate as needed up to a maximum daily dose: 3.3 mg/kg/day or 100 mg/day, whichever is less

Spironolactone Dose in the treatment of primary aldosteronism (caused by adrenal hyperplasia):

• Oral: 1 to 3 mg/kg per day;
• maximum daily dose: 100 mg/day.

Spironolactone Pregnancy Risk Category: C/D

• Spironolactone crosses over to the placenta
• Normal pregnancies are not a good time to use diuretics for edema.
• However, it is possible to use them if edema is caused by pathological causes (as in the patient who is not pregnant). Monitor.
• Treatment of heart failure is similar for pregnant and unpregnant women.
• However, it should be avoided within the first three months because of its antiandrogenic effects.
• Mineralocorticoid receptor inhibitors should not be used to treat uncomplicated chronic hypertension in pregnant women.
• They should also be avoided in women with reproductive potential.
• Other agents are preferable when hypertension is treated during pregnancy.

Spironolactone use during breastfeeding:

• Breast milk contains the active metabolite of Spironolactone (canrenone).
• A case report describing maternal use of spironolactone 25mg twice daily during pregnancy and then again 4 times daily following delivery is available.
• Maternal serum and milk samples were collected 17 days after the birth. Two hours after giving the maternal dose, canrenone levels were at 144 ng/ml in serum and 104 mg/mL in milk.
• Canrenone levels were measured 14.5 hours following the dose at a concentration of 92 ng/ml in serum and 47 mg/mL in milk.
• According to the authors, the maximum canrenone that a nursing infant should consume is 0.2% of its maternal dose of spironolactone.
• Although the effects of this metabolite on humans are unknown, it was found to cause cancer in rats.
• Diuretics can reduce milk volume and decrease lactation.
• According to the manufacturer of the product, the decision about whether to continue breastfeeding or stop it during therapy should consider the risks to the infant as well as the benefits to the mother.
• If spironolactone is necessary, an alternative method should be used.

Spironolactone Dose in Kidney Disease:

Manufacturer's labeling:

• Tablet:

  • Edema, hypertension, primary aldosteronism:

    • There are no specific dosage adjustments provided in the drug manufacturer's labeling (has not been studied);
    • use with caution.

  • Heart failure:

    • eGFR >50 mL/minute/1.73 m²:

      • No initial dosage adjustment is necessary.

    • eGFR 30 to 50 mL/minute/1.73 m²:

      • Initial: 25 mg every other day.

    • eGFR <30 mL/minute/1.73 m²:

      • There are no specific dosage adjustments provided in the manufacturer's labeling.

• Suspension:

  • Edema, hypertension:

    • There are no dosage adjustments provided in the drug manufacturer's labeling;
    • spironolactone is substantially excreted by the kidney;
    • use with caution.

  • Heart failure:

    • eGFR >50 mL/minute/1.73 m²:

      • No initial dosage adjustment is necessary.

    • eGFR 30 to 50 mL/minute/1.73 m²:

      • Initial: 10 mg once daily.

    • eGFR <30 mL/minute/1.73 m²:

      • There are no specific dosage adjustments provided in the manufacturer's labeling.

Alternate recommendations:

• Tablet:

  • Heart failure (ACC/AHA [Yancy 2013]):

    • eGFR ≥50 mL/minute/1.73 m²:

      • Initial dose: 12.5 to 25 mg once daily;
      • The maintenance dose (after 4 weeks of treatment with potassium ≤5 mEq/L): 25 mg once or twice daily.

    • eGFR 30 to 49 mL/minute/1.73 m²:

      • Initial dose: 12.5 mg once daily or every other day;
      • The maintenance dose (after 4 weeks of treatment with potassium ≤5 mEq/L): 12.5 to 25 mg once daily.

    • eGFR <30 mL/minute/1.73 m²:

      • Not recommended.

  • Patients ≥65 years:

    • CrCl <30 mL/minute (regardless of indication):
      • Avoid use due to the risk of hyperkalemia.

Spironolactone Dose in Liver disease:

• There are no specific dosage adjustments provided in the drug manufacturer's labeling;
• initiate with a low dose and titrate slowly (cirrhosis).
• Use with caution;
• minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Side Effects of Spironolactone (Aldactone):

• Endocrine & Metabolic:

  • Gynecomastia (Common side effect)
  • Amenorrhea
  • Asymptomatic Hyperuricemia
  • Decreased Libido
  • Electrolyte Disorder
  • Gout
  • Hyperglycemia
  • Hyperkalemia
  • Hyperuricemia
  • Hypocalcemia
  • Hypochloremic Alkalosis
  • Hypomagnesemia
  • Hyponatremia
  • Hypovolemia

• Cardiovascular:

  • Vasculitis

• Central Nervous System:

  • Ataxia
  • Confusion
  • Dizziness
  • Drowsiness
  • Headache
  • Lethargy
  • Nipple Pain

• Dermatologic:

  • Alopecia
  • Chloasma
  • Erythematous Maculopapular Rash
  • Pruritus
  • Stevens-Johnson Syndrome
  • Toxic Epidermal Necrolysis
  • Urticaria

• Gastrointestinal:

  • Abdominal Cramps
  • Diarrhea
  • Gastritis
  • Gastrointestinal Hemorrhage
  • Gastrointestinal Ulcer
  • Nausea
  • Vomiting

• Genitourinary:

  • Erectile Dysfunction
  • Irregular Menses
  • Mastalgia
  • Postmenopausal Bleeding

• Hematologic & Oncologic:

  • Agranulocytosis
  • Leukopenia
  • Thrombocytopenia

• Hepatic:

  • Hepatotoxicity

• Hypersensitivity:

  • Anaphylaxis

• Immunologic:

  • DRESS Syndrome

• Neuromuscular & Skeletal:

  • Lower Limb Cramp

• Renal:

  • Renal Failure Syndrome
  • Renal Insufficiency

• Miscellaneous:

  • Fever

Contraindications to Spironolactone (Aldactone):

• Hyperkalemia;
• Addison disease
• Concomitant use of eplerenone

Canadian labeling: Additional contraindications not in US labeling

• Hypersensitivity to spironolactone and any component of the formulation
• Concomitant use of heparin and low molecular weight Heparin
• pregnancy;
• Breastfeeding

Warnings and precautions

• Fluid and electrolyte imbalances:

  • A fluid and electrolyte imbalance, such as hypomagnesemia or hyponatremia or hypocalcemia, hypocalcemia, Hypochloremic alkalosis (hyperglycemia), hypocalcemia, hyponatremia or hypocalcemia can occur.
  • Patients with kidney disease, heart failure, and cirrhosis could be at risk.
  • Correct electrolyte imbalances and monitor them to prevent dehydration.

• Gout

  • Hyperuricemia can be symptomatic and may lead to gout (rare).

• Gynecomastia

  • It is possible; the risk of developing a serious condition (e.g., after 1 to 2 months or more of therapy) is variable.
  • Most often, therapy is reversible after discontinuation.

• Hyperkalemia:

  • Hyperkalemia can occur. Patients who take certain drugs (e.g. ACE inhibitors, angiotensin-receptor blockers, NSAIDs) are at greater risk.
  • Monitor serum potassium closely.
  • Hyperkalemia can also be caused by concurrent use of higher doses of ACE inhibitors (e.g. >= lisinopril 10mg daily for adults)
  • Hyperkalemia can be treated by reducing or interrupting therapy.
  • Hyperkalemia patients should not be used.
  • Hyperkalemia can be dangerous.

• Tumorigenic:

  • In chronic toxicity animal experiments, it was shown to be tumorigenic. Avoid excessive use.

• Catheterization of the adrenal vein:

  • Do not use this product prior to an adrenal vein catheterization.

• Heart failure:

  • If spironolactone treatment is being considered for heart failure patients, the eGFR must be greater than 30 mL/minute/1.73m and creatinine should not exceed 2 mg/dL (men) and 2.5 mg/dL respectively (women). There should also be no recent worsening of symptoms.
  • Potassium should be less than 5 mEq/L without any history of severe hyperkalemia.
  • If serum potassium levels are high, they should be closely monitored and managed. 
  • ACC/AHA recommends discontinuing treatment if serum potassium levels exceed 5.5 mEq/L. This should be done in conjunction with careful medical evaluation.
  • Avoid routine triple therapy that combines an ACE inhibitor, ARB and spironolactone.
  • Patients with heart disease should be instructed to stop using loop diuretic therapy if they experience diarrhea or dehydration.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious.
  • Hepatic coma may be precipitated by minor changes in fluid or electrolyte balance.

• Renal impairment

  • Hyperkalemia risk is higher with declining renal function, concurrent use of higher doses of ACE inhibitors (eg >= lisinopril ten mg daily for adults)
  • Patients with impaired renal function should be cautious.

Spironolactone: Drug Interaction

Monitoring parameters:

• Blood pressure
• Serum electrolytes (potassium within one week of dose titration or initiation, and sodium regularly thereafter)
• Uric acid
• Glucose
• Renal function
• Volume status

• Spironolactone for Heart Failure:

  • Initiation should be completed within 3 days, 1 week, and 3 months. Then, the renal function and serum potassium should be tested every 3 months.
  • A new round of monitoring should take place after you add or increase the dose of any concomitant ACEIs and/or ARBs.
  • Keep potassium levels at 5 mg/L if renal function is compromised or serum potassium rises to >5.5 mg/L. If this happens, you should stop taking potassium for 72 hours and then consider reducing the dose.

• Transgender hormone therapy with Spironolactone:

  • Testosterone levels (goal: 50ng/dL) should be taken every 3 months for the first year, then once a year or twice a year.
  • For the first year, serum electrolytes should be taken every 3 months and then once a year.
  • Routine cancer screening and laboratory testing for all tissues in non-transgender people.

How to administer Spironolactone (Aldactone)?

Oral:

• Tablet:
  • Administer with or without food; however, administer consistently with respect to food.
• Suspension:
  • Shake well before administering the dose.
  • Administer with or without food; however, administer consistently with respect to food.

Mechanism of action of Spironolactone (Aldactone):

• Competes in the distal renal tubules with aldosterone to increase sodium chloride, water excretion, and conserve potassium and hydrogen.
• May also block aldosterone's effect on arteriolar smooth muscles.

Notice:

• The serum concentration in suspension is 15%-37% higher than that of the tablet
• Doses of suspension greater than 100 mg can result in higher levels of spironolactone than anticipated.

Duration:

• Tablet: 2 to 3 days

Bioavailability:

• High-fat/ High-calorie meal increased the bioavailability of spironolactone ~90%.

Protein binding:

• >90%

Metabolism:

• Rapid and extensive;
• hepatic forming multiple metabolites, including active metabolites canrenone, 7-alpha-spirolactone, and 6-beta-hydroxy-7-alpha

Half-life elimination:

• Tablet:
  • Spironolactone: about 1.4 hours;
  • Canrenone:  about16.5 hours (terminal); 7-alpha-spirolactone: 13.8 hours (terminal)
• Suspension:
  • Spironolactone: 1 to 2 hours;
  • Canrenone, 7-alpha-spirolactone, and 6-betahydroxy-7-alpha: 10 to 35 hours.

Time to peak, serum:

• Tablet: about 2.6 to 4.3 hours (primarily as active metabolites)
• Suspension: Spironolactone: about 0.5 to 1.5 hours; Canrenone: 2.5 to 5 hours

Excretion:

• Urine (primarily as metabolites) and bile (secondary)

International Brands of Spironolactone:

• Aldactone
• CaroSpir
• TEVA-Spironolactone
• Aldactin
• Aldacton
• Aldactone
• Aldactone A
• Aldoxol
• Alizar
• Alspiron
• Altone
• Antagerone
• Belactone
• Diulactone
• Epilactone
• Flumach
• Huma-Spiroton
• Hyles
• Indurit
• Lactone
• Letonal
• Noractone
• Osiren
• Osyrol
• Pondactone
• S-Tone
• Skyton
• Spectone
• Spilac
• Spinolac
• Spiractin
• Spiretic
• Spirix
• Spiroctan
• Spirofar
• Spirola
• Spirolacton
• Spirolon
• Spiron
• Spirone
• Spirono-Isis
• Spironolacton-ratiopharm
• SpironolactoneEurogenerics
• Spironolactone-Searle
• Spiros
• Spirotone
• Unilactone
• Uractone
• Uractonum
• Verospiron
• Vivitar

Spironolactone Brand Names in Pakistan: