SPIRONOLACTONE (Page 3 of 5)

8.2 Lactation

Risk Summary

Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days postpartum reports the presence of the active metabolite, canrenone, in human breast milk in low amounts that are expected to be clinically inconsequential. In this case, there were no adverse effects reported for the breastfed infant after short term exposure to spironolactone; however, long term effects on a breastfed infant are unknown. There are no data on spironolactone effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for spironolactone and any potential adverse effects on the breastfed child from spironolactone or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Spironolactone tablets are substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor renal function.

8.6 Use in Renal Impairment

Spironolactone tablets are substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with renal impairment are at increased risk of hyperkalemia. Monitor potassium closely.

8.7 Use in Hepatic Impairment

Spironolactone tablets can cause sudden alterations of fluid and electrolyte balance which may precipitate impaired neurological function, worsening hepatic encephalopathy and coma in patients with hepatic disease with cirrhosis and ascites. In these patients, initiate spironolactone tablets in the hospital [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis. In patients with cirrhosis, start with lowest initial dose and titrate slowly [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

The oral LD50 of spironolactone tablets is greater than 1000 mg/kg in mice, rats, and rabbits.

Acute overdosage of spironolactone tablets may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function.

Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue spironolactone tablets.

11 DESCRIPTION

Spironolactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17‑ hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the following structural formula:

Structure

Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform.

Spironolactone tablets, 25 mg contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, docusate sodium 85%/sodium benzoate 15%, entrapped peppermint flavor, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Spironolactone tablets, 50 mg and 100 mg contain the following inactive ingredients: anhydrous lactose, carnauba wax, colloidal silicon dioxide, docusate sodium 85%/sodium benzoate 15%, entrapped peppermint flavor, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium starch glycolate, titanium dioxide, and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Spironolactone and its active metabolites are specific pharmacologic antagonists of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule.

12.2 Pharmacodynamics

Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema and ascites in those conditions.

Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.

12.3 Pharmacokinetics

Absorption

The mean time to reach peak plasma concentration of spironolactone and the active metabolite, canrenone, in healthy volunteers is 2.6 and 4.3 hours, respectively.

Effect of food: Food increased the bioavailability of spironolactone (as measured by AUC) by approximately 95.4%. Patients should establish a routine pattern for taking spironolactone tablets with regard to meals [see Dosage and Administration (2.1)].

Distribution

Spironolactone and its metabolites are more than 90% bound to plasma proteins.

Elimination

The mean half-life of spironolactone is 1.4 hour. The mean half-life values of its metabolites including canrenone, 7-α-(thiomethyl) spirolactone (TMS), and 6-ß-hydroxy-7-α-(thiomethyl) spirolactone (HTMS) are 16.5, 13.8, and 15 hours, respectively.

Metabolism: Spironolactone is rapidly and extensively metabolized. Metabolites can be divided into two main categories: those in which sulfur of the parent molecule is removed (e.g., canrenone) and those in which the sulfur is retained (e.g., TMS and HTMS). In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Excretion: The metabolites are excreted primarily in the urine and secondarily in bile.

Specific Populations

The impact of age, sex, race/ethnicity, and renal impairment on the pharmacokinetics of spironolactone have not been specifically studied.

Patients with Hepatic Impairment: The terminal half-life of spironolactone has been reported to be increased in patients with cirrhotic ascites [see Use in Specific Populations (8.7)].

Drug Interaction Studies:

Drugs and Supplements Increasing Serum Potassium: Concomitant administration of spironolactone tablets with potassium supplementation, salt substitutes containing potassium, a diet rich in potassium, or drugs that can increase potassium, including ACE inhibitors, angiotensin II antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparin and low molecular weight heparin, may lead to severe hyperkalemia [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Lithium: Spironolactone tablets reduces the renal clearance of lithium, inducing a high risk of lithium toxicity [see Drug Interactions (7.2)].

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics [see Drug Interactions (7.3)].

Acetylsalicylic acid: A single dose of 600 mg of acetylsalicylic acid inhibited the natriuretic effect of spironolactone, which was hypothesized be due to inhibition of tubular secretion of canrenone, causing decreased effectiveness of spironolactone [see Drug Interactions (7.6)].

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