Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically.
In addition to causing hyperkalemia, spironolactone tablets can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically.
Spironolactone tablets can cause gynecomastia. In the Randomized Spironolactone Evaluation Study, patients with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1-2 months to over a year. Gynecomastia is usually reversible.
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hyperkalemia [see Warnings and Precautions (5.1)]
- Hypotension and Worsening Renal Function [see Warnings and Precautions (5.2)]
- Electrolyte and Metabolic Abnormalities [see Warnings and Precautions (5.3)]
- Gynecomastia [see Warnings and Precautions (5.4)]
- Impaired neurological function/coma in patients with hepatic impairment, cirrhosis and ascites [see Use in Specific Populations (8.7)]
The following adverse reactions associated with the use of spironolactone were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure.
Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.
Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain.
Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.
Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.
Musculoskeletal: Leg cramps.
Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.
Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.
Renal: Renal dysfunction (including renal failure).
Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis.
Concomitant administration of spironolactone tablets with potassium supplementation or drugs that can increase potassium may lead to severe hyperkalemia. In general, discontinue potassium supplementation in heart failure patients who start spironolactone tablets [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving spironolactone tablets.
Examples of drugs that can increase potassium include:
- ACE inhibitors
- angiotensin receptor blockers
- non-steroidal anti-inflammatory drugs (NSAIDs)
- heparin and low molecular weight heparin
Like other diuretics, spironolactone tablets reduce the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when spironolactone tablets are coadministered [see Clinical Pharmacology (12.3)] .
In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics. Therefore, when spironolactone tablets and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [see Clinical Pharmacology (12.3)] .
Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the apparent exposure to digoxin. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. In patients taking concomitant digoxin, use an assay that does not interact with spironolactone.
Hyperkalemic metabolic acidosis has been reported in patients given spironolactone tablets concurrently with cholestyramine.
Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone tablets and acetylsalicylic acid are used concomitantly, spironolactone tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained [see Clinical Pharmacology (12.3)] .
Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis [see data] . Rat embryofetal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Limited available data from published case reports and case series did not demonstrate an association of major malformations or other adverse pregnancy outcomes with spironolactone . There are risks to the mother and fetus associated with heart failure, cirrhosis and poorly controlled hypertension during pregnancy [see Clinical Considerations] . Because of the potential risk to the male fetus due to anti-androgenic properties of spironolactone and animal data, avoid spironolactone in pregnant women or advise a pregnant woman of the potential risk to a male fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
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