Spironolactone (Page 2 of 4)

6 ADVERSE REACTIONS

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.

Metabolism: Hyperkalemia, electrolyte disturbances [see Warnings and Precautions (5.1, 5.3)], hyponatremia, hypovolemia.

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.

7 DRUG INTERACTIONS

7.1 Drugs and Supplements Increasing Serum Potassium

Concomitant administration of spironolactone 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 [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.

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
trimethoprim

7.2 Lithium

Like other diuretics, spironolactone reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when spironolactone is coadministered [see Clinical Pharmacology (12.3)].

7.3 Nonsteroidal anti-inflammatory drugs (NSAIDs)

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics. Therefore, when spironolactone and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [see Clinical Pharmacology (12.3)].

7.4 Digoxin

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.

7.5 Cholestyramine

Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine.

7.6 Acetylsalicylic Acid

Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone and acetylsalicylic acid are used concomitantly, spironolactone 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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with congestive heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure.

Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Data

Animal Data

Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects.

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.

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