Spironolactone (Page 4 of 5)

Pregnancy

Teratogenic Effects

Pregnancy Category C.

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. There are no adequate and well-controlled studies with spironolactone in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of spironolactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

Nursing Mothers

Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.

Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Digestive:

Gynecomastia (see ), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established. Reproductive: PRECAUTIONS

Leukopenia (including agranulocytosis), thrombocytopenia. Hematologic:

Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Hypersensitivity:

Hyperkalemia, electrolyte disturbances (see and ). Metabolism: WARNINGSPRECAUTIONS

Leg cramps. Musculoskeletal:

Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Nervous System/Psychiatric:

A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration. Liver/Biliary:

Renal dysfunction (including renal failure). Renal:

Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis. Skin:

OVERDOSAGE

The oral LD of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. 50

Acute overdosage of spironolactone 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.

Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Treatment:

Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, spironolactone should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

DOSAGE AND ADMINISTRATION

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

Spironolactone is administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Long Test:

Spironolactone is administered at a daily dosage of 400 mg for four days. If serum potassium increases during spironolactone administration but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. Short Test:

After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, spironolactone may be administered in doses of 100 mg to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

An initial daily dosage of 100 mg of spironolactone administered in either single or divided doses is recommended, but may range from 25 mg to 200 mg daily. When given as the sole agent for diuresis, spironolactone should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to spironolactone has not occurred, a second diuretic that acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of spironolactone when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of spironolactone should remain unchanged when other diuretic therapy is added. Edema in Adults (Congestive Heart Failure, Hepatic Cirrhosis, or Nephrotic Syndrome):

For adults, an initial daily dosage of 50 mg to 100 mg of spironolactone administered in either single or divided doses is recommended. Spironolactone may also be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents. Treatment with spironolactone should be continued for at least two weeks since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient. Essential Hypertension:

Spironolactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate. Hypokalemia:

Severe Heart Failure In Conjunction With Standard Therapy (NYHA class III to IV):

Treatment should be initiated with spironolactone 25 mg once daily if the patient’s serum potassium is less than or equal to 5.0 mEq/L and the patient’s serum creatinine is less than or equal to 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once daily may have their dosage reduced to 25 mg every other day. for advice on monitoring serum potassium and serum creatinine. See WARNINGS: Hyperkalemia in Patients with Severe Heart Failure

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