No

Antineoplastic Agent, Miscellaneous

Suppression of adrenal function in selected patients with Cushing's syndrome; also used successfully in postmenopausal patients with advanced breast carcinoma and in patients with metastatic prostate carcinoma as salvage (third-line hormonal agent)

D

Suspected of causing virilization when given throughout pregnancy

Hypersensitivity to aminoglutethimide or any component and glutethimide

Monitor blood pressure in all patients at appropriate intervals; hypothyroidism may occur; mineralocorticoid replacement therapy may be necessary in up to 50% of patients (ie, fludrocortisone); if glucocorticoid replacement therapy is necessary, 20-30 mg of hydrocortisone daily in the morning will replace endogenous secretion (steroid replacement regimen is controversial - high-dose versus low-dose)

Most adverse effects will diminish in incidence and severity after the first 2-6 weeks

Central nervous system: Headache, dizziness, drowsiness, and lethargy are frequent at the start of therapy, clumsiness

Dermatologic: Skin rash

Gastrointestinal: Nausea, vomiting, anorexia

Hepatic: Cholestatic jaundice

Neuromuscular & skeletal: Myalgia

Renal: Nephrotoxicity

Respiratory: Pulmonary alveolar damage

Miscellaneous: Systemic lupus erythematosus

1% to 10%:

Cardiovascular: Hypotension and tachycardia, orthostatic hypotension

Dermatologic: Hirsutism in females

Endocrine & metabolic: Adrenocortical insufficiency

Hematologic: Rare cases of neutropenia, leukopenia, thrombocytopenia, pancytopenia, and agranulocytosis have been reported

<1%: Adrenal suppression, lipid abnormalities (hypercholesterolemia), hyperkalemia, hypothyroidism, goiter

Symptoms of overdose include ataxia, somnolence, lethargy, dizziness, distress, fatigue, coma, hyperventilation, respiratory depression, hypovolemic shock

Treatment is supportive

CYP 450 hepatic microsomal enzyme inducer

Dexamethasone: Reported to increase metabolism

Digitoxin: Increases clearance of digitoxin after 3-8 weeks of aminoglutethimide therapy

Theophylline: Aminoglutethimide increases metabolism of theophylline

Warfarin: Decreases anticoagulant response to warfarin

Increased toxicity: Propranolol: Case report of enhanced aminoglutethimide toxicity (rash and lethargy)

Blocks the enzymatic conversion of cholesterol to delta-5-pregnenolone, thereby reducing the synthesis of adrenal glucocorticoids, mineralocorticoids, estrogens, aldosterone, and androgens

Onset of action (adrenal suppression): 3-5 days

Absorption: Oral: Well absorbed (90%)

Distribution: Crosses the placenta

Protein binding: Minimally bound to plasma proteins (20% to 25%)

Metabolism: Major metabolite is N-acetylaminoglutethimide

Half-life: 7-15 hours; shorter following multiple administrations than following single doses (induces hepatic enzymes increasing its own metabolism)

Elimination: 34% to 50% excreted in urine as unchanged drug and 25% excreted as metabolite

Adults: Oral:

Mineralocorticoid (fludrocortisone) replacement therapy may be necessary in up to 50% of patients. If glucocorticoid replacement therapy is necessary, 20-30 mg hydrocortisone orally in the morning will replace endogenous secretion.

Dosing adjustment in renal impairment: Dose reduction may be necessary

Drowsiness is common

May cause hypotension which may be exacerbated by psychotropics; may cause bone marrow suppression; use caution with clozapine and carbamazepine; propranolol may increase the risk of drowsiness

No information available to require special precautions

Over 10% of patients likely to experience nausea; approximately 10% may experience orthostatic hypotension

May be taken with food to reduce incidence of nausea. You may experience drowsiness or dizziness; avoid driving or engaging in tasks that require alertness until response to drug is known. Small frequent meals may reduce incidence of nausea or vomiting. Masculinization may occur and is reversible when treatment is discontinued. Report rash, unresolved nausea, vomiting, lethargy, yellowing of skin or eyes, easy bruising or bleeding, change in color of urine or stool, increased growth of facial hair, thick tongue, severe mood swings, palpitations, or respiratory difficulty. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed.

Administer in divided doses, 2-3 times/day, to reduce incidence of nausea and vomiting

Tablet, scored: 250 mg

Goldhirsch A and Gelber RD, "Endocrine Therapies of Breast Cancer," Semin Oncol, 1996, 23(4):494-505.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Kaufmann M, "A Review of Endocrine Options for the Treatment of Advanced Breast Cancer," Oncology, 1997, 54(Suppl 2):2-5.

Lonning PE, Kvinnsland S, and Lnning PE, "Mechanisms of Action of Aminoglutethimide as Endocrine Therapy of Breast Cancer," Drugs, 1988, 35(6):685-710.

Roseman BJ, Budzdar AU, and Singletary SE, "Use of Aromatase Inhibitors in Postmenopausal Women With Advanced Breast Cancer," J Surg Oncol, 1997, 66(3):215-20.

Santen RJ and Misbin RI, "Aminoglutethimide: Review of Pharmacology and Clinical Use," Pharmacotherapy, 1981, 1(2):95-120.