Aminoglutethimide

Pronunciation

(a mee noe gloo TETH i mide)

U.S. Brand Names

Cytadren®

Synonyms

AG; AGT; BA-16038; Elipten

Generic Available

Use

Suppression of adrenal function in selected patients with Cushing's syndrome

Use - Unlabeled/Investigational

Treatment of prostate cancer (androgen synthesis inhibitor)

Pregnancy Risk Factor

Pregnancy Implications

Suspected of causing virilization when given throughout pregnancy

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to aminoglutethimide, glutethimide, or any component of the formulation; pregnancy; breast-feeding

Warnings/Precautions

Monitor blood pressure in all patients at appropriate intervals. Hypothyroidism may occur. Mineralocorticoid replacement is necessary in up to 50% of patients . Glucocorticoid replacement is necessary in most patients.

Adverse Reactions

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

>10%:

Central nervous system: Headache, dizziness, drowsiness, lethargy, clumsiness

Dermatologic: Skin rash

Gastrointestinal: Nausea, anorexia

Hepatic: Cholestatic jaundice

Neuromuscular & skeletal: Myalgia

Renal: Nephrotoxicity

Respiratory: Pulmonary alveolar damage

1% to 10%:

Cardiovascular: Hypotension, tachycardia, orthostasis

Dermatologic: Hirsutism, pruritus

Endocrine & metabolic: Adrenocortical insufficiency

Gastrointestinal: Vomiting

<1%: Adrenal suppression, hepatotoxicity, hypercholesterolemia, hyperkalemia, hypothyroidism, goiter, masculinization of females, pulmonary hypersensitivity, urticaria; rare cases of neutropenia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis have been reported

Overdosage/Toxicology

Symptoms of overdose include ataxia, somnolence, lethargy, dizziness, distress, fatigue, coma, hyperventilation, respiratory depression, hypovolemia, and shock. Treatment is supportive.

Drug Interactions

Induces CYP1A2 (strong), 2C19 (strong), 3A4 (strong)

CYP1A2 substrates: Aminoglutethimide may decrease the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, estrogens, fluvoxamine, mirtazapine, ropinirole, and theophylline.

CYP2C19 substrates: Aminoglutethimide may decrease the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, proton pump inhibitors, sertraline, and voriconazole.

CYP3A4 substrates: Aminoglutethimide may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.

Dexamethasone: Aminoglutethimide increases metabolism of dexamethasone; hydrocortisone is preferred if glucocorticoid treatment is needed.

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

Medroxyprogesterone: Aminoglutethimide increases medroxyprogesterone clearance.

Megestrol: Aminoglutethimide increases megestrol clearance.

Tamoxifen: Aminoglutethimide increases tamoxifen clearance.

Theophylline: Aminoglutethimide increases metabolism of theophylline.

Warfarin: Aminoglutethimide increases warfarin clearance.

Stability

Store at controlled room temperature not >30°C (86°F).

Mechanism of Action

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

Pharmacodynamics/Kinetics

Onset of action: Adrenal suppression: 3-5 days; following withdrawal of therapy, adrenal function returns within 72 hours

Absorption: 90%

Distribution: Crosses placenta

Protein binding, plasma: 20% to 25%

Metabolism: Major metabolite is N-acetylaminoglutethimide; induces its own metabolism

Half-life elimination: 7-15 hours; shorter following multiple doses

Excretion: Urine (34% to 50% as unchanged drug, 25% as metabolites)

Dosage

Oral: Adults:

Adrenal suppression: 250 mg every 6 hours may be increased at 1- to 2-week intervals to a total of 2 g/day

Prostate cancer (unlabeled use): 250 mg 4 times/day

Dosing adjustment in renal impairment: Dose reduction may be necessary

Administration

Administer every 6 hours to reduce incidence of nausea and vomiting.

Monitoring Parameters

Follow adrenal cortical response by careful monitoring of plasma cortisol until the desired level of suppression is achieved. 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.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; may be taken with food to reduce incidence of nausea. May cause drowsiness or dizziness (avoid driving or engaging in tasks that require alertness until response to drug is known); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum or sucking lozenges may reduce incidence of nausea or vomiting); or masculinization (reversible when treatment is discontinued). Report rash, unresolved nausea or 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. Consult prescriber for appropriate barrier contraceptive measures. Do not breast-feed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Nausea and orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Drowsiness is common

Mental Health: Effects on Psychiatric Treatment

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

Oncology: Emetic Potential

Very low (<10%)

Dosage Forms

Tablet [scored]: 250 mg

References

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

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

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

Robinson MR, "Aminoglutethimide: Medical Adrenalectomy in the Management of Carcinoma of the Prostate. A review After 6 Years," Br J Urol , 1980, 52(4):328-9.

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.

Sanford EJ, Drago JR, Rohner TJ Jr, et al, "Aminoglutethimide medical adrenalectomy for advanced prostatic carcinoma," J Urol , 1976, 115(2):170-4.

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

International Brand Names

Aminoglutetimid® (PL, RO); Cytadren® (AU, NZ); Mamomit® (HR, RU, SI); Orimeten® (AR, AT, BE, BG, BR, CL, CZ, DE, ES, GB, HK, IT, LU, MT, NL, RU); Orimétène® (FR); Rodazol® (CZ); Rogluten® (RO)

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