Aminoglutethimide

U.S. BRAND NAMES — Cytadren®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Aromatase Inhibitor
Enzyme Inhibitor
Hormonal Antagonist, Anti-Adrenal
Nonsteroidal Aromatase Inhibitor

DOSING: ADULTS
Cushing disease: Oral: 250 mg every 6 hours may be increased at 1- to 2-week intervals to a total of 2 g/day

Breast cancer, prostate cancer (unlabeled use): Oral: 250 mg 4 times/day

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Dose reduction may be necessary.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet [scored]: 250 mg

DOSAGE FORMS: CONCISE
Tablet [scored]:
Cytadren®: 250 mg

GENERIC EQUIVALENT AVAILABLE — No

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

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

USE - UNLABELED / INVESTIGATIONAL — Treatment of breast and prostate cancer (androgen synthesis inhibitor)

ADVERSE REACTIONS SIGNIFICANT — 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% (Limited to important or life-threatening): Adrenal suppression, hepatotoxicity, hypercholesterolemia, hyperkalemia, hypothyroidism, goiter, masculinization of females, pulmonary hypersensitivity, urticaria; rare cases of neutropenia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis have been reported

CONTRAINDICATIONS — Hypersensitivity to aminoglutethimide, glutethimide, or any component of the formulation; pregnancy

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypothyroidism: With use, hypothyroidism may occur.

Other warnings/precautions: Blood pressure monitoring: In all patients, monitor blood pressure at appropriate intervals. Mineralocorticoid/glucocorticoid replacement: Mineralocorticoid replacement is necessary in up to 50% of patients. Glucocorticoid replacement is necessary in most patients.

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.

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.

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — Suspected of causing virilization when given throughout pregnancy

LACTATION — Excretion in breast milk unknown/contraindicated

PRICING — (data from drugstore.com)
Tablets (Cytadren)
250 mg (30): $47.99

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.

TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include ataxia, somnolence, lethargy, dizziness, distress, fatigue, coma, hyperventilation, respiratory depression, hypovolemia, and shock. Treatment is supportive.

INTERNATIONAL BRAND NAMES — Aminoglutetimid (PL); Cytadren (AU, NZ); Mamomit (HR); Orimeten (AR, AT, BE, BF, BG, BJ, BR, CH, CI, CL, CN, CZ, DE, EG, ES, ET, FI, GH, GM, GN, HU, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, NL, NO, PL, PT, SC, SD, SE, SL, SN, TZ, UG, ZA, ZM, ZW); Orimetene (GR, HK, TW)

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%

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)