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AMINOGLUTETHIMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aminoglutethimide is aromatase inhibitor used in the treatment of breast cancer and prostate cancer. It is also used to suppress adrenal function in selected patients with Cushing's syndrome, primarily as an interim measurement prior to definitive treatment such as surgery, or as long term treatment in rare cases where surgery is not appropriate .

Specific Substances

    1) aminoglutethimide
    2) Molecular formula C13H16N2O2
    3) CAS125-84-8
    1.2.1) MOLECULAR FORMULA
    1) C13H16N2O2

Available Forms Sources

    A) FORMS
    1) Aminoglutethimide is available as white, round, 250 mg tablets that are scored into quarters (Prod Info CYTADREN(R) tablets, 2002).
    B) USES
    1) Aminoglutethimide is aromatase inhibitor used in the treatment of breast cancer and prostate cancer. It is also used to suppress adrenal function in selected patients with Cushing's syndrome, primarily as an interim measurement prior to definitive treatment such as surgery, or as long term treatment in rare cases where surgery is not appropriate (Prod Info CYTADREN(R) tablets, 2002).
    2) Aminoglutethimide was marketed previously as an anticonvulsant, but was withdrawn for that indication in 1966 because of its effects on the adrenal gland(Prod Info CYTADREN(R) tablets, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Drowsiness, morbilliform rash, nausea, anorexia, dizziness and headache are common. Leukopenia, thrombocytopenia, adrenal insufficiency, hypothyroidism, masculinization and hirsutism in females, precocious sexual development in males, hypotension (particularly orthostatic), tachycardia, vomiting, and cholestatic jaundice have been reported.
    B) WITH POISONING/EXPOSURE
    1) Limited data available. Somnolence, lethargy, fatigue, weakness, and coma have been reported. Anticipated effects after overdose include hypotension, hypovolemia, nausea, vomiting, ataxia, respiratory depression, hyponatremia, hypochloremia, hyperkalemia, hypoglycemia. Manifestations may be similar to acute adrenal insufficiency.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Hypotension (particularly orthostatic hypotension), hypovolemia and tachycardia may develop after overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Lethargy, dizziness, weakness, and sleepiness are common with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) CNS depression and coma have been reported after overdose.
    0.2.20) REPRODUCTIVE
    A) Aminoglutethimide is classified as FDA pregnancy category D. Pseudohermaphrodism has been reported in 2 female infants of mothers treated with aminoglutethimide along with other medications. Fetal implantation, increased fetal mortality, and teratogenic effects have been reported in animal studies. Data regarding aminoglutethimide use and human lactation are not available.

Laboratory Monitoring

    A) Monitor vital signs, especially blood pressure. Monitor patient for CNS and respiratory depression.
    B) Monitor serum electrolytes, including sodium, potassium and calcium, as well as blood glucose.
    C) Monitor CBC with differential and platelet count.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) HYPOTENSION - Administer intravenous 0.9% saline 10 to 20 ml/kg initially; larger volumes may be required, central venous pressure monitoring may be useful to guide fluid resuscitation. If acute adrenal insufficiency is suspected clinically, administer corticosteroids, eg hydrocortisone 100 mg intravenously over 3 hours followed by 10 mg/hr infusion until patient can tolerate oral hydrocortisone. Dexamethasone should not be used as its metabolism is accelerated by aminoglutethimide. Administer dopamine or norepinephrine if hypotension persists.
    C) ADRENAL INSUFFICIENCY - Hypotension, hyponatremia, hyperkalemia and/or hypoglycemia are likely related to adrenal insufficiency. Treat with intravenous hydration with 0.9% saline, 50 ml of 50% dextrose intravenously, and exogenous corticosteroids as above. Mineralocorticoid replacement may also be necessary, fludrocortisone 0.1 to 0.2 mg/day orally .

Range Of Toxicity

    A) No deaths have been reported from aminoglutethimide overdose. Ingestion of 3 to 4 grams caused coma An adult ingested 7 grams, a 16-year-old ingested 7.5 to 10 grams, and a 10-year-old ingested 10 grams; all survived with supportive care.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Drowsiness, morbilliform rash, nausea, anorexia, dizziness and headache are common. Leukopenia, thrombocytopenia, adrenal insufficiency, hypothyroidism, masculinization and hirsutism in females, precocious sexual development in males, hypotension (particularly orthostatic), tachycardia, vomiting, and cholestatic jaundice have been reported.
    B) WITH POISONING/EXPOSURE
    1) Limited data available. Somnolence, lethargy, fatigue, weakness, and coma have been reported. Anticipated effects after overdose include hypotension, hypovolemia, nausea, vomiting, ataxia, respiratory depression, hyponatremia, hypochloremia, hyperkalemia, hypoglycemia. Manifestations may be similar to acute adrenal insufficiency.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension (particularly orthostatic hypotension), hypovolemia and tachycardia may develop after overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension (occasionally orthostatic hypotension) developed in about 3% of patients taking aminoglutethimide (Prod Info CYTADREN(R) tablets, 2002).
    2) WITH POISONING/EXPOSURE
    a) Hypotension and hypovolemia may develop after overdose(Prod Info CYTADREN(R) tablets, 2002).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia developed in about 2% of patients taking aminoglutethimide (Prod Info CYTADREN(R) tablets, 2002).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPOVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression may develop after overdose (Prod Info CYTADREN(R) tablets, 2002).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Lethargy, dizziness, weakness, and sleepiness are common with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) CNS depression and coma have been reported after overdose.
    3.7.2) CLINICAL EFFECTS
    A) LETHARGY
    1) WITH THERAPEUTIC USE
    a) Drowsiness developed in about one third of patients with Cushing's syndrome treated with aminoglutethimide for at least 4 weeks (Prod Info CYTADREN(R) tablets, 2002). Fatigue and weakness are also common complaints (Bruning & Bonfrer, 1983; Lundgren et al, 1989).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in about 5% of patients with Cushing's syndrome treated with aminoglutethimide for at least 4 weeks, and is likely related to orthostatic hypotension (Prod Info CYTADREN(R) tablets, 2002). In a study of 85 patients with breast cancer treated with aminoglutethimide, 35 (41%) developed dizziness (Brufman & Biran, 1986).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in about 5% of patients with Cushing's syndrome treated with aminoglutethimide for at least 4 weeks (Prod Info CYTADREN(R) tablets, 2002). In a study of 85 patients with breast cancer treated with aminoglutethimide, 25 (29%) developed headache (Brufman & Biran, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting developed in about 12% of patients with Cushing's syndrome treated with aminoglutethimide for at least 4 weeks(Prod Info CYTADREN(R) tablets, 2002).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may develop after overdose(Prod Info CYTADREN(R) tablets, 2002).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC JAUNDICE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice was reported in an 84-year-old woman with metastatic adenocarcinoma of the breast following therapy with oral aminoglutethimide (250 mg four times daily) for two months and hydrocortisone 40 mg daily. Jaundice subsided after withdrawal of aminoglutethimide. The authors suspect an idiosyncratic hypersensitivity reaction (Gerber & Miller, 1982).
    b) Cholestatic jaundice was reported in a 69-year-old woman receiving aminoglutethimide 250 mg two to four times daily for approximately 3 weeks. Symptoms subsided after withdrawal of the drug and elevation of hepatic enzyme levels occurred upon rechallenge of the drug (Perrault & Domovitch, 1984).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported in patients taking aminoglutethimide (DiCostanzo et al, 1990). Of 1333 patients treated with aminoglutethimide for breast or prostate cancer, 7 patients developed thrombocytopenia alone and 3 developed thrombocytopenia with leukopenia (Messeih et al, 1985).
    b) Fatal thrombocytopenia occurred in a 50-year-old woman after 2 weeks of treatment with aminoglutethimide 250 mg daily in combination with oral prednisolone 10 mg three times/day for recurrent breast cancer. The patient was admitted with bone pain, nausea, hematuria, bleeding from an ulcerated breast lesion, and petechial skin hemorrhages. Platelet count was 38,000/mm(3) with a hemoglobin of 8.5%. The drug was discontinued and the patient treated with fresh whole blood and platelet transfusions; bleeding continued despite transfusions and the patient died the following week. The platelet count never increased to greater than 40,000 (Kissin & Kark, 1983).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Of 1333 patients taking aminoglutethimide for breast or prostate cancer, 2 developed leukopenia alone and 3 developed leukopenia with thrombocytopenia(Messeih et al, 1985).
    C) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) The manufacturer is aware of 36 cases of marrow failure secondary to aminoglutethimide over a 22-year period. The Committee on the Safety of Medicines in the UK has reported 4 cases of marrow depression and aplasia, 7 cases of agranulocytosis, and 1 case of thrombocytopenia (resulting in a total of 6 fatalities) associated with aminoglutethimide (Vincent et al, 1985).
    D) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Aminoglutethimide therapy (with hydrocortisone) was associated with the occurrence of agranulocytosis 5 to 8 weeks after initiation of therapy in three elderly patients. In two patients, withdrawal of aminoglutethimide resulted in resolution of symptoms and normalization of white blood cell counts; however, the third patient died secondary to septicemia. The temporal relationship in previous reports of leukopenia secondary to aminoglutethimide suggested the drug as the cause of agranulocytosis. A direct toxic effect on bone marrow is suggested (Vincent et al, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) MORBILLIFORM ERUPTION
    1) WITH THERAPEUTIC USE
    a) Morbilliform rash developed in about 16% of patients with Cushing's syndrome taking aminoglutethimide for 4 weeks or more(Prod Info CYTADREN(R) tablets, 2002).
    1) The rash may be more severe and confluent in areas where is patient receives or has received radiation therapy (Williams & Leslie, 1987; Vanek et al, 1990).
    B) CAPILLARITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 62-year-old woman with adrenal adenoma was treated with 250 mg aminoglutethimide every 6 hours in preparation for surgery, After 7 days of therapy she developed a fine maculopapular rash on the face, trunk and arms. The following day she had pigmented macules on the ankles and anteromedial aspects of the lower legs, consistent with capillaritis. Rashes resolved on the 10th day of aminoglutethimide therapy (Stratakis & Chrousos, 1994).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Generalized rash with oral mucous membrane involvement and/or systemic manifestations such as fever and confusion has been reported less frequently (Rowell et al, 1987).
    b) CASE REPORT - A 69-year-old woman with metastatic breast cancer was started on aminoglutethimide and prednisone; other medications included imipramine, buprenorphine, metoclopramide and oxazepam, all of which she had been taking for more than 2 months. After 12 days she developed a widespread morbilliform rash and somnolence. Two days later she was admitted with fever and confusion and superficial oral ulcerations and conjunctival injection were noted on exam. She had mild neutropenia and thrombocytopenia, and all cultures were negative. Prednisone was increased and all other medications discontinued. Fever and confusion resolved within 36 hours and the rash desqamated and resolved over 12 days (Coltart, 1984).
    c) CASE REPORT - A 64-year-old woman with metastatic breast cancer was started on aminoglutethimide and prednisone. She developed somnolence within one week and was admitted after 3 weeks with a 7 day history of maculopapular rash, oral ulceration, malaise, and fever. The rash resembled pustular psoriasis. Aminoglutethimide was stopped and fever resolved within 48 hours. Rash and stomatitis resolved over 10 days with marked desquamation (Coltart, 1984).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Aminoglutethimide can cause adrenal insufficiency, especially in patients with physiologic stressors such as surgery, trauma or acute illness. Manifestations can include hypotension, dizziness, weakness, hyponatremia, hyperkalemia and hypoglycemia (Prod Info CYTADREN(R) tablets, 2002).
    b) Adrenal insufficiency developed in about 3% of patients with Cushing's syndrome treated with aminoglutethimide for 4 weeks or more(Prod Info CYTADREN(R) tablets, 2002).
    B) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Hypothyroidism develops occasionally with therapy(Prod Info CYTADREN(R) tablets, 2002).
    C) VIRILIZATION
    1) WITH THERAPEUTIC USE
    a) Masculinization and hirsutism have occasionally developed in females and precocious puberty in males(Prod Info CYTADREN(R) tablets, 2002).
    D) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Hypoglycemia may develop after overdose, likely as a manifestation of adrenal insufficiency(Prod Info CYTADREN(R) tablets, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Aminoglutethimide is classified as FDA pregnancy category D. Pseudohermaphrodism has been reported in 2 female infants of mothers treated with aminoglutethimide along with other medications. Fetal implantation, increased fetal mortality, and teratogenic effects have been reported in animal studies. Data regarding aminoglutethimide use and human lactation are not available.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified aminoglutethimide as FDA pregnancy category D (Prod Info CYTADREN(R) tablets, 2002).
    B) PSEUDOHERMAPHRODISM
    1) Two cases of pseudohermaphrodism were reported in female infants of women treated with aminoglutethimide along with other anticonvulsant agents (Prod Info CYTADREN(R) tablets, 2002).
    2) There is a single case report of pseudohermaphroditism occurring during treatment with aminoglutethimide, phenytoin, and mephobarbital during pregnancy. At birth, the child had an enlarged clitoris and a single perineal opening. The uterus, tubes and ovaries were normal with no testicular elements. Normal female genitalia was reconstructed (LeMaire et al, 1972). This report does not, however, firmly establish a link between aminoglutethimide and teratogenicity.
    C) ANIMAL STUDIES
    1) In rats receiving doses equivalent to 0.5 to 1.25 times the maximum human dose, there was a decrease in fetal implantation, an increase in fetal deaths, and a variety of teratogenic effects. Aminoglutethimide caused pseudohermaphrodism in the offspring of rats treated with approximately 3 times the maximum human dose (Prod Info CYTADREN(R) tablets, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) At the time of this review, no data were available to assess the potential effects of exposure to aminoglutethimide during lactation in humans (Prod Info CYTADREN(R) tablets, 2002).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Studies in female rats at doses equivalent to 0.5 and 1.25 times the maximum daily human dose demonstrated a decrease in fetal implantation (Prod Info CYTADREN(R) tablets, 2002).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS125-84-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) RATS
    1) In two year carcinogenicity studies conducted in rats at doses of 10 to 60 mg/kg/day (0.04 to 0.2 times the maximum daily human dose based on body surface area), there was a dose related increase in the incidence of benign and malignant neoplasms of the adrenal cortex and thyroid follicular cells in both sexes. A borderline increase (p = 0.05) in ovarian tubular adenomas was reported at 60 mg/kg/day. Urinary bladder papillomas were significantly increased in males (Prod Info CYTADREN(R) tablets, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, especially blood pressure. Monitor patient for CNS and respiratory depression.
    B) Monitor serum electrolytes, including sodium, potassium and calcium, as well as blood glucose.
    C) Monitor CBC with differential and platelet count.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor vital signs, especially blood pressure. Monitor patient for CNS and respiratory depression.
    B) Monitor serum electrolytes, including sodium, potassium and calcium, as well as blood glucose.
    C) Monitor CBC with differential and platelet count.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Because of the risk of significant CNS depression, prehospital administration of activated charcoal is not advised.
    6.5.3) TREATMENT
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) MONITORING OF PATIENT
    1) Monitor vital signs, especially blood pressure. Monitor for CNS and/or respiratory depression. Monitor serum electrolytes, especially potassium, sodium and calcium, and monitor blood glucose.
    C) ADRENAL CORTICAL HYPOFUNCTION
    1) Hypotension, hyponatremia, hyperkalemia and/or hypoglycemia are likely related to adrenal insufficiency. Treat with intravenous hydration with 0.9% saline, 50 ml of 50% dextrose intravenously, and exogenous corticosteroids. One regimen is hydrocortisone 100 mg intravenously over 3 hours followed by 10 mg/hr infusion until patient can tolerate oral hydrocortisone. Dexamethasone should not be used as its metabolism is accelerated by aminoglutethimide (Prod Info CYTADREN(R) tablets, 2002). Mineralocorticoid replacement may also be necessary, fludrocortisone 0.1 to 0.2 mg/day orally (Prod Info FLORINEF(R) acetate oral tablets, 2003).
    D) HYPOTENSIVE EPISODE
    1) Administer intravenous 0.9% saline 10 to 20 ml/kg initially; larger volumes may be required, central venous pressure monitoring may be useful to guide fluid resuscitation.
    2) If acute adrenal insufficiency is suspected clinically, administer corticosteroids, eg hydrocortisone 100 mg intravenously over 3 hours followed by 10 mg/hr infusion until patient can tolerate oral hydrocortisone. Dexamethasone should not be used as its metabolism is accelerated by aminoglutethimide (Prod Info CYTADREN(R) tablets, 2002). Mineralocorticoid replacement may also be necessary, fludrocortisone 0.1 to 0.2 mg/day orally (Prod Info FLORINEF(R) acetate oral tablets, 2003).
    3) Administer dopamine or norepinephrine if hypotension persists. Evaluate for contributing causes of hypotension such as sepsis.
    4) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    5) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Range Of Toxicity

Summary

    A) No deaths have been reported from aminoglutethimide overdose. Ingestion of 3 to 4 grams caused coma An adult ingested 7 grams, a 16-year-old ingested 7.5 to 10 grams, and a 10-year-old ingested 10 grams; all survived with supportive care.

Therapeutic Dose

    7.2.1) ADULT
    A) CUSHING'S SYNDROME
    1) Initial dose 250 mg four times daily. May be increased by 250 mg increments guided by plasma cortisol measurement. Maximum daily dose 2 grams (Prod Info CYTADREN(R) tablets, 2002).
    B) BREAST CANCER
    1) Usual dose is 250 mg four times daily, given in conjunction with a replacement glucocorticoid to prevent reflex increase in ACTH production. Lower doses have been used in some studies in an attempt to obviate the need for replacement glucocorticoid administration (Cocconi, 1994).
    7.2.2) PEDIATRIC
    A) Clinical experience is limited. In 9 patients aged 2.5 to 16 years (4 of them aged 10 years or less) daily doses ranged from 375 mg to 1.5 g; in general smaller children received smaller doses (2.5-year-old received 500 to 750 mg/day; 3.5-year-old received 500 mg daily, children over 10 years of age received 750 mg to 1.5 g daily) (Prod Info CYTADREN(R) tablets, 2002). Duration of therapy ranged from 3 days to 6.5 months.

Minimum Lethal Exposure

    A) No deaths have been reported from aminoglutethimide overdose.

Maximum Tolerated Exposure

    A) A 33-year-old woman ingested 7 grams, a 16-year-old girl ingested 7.5 to 10 grams, and a 10-year-old boy ingested 10 grams; all survived with supportive care (Prod Info CYTADREN(R) tablets, 2002). Coma was reported after ingestion of 3 to 4 grams in one patient; mental status was normal after about 40 hours (Prod Info CYTADREN(R) tablets, 2002).

Workplace Standards

    A) ACGIH TLV Values for CAS125-84-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS125-84-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS125-84-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS125-84-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 1800 mg/kg (Prod Info CYTADREN(R) tablets, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Aminoglutethimide inhibits enzymatic conversion of cholesterol to pregnenolone, thus decreasing the production of adrenal glucocorticoids, mineralocorticoids, estrogens and androgens (Prod Info CYTADREN(R) tablets, 2002).
    1) Decreased adrenal cortisol excretion causes increased secretion of adrenocorticotropic hormone (ACTH) by the pituitary. This increased ACTH secretion can be suppressed by simultaneous administration of an exogenous glucocorticoid (Prod Info CYTADREN(R) tablets, 2002).
    2) After withdrawal of aminoglutethimide therapy, adrenal steroid synthesis returns, usually in about 72 hours (Prod Info CYTADREN(R) tablets, 2002).
    B) Aminoglutethimide also blocks the hydroxylation steps required for the aromatization of androgens to estrogens. A 1000 mg daily dose produced a 98% decrease in the conversion of radiolabeled androstenedione to estrone in one study (Cocconi, 1994).

Physicochemical

Physical Characteristics

    A) Fine white or creamy white crystalline powder (Prod Info CYTADREN(R) tablets, 2002).

Molecular Weight

    A) 232.28

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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