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MITOTANE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Mitotane is an antineoplastic agent that selectively inhibits adrenal cortex activity.

Specific Substances

    1) 1,1-Dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethane
    2) 2,4'-Dichlorophenyldichloroethane
    3) 2,(o-Chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloroethane
    4) 2,4'-Ddd
    5) CB-313
    6) o,p'-DDD
    7) NSC-38721
    8) NCI-C04933
    9) WR-13045
    10) O,PDDD
    11) CAS 53-19-0
    1.2.1) MOLECULAR FORMULA
    1) C14-H10-C14

Available Forms Sources

    A) FORMS
    1) Mitotane is available as 500 mg tablets (Prod Info LYSODREN(R) oral tablets, 2010).
    B) USES
    1) Mitotane is indicated for the treatment of inoperable functional and non-functional adrenal cortical carcinoma (Prod Info LYSODREN(R) oral tablets, 2010).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Mitotane is indicated for the treatment of inoperable functional and non-functional adrenal cortical carcinoma.
    B) PHARMACOLOGY: The exact mechanism of action of mitotane is not known. It does cause cytotoxic atrophy of the adrenal cells which is associated with unresponsiveness to ACTH administration. In addition, mitotane, in an independent manner, appears to alter the pattern of corticoid metabolism. Mitotane reduced the excretion of 17-hydroxycorticosteroids without concomitant reductions in plasma cortisol or cortisol secretion rates, as well as, increased the formation of 6-beta-hydroxyl cortisol.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON; about 80%: Anorexia, nausea, vomiting, anorexia, diarrhea; 15% to 40%: CNS depression (eg; lethargy, somnolence, dizziness or vertigo), and skin rashes. INFREQUENT: Ocular effects (eg, blurred vision, diplopia, lens opacity, and retinopathy), hematuria, hemorrhagic cystitis, albuminuria, hypertension, orthostatic hypotension, flushing, and hyperpyrexia.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hyperpyrexia has been reported in patients receiving mitotane therapeutically (Prod Info LYSODREN(R) oral tablets, 2010).
    0.2.20) REPRODUCTIVE
    A) Preterm births and early pregnancy loss have been reported in patients treated with mitotane during pregnancy. A woman became pregnant while taking mitotane for adrenocortical carcinoma. Mitotane treatment was stopped at gestational week 6. A fetal ultrasound performed at gestational week 16 revealed a morphologically normal female fetus with no evidence of intrauterine growth retardation or abnormal adrenals. Because of liver and lung metastases, the pregnancy was terminated at gestational week 21. Mitotane has been detected in breast milk.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor thyroid function tests in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids, dopamine, or norepinephrine.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, electrolyte abnormalities, and CNS depression.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    I) TOXICOKINETICS
    1) Absorption: about 40% of a dose of mitotane is absorbed from the gastrointestinal tract. Mitotane is primarily distributed to fatty tissues. Metabolism: primarily metabolized by the liver. Excretion: renal: about 10% to 25% excreted in the urine as metabolites; bile: about 1% to 17% is excreted in the bile as metabolites. Elimination half-life: 18 to 159 days.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause CNS depression (eg, benzodiazepines, opiates/opioids, antipsychotic medications).

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: INITIAL: 2 to 6 grams orally daily in 3 or 4 divided doses/day. Increase dose incrementally to achieve serum concentrations of 14 to 20 mg/L or as tolerated. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia occurred in 3 of 36 patients who were receiving mitotane for the treatment of Cushing's disease (Schteingart et al, 1980).
    B) COAG./BLEEDING TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Following the administration of mitotane to treat adrenocortical cancer, 6 out of 7 patients experienced prolonged bleeding times. The prolongation appeared as early as 1 week following the initiation of therapy. Four of the 6 experiencing this alteration demonstrated an aspirin-like effect, reduced platelet aggregation upon stimulation with ADP or arachidonic acid. Platelet count, activated PTT, PT, thrombin clotting time, and fibrinogen all remained normal during mitotane administration. Although all patients also received hydrocortisone, fludrocortisone acetate and sometimes metoclopramide and loperamide, the authors concluded that mitotane was the most probable cause of the defect in platelet function (Haak et al, 1991).
    C) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old woman presented with fever (greater than 39 degrees C) and chills seven days after beginning mitotane therapy for treatment of paraneoplastic Cushing's syndrome. Laboratory analysis showed pancytopenia (hemoglobin 79 g/L, neutrophils 1.3 x 10(9)/liter, and platelets 40 x 10(9)/liter) and blood cultures were positive for Klebsiella pneumoniae. The patient's hematological abnormalities resolved 12 days after cessation of mitotane therapy. The authors speculated that the pancytopenia may have been associated with mitotane therapy, however the exact mechanism of action is unknown (Andres et al, 2001).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Transient skin rashes have occurred in approximately 15% of patients receiving mitotane therapy. The effect appeared to subside while the patient was maintained on the drug without changing the dose (Prod Info LYSODREN(R) oral tablets, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a small study (n=36), all patients receiving mitotane had low serum thyroxine levels with normal triiodothyronine resin uptake and radioactive iodine uptake while receiving mitotane for treatment of Cushing's syndrome (Schteingart et al, 1980).
    B) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) Gynecomastia has been infrequently reported following therapeutic administration of mitotane (Dickstein et al, 1998; Schteingart et al, 1980).

Reproductive

    3.20.1) SUMMARY
    A) Preterm births and early pregnancy loss have been reported in patients treated with mitotane during pregnancy. A woman became pregnant while taking mitotane for adrenocortical carcinoma. Mitotane treatment was stopped at gestational week 6. A fetal ultrasound performed at gestational week 16 revealed a morphologically normal female fetus with no evidence of intrauterine growth retardation or abnormal adrenals. Because of liver and lung metastases, the pregnancy was terminated at gestational week 21. Mitotane has been detected in breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Fetal harm may occur with the use of mitotane in pregnant women. Preterm births and early pregnancy loss have been reported in patients treated with mitotane during pregnancy. Therefore, advise women of childbearing potential to use effective contraception during therapy and after discontinuation for as long as mitotane plasma concentrations are detectable (approximately 6 to 9 weeks) (Prod Info LYSODREN(R) oral tablets, 2016; Prod Info LYSODREN(R) oral tablets, 2013).
    B) CASE REPORT
    1) A 29-year-old woman diagnosed with adrenocortical carcinoma underwent surgery and received mitotane 1.5 to 3 g/day. One year after surgery, the patient presented with metastatic disease and received 4 cycles of chemotherapy with etoposide, doxorubicin, and cisplatin. After 18 months of therapy, mitotane levels reached the therapeutic range and serial PET scans were negative. The patient chose to discontinue oral contraceptives and regular menstrual periods resumed. After 3 months, the patient became pregnant. Mitotane treatment was stopped at gestational week 6 (mitotane level, 9.8 mg/L) and treatment with hydrocortisone was continued. A fetal ultrasound performed at gestational week 16 revealed a morphologically normal female fetus with no evidence of intrauterine growth retardation or abnormal adrenals. At gestational week 18, the patient presented with rapidly evolved Cushing syndrome and hypercortisolism. Liver and lung metastases were revealed and a hepatectomy was unsuccessful. At gestational week 21, the pregnancy was terminated. Prior to the procedure, mitotane levels were undetectable in both the amniotic fluid and the fetal cord blood samples. The patient resumed chemotherapy and underwent surgery 6 months after the pregnancy termination but suffered refractory shock immediately thereafter and died (Tripto-Shkolnik et al, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Mitotane is excreted into human breast milk; however, its effects on milk production or the breastfed infant are unknown. Breastfeeding women should be advised to discontinue nursing during mitotane therapy and for as long as mitotane plasma concentrations are detectable (approximately 6 to 9 weeks) (Prod Info LYSODREN(R) oral tablets, 2016; Prod Info LYSODREN(R) oral tablets, 2013).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of mitotane exposure on fertility (Prod Info LYSODREN(R) oral tablets, 2016).

Summary Of Exposure

    A) USES: Mitotane is indicated for the treatment of inoperable functional and non-functional adrenal cortical carcinoma.
    B) PHARMACOLOGY: The exact mechanism of action of mitotane is not known. It does cause cytotoxic atrophy of the adrenal cells which is associated with unresponsiveness to ACTH administration. In addition, mitotane, in an independent manner, appears to alter the pattern of corticoid metabolism. Mitotane reduced the excretion of 17-hydroxycorticosteroids without concomitant reductions in plasma cortisol or cortisol secretion rates, as well as, increased the formation of 6-beta-hydroxyl cortisol.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON; about 80%: Anorexia, nausea, vomiting, anorexia, diarrhea; 15% to 40%: CNS depression (eg; lethargy, somnolence, dizziness or vertigo), and skin rashes. INFREQUENT: Ocular effects (eg, blurred vision, diplopia, lens opacity, and retinopathy), hematuria, hemorrhagic cystitis, albuminuria, hypertension, orthostatic hypotension, flushing, and hyperpyrexia.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hyperpyrexia has been reported in patients receiving mitotane therapeutically (Prod Info LYSODREN(R) oral tablets, 2010).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision, diplopia, lens opacity and retinopathy with hemorrhages and papilledema have been reported infrequently following therapeutic administration of mitotane (Sweetman, 2002; Prod Info LYSODREN(R) oral tablets, 2010; Grant & Schuman, 1993).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Hypertension, orthostatic hypotension, and flushing have been reported as infrequent cardiovascular adverse effects of mitotane therapy (Prod Info LYSODREN(R) oral tablets, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) CNS effects have been reported in 40% of patients receiving mitotane. CNS depression (eg; lethargy, somnolence) has been reported in 25% of patients (Prod Info LYSODREN(R) oral tablets, 2010).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness or vertigo has occurred in 15% of patients receiving mitotane therapeutically (Prod Info LYSODREN(R) oral tablets, 2010).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Long-term continuous administration of high doses of mitotane may result in permanent brain damage and impairment of cognitive function (Prod Info LYSODREN(R) oral tablets, 2010).
    b) Cerebellar ataxia, brisk arm and leg tendon reflexes, and moderate to severe neuropsychological impairment, in the areas of language (expressive oral language, reading, and writing), performance of calculations, constructional ability, memory quotient, and performance IQs, occurred in a 40-year-old woman during 2-year mitotane therapy following complete removal of an adrenocortical carcinoma. The daily dose of mitotane given was 2 to 3 grams. The patient also received daily corticosteroid replacement therapy. The neuropsychological impairment appeared to occur at mitotane serum levels greater than 15 mg/liter. The patient showed complete neurological and neuropsychological recovery after discontinuation of mitotane therapy (Bollen & Lanser, 1992).
    D) AMNESIA
    1) WITH THERAPEUTIC USE
    a) Eighteen of 36 patients had decreased memory while taking mitotane for the treatment of Cushing's syndrome (Schteingart et al, 1980).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS53-19-0 (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
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential. However, the mechanism of action suggests that mitotane most likely has less carcinogenic potential compared with other chemotherapeutic drugs (Prod Info LYSODREN(R) oral tablets, 2009a).

Genotoxicity

    A) At the time of this review, no data were available to assess the genotoxic or mutagenic effects of mitotane (Prod Info LYSODREN(R) oral tablets, 2009a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and anorexia have occurred in approximately 80% of patients following therapeutic administration of mitotane (Prod Info LYSODREN(R) oral tablets, 2010). Anorexia and nausea occurred in 32 of 36 patients who were receiving mitotane for the treatment of Cushing's disease (Schteingart et al, 1980).
    b) Diarrhea may commonly occur with mitotane therapy (Prod Info LYSODREN(R) oral tablets, 2010).
    B) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) Hypersialorrhea occurred in 3 patients receiving mitotane in the treatment of Cushing's syndrome. Recovery was seen in 1 week after discontinuation of mitotane (Bricare & Luton , 1975).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) HEMORRHAGIC CYSTITIS
    1) WITH THERAPEUTIC USE
    a) Hemorrhagic cystitis has been rarely reported with mitotane therapy (Prod Info LYSODREN(R) oral tablets, 2010).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria has been rarely reported with mitotane therapy (Prod Info LYSODREN(R) oral tablets, 2010).
    C) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) Albuminuria has been rarely reported with mitotane therapy (Prod Info LYSODREN(R) oral tablets, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor thyroid function tests in symptomatic patients.

Methods

    A) Chromatography
    1) High-performance liquid chromatography has been used to determine the concentration of mitotane and its metabolites in human plasma. The limits of detection for mitotane have ranged from 0.25 to 0.5 micromoles/liter(Anderson et al, 1999; Anderson et al, 1995).
    2) Gas chromatography with electron-capture detection was used for determination of mitotane and it's metabolite, o,p'-DDE, in human plasma. The absolute recoveries of these compounds from plasma ranged from approximately 85% to approximately 95%(Benecke et al, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, electrolyte abnormalities, and CNS depression.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with a small inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    D) Monitor thyroid function tests in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    4) Monitor thyroid function tests in symptomatic patients.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) 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).
    3) 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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: INITIAL: 2 to 6 grams orally daily in 3 or 4 divided doses/day. Increase dose incrementally to achieve serum concentrations of 14 to 20 mg/L or as tolerated. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) INOPERABLE ADRENAL CARCINOMA
    1) INITIAL: 2 to 6 grams orally daily in 3 or 4 divided doses/day (Prod Info LYSODREN(R) oral tablets, 2016).
    2) TITRATION: Increase dose incrementally to achieve serum concentrations of 14 to 20 mg/L or as tolerated (Prod Info LYSODREN(R) oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) INOPERABLE ADRENAL CARCINOMA
    1) Safety and efficacy have not been established in pediatric patients (Prod Info LYSODREN(R) oral tablets, 2013).

Maximum Tolerated Exposure

    A) CASE REPORT
    1) Cerebellar ataxia, brisk arm and leg tendon reflexes, and moderate to severe neuropsychological impairment, in the areas of language (expressive oral language, reading, and writing), performance of calculations, constructional ability, memory quotient, and performance IQs, occurred in a 40-year-old woman during 2-year mitotane therapy following complete removal of an adrenocortical carcinoma. Cognitive effects appeared at serum levels above 15 mg/L and resolved with drug discontinuation. The daily dose of mitotane given was 2 to 3 grams. The patient also received daily corticosteroid replacement therapy (Bollen & Lanser, 1992).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Neuropsychological impairment in the areas of language, performance of calculations, constructional ability, memory quotient, and performance IQs, occurred at mitotane serum levels greater than 15 mg/liter in a 40-year-old woman during 2-year mitotane therapy. The daily dose of mitotane that the patient received was 2 to 3 grams (Bollen & Lanser, 1992).

Workplace Standards

    A) ACGIH TLV Values for CAS53-19-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS53-19-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS53-19-0 :
    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 CAS53-19-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) > 4 g/kg (RTECS, 2003)
    B) LD50- (ORAL)RAT:
    1) > 5 g/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Mitotane, an isomer found in the insecticide DDD, is an antineoplastic agent indicated in the treatment of adrenocortical carcinoma. The exact mechanism of action of mitotane is not known. It does cause cytotoxic atrophy of the adrenal cells which is associated with unresponsiveness to ACTH administration. In addition, mitotane, in an independent manner, appears to alter the pattern of corticoid metabolism. Mitotane reduced the excretion of 17-hydroxycorticosteroids without concomitant reductions in plasma cortisol or cortisol secretion rates, as well as, increased the formation of 6-beta-hydroxyl cortisol (Prod Info LYSODREN(R) oral tablets, 2013; Bledsoe et al, 1964).

Physicochemical

Physical Characteristics

    A) Mitotane is a white granular solid composed of clear colorless crystals. It is tasteless, has a slight aromatic odor, and is soluble in ethanol, isooctane, and carbon tetrachloride (Prod Info LYSODREN(R) oral tablets, 2009).

Molecular Weight

    A) 320.05 (Prod Info LYSODREN(R) oral tablets, 2009)

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.
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