Mitotane

Actions The primary action is upon the adrenal cortex. The production of adrenal steroids is reduced. The biochemical mechanism of action is unknown. Data suggest that the drug modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex. Use of mitotane alters the peripheral metabolism of cortisol, even though plasma levels of corticosteroids do not fall. The drug causes increased formation of 6-b-hydroxycortisol. Approximately 40% of oral mitotane is absorbed; it can be found in all body tissues but is primarily stored in fat. Approximately 10% to 25% of the drug is excreted in the urine as an unidentified water-soluble metabolite. Up to 60% is excreted unchanged in the stool.

 Indications Inoperable adrenal cortical carcinoma.

 Contraindications Standard considerations.

 Route/Dosage

Inoperable Adrenal Cortical Carcinoma

ADULTS: PO Initially 1 to 6 g/day (£ 10 g/day) in divided doses, either tid or qid. Titrate ³ 9 to 10 g/day until adverse effects occur. The maximum tolerated dosage ranges from 2 to 16 g/day. Doses as high as 20 g/day have been used.

Interactions

CNS depressants (eg, narcotics, analgesics, alcohol, antiemetics, benzodiazepines, sedatives, tranquilizers)

Potentiation of CNS effects with mitotane.

Corticosteroids

May increase corticosteroid metabolism, requiring higher corticosteroid doses with long-term mitotane therapy.

Spironolactone

May block the adrenolytic effects of mitotane.

Warfarin

Increases warfarin metabolism; increased warfarin doses may be required

Lab Test Interferences Protein-bound iodine levels and urinary 17-hydroxycorticosteroids may be decreased by mitotane.

 Adverse Reactions

CNS: Depression (25%), lethargy and somnolence, vertigo or dizziness (15%); brain damage and functional impairment with long-term continuous administration (neurologic and behavioral assessment necessary in patients treated > 2 yr). DERMATOLOGIC: Maculopapular rashes, flushing, erythema. ENDOCRINE: Adrenocortical insufficiency requiring corticosteroid supplementation, gynecomastia. GI: Moderate potential for nausea and vomiting, GI disturbances, diarrhea. GU: Hemorrhagic cystitis. MUSCULOSKELETAL: Aching muscles, muscle twitching, arthralgia. SPECIALSENSES: Double vision, blurred vision, lens opacity, toxic retinopathy. OTHER: Fever.

 Precautions

Pregnancy: Category C. Lactation: Undetermined. Shock or severe trauma: Temporarily discontinue mitotane immediately following shock or severe trauma, because adrenal suppression is its prime action. Tumor tissue: Surgically remove all possible tumor tissue from large metastatic masses before administration to minimize the possibility of infarction and hemorrhage in the tumor caused by a rapid, cytotoxic effect of the drug. Long-term therapy: Continuous administration of high doses may lead to brain damage and impairment of function. Hepatic function impairment: Administer with care to patients with liver disease other than metastatic lesions of the adrenal cortex. Adjustment in hepatic insufficiency: Patients with hepatic insufficiency may require a decrease in mitotane dosage; however, specific recommendations are not established. Adrenal insufficiency: Adrenal insufficiency may develop; consider adrenal steroid replacement in these patients.

 Administration/Storage

• Store at room temperature in a tight, light-resistant container.
• Initiate treatment in a hospital until a stable dosage regimen is achieved. Do not give mitotane with a fatty meal; fat may impair absorption of mitotane.
• Administer PO.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.

 Assessment/Interventions

• Continuous treatment with the maximum tolerated dosage of mitotane appears to be more effective than intermittent courses.
• Temporarily discontinue mitotane and initiate corticosteroid therapy in situations that can cause acute adrenal insufficiency (eg, shock, trauma, infection).

 Patient/Family Education

• Notify health care provider if nausea, vomiting, loss of appetite, diarrhea, mental depression, skin rash, or darkening of the skin occurs.
• Medication may cause aching muscles, fever, flushing or muscle twitching; notify health care provider if these become pronounced.
• May produce drowsiness, dizziness, and tiredness; observe caution when driving or performing other tasks requiring alertness.
• Contraceptive measures are recommended during therapy.