Mitotane

Trade Names:
Lysodren
- Tablets 500 mg

Pharmacology

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The primary action is on 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-beta-hydroxycortisol.

Pharmacokinetics

Absorption

Approximately 40% of oral dose is absorbed.

Distribution

Mitotane is found in most tissues, but mainly in fat tissues.

Metabolism

Primary metabolites are oxidation products.

Elimination

Approximately 10% is recovered in the urine as a water-soluble metabolite. No unchanged metabolites are found in urine or bile. Up to 60% is excreted unchanged in feces; 1% to 17% of metabolite is excreted in bile with the rest stored in the tissues. The t _½ is 18 to 159 days.

Special Populations

Administer with care in patients with liver disease other than metastatic lesions of the adrenal cortex. Interference with metabolism may occur, causing drug accumulation.

Indications and Usage

Inoperable adrenal cortical carcinoma.

Contraindications

Standard considerations.

Dosage and Administration

PO Initially 2 to 6 g/day in divided doses, 3 or 4 times daily. Titrate at least 9 to 10 g/day until adverse reactions occur. The max tolerated dose ranges from 2 to 16 g/day. Doses as high as 18 to 19 g/day have been used.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

Potentiation of CNS effects with mitotane.

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

May block the adrenolytic effects of mitotane.

Increases warfarin metabolism; increased warfarin doses may be required.

Laboratory Test Interactions

Protein-bound iodine levels and urinary 17-hydroxy-corticosteroids may be decreased by mitotane.

Adverse Reactions

Cardiovascular

Hypertension, orthostatic hypotension, flushing (infrequent).

CNS

Lethargy, somnolence (25%); dizziness, vertigo (15%).

Dermatologic

Skin toxicity (primarily rash [15%]).

EENT

Toxic retinopathy, visual blurring, diplopia, lens opacity (infrequent).

GI

Anorexia, nausea, vomiting, diarrhea (80%).

Genitourinary

Hematuria, hemorrhagic cystitis, albuminuria (infrequent).

Miscellaneous

Generalized aching, hyperpyrexia (infrequent).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Administer with care to patients with liver disease other than metastatic lesions of the adrenal cortex. Patients with hepatic function impairment 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.

Long-term therapy

Continuous administration of high doses may lead to brain damage and impairment of function.

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.

Patient Information

• Advise patient to read the patient information leaflet before starting therapy and with each refill.
• Advise patient that medication is usually started in the hospital while the dose is being adjusted and stabilized.
• Instruct patient to take exactly as prescribed and not to change the dose or discontinue unless advised by health care provider.
• Advise patient that dose is started low and increased as tolerated until max has been obtained.
• Advise patient that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
• Advise patient that if a dose is missed to take it as soon as remembered, but if several hours have passed or it is nearing the time for the next scheduled dose, to skip that dose and take the next dose at the regularly scheduled time. Caution patient to never double the dose to catch up.
• Instruct patient to inform health care provider if any of the following occur: excessive drowsiness or dizziness; persistent nausea, vomiting, diarrhea; fever; low BP or dizziness when arising from a sitting or lying position; skin rash; recurrence or worsening of symptoms of tumors.
• Caution patient that drug may cause drowsiness and dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise women of childbearing potential to use effective contraception during treatment and for 3 mo following discontinuation of mitotane.

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