Mitotane is an adrenal cytotoxic agent, and can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Available data suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. In man, mitotane administration alters cortisol's extra-adrenal metabolism, leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma corticosteroid concentrations do not fall. The drug apparently causes increased formation of 6-beta-hydroxy cortisol.

Approximately 40% of oral mitotane is absorbed, and approximately 10% is recovered in the urine as a water soluble metabolite. A small amount is excreted in the bile and the balance is stored in the tissues. When administered parenterally, approximately 25% of the dose is found in the urine as a water soluble metabolite.

Both unchanged drug and a metabolite were measured during and after dosing. The concentrations in patients receiving doses from 5 to 15 g/day varied from 7 to 90 µg/mL of unchanged mitotane and 29 to 54 µg/mL of the metabolite. These studies indicated no relationship between blood concentrations and therapeutic and/or toxic effects.

Following discontinuation of the drug, blood concentrations fell, but persisted for several weeks. In most patients, blood concentrations became undetectable after 6 to 9 weeks. In 1 patient who had received a total of 1 900 g of mitotane, high blood concentrations were found 10 weeks after stopping the drug. Autopsy data have provided evidence that mitotane is found in most body tissues. Fat tissues were the primary storage site. In 1 patient a very large number of tissues were examined and the drug was found in essentially every tissue.

Mitotane appears to be partly converted to a water soluble metabolite. This material has not been characterized, but is only found in the urine and blood of patients receiving mitotane. Examination of bile was made and found to contain no unchanged mitotane. There was metabolite in the bile, and this would indicate that biliary excretion is a significant route of removal of this metabolite from the body.

There is no evidence of a cure as a consequence of mitotane administration. A number of patients have been treated intermittently, treatment being restarted when severe symptoms reappear. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggest that continuous treatment with the maximum possible mitotane dosage would be the best approach.

There was significant reduction in tumor mass following mitotane administration in about 50%, and a significant reduction in elevated steroid excretion in about 80% of the evaluable patients studied to date. Clinical effectiveness can be shown by reduction in tumor mass, reduction in pain, weakness or anorexia, and reduction of steroid symptoms.

Mitotane is indicated only in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional type.

Known hypersensitivity to mitotane.

Mitotane should be temporarily discontinued immediately following shock or severe trauma since adrenal suppression is its prime action. Exogenous steroids should also be administered in such circumstances since the depressed adrenal may not immediately start to secrete steroids.

Mitotane should be administered with care to patients with liver disease other than metastatic lesion of the adrenal cortex, since the metabolism of mitotane may be interfered with and the drug may accumulate.

All possible tumour tissue should be surgically removed from large metastatic masses before mitotane administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumour due to a rapid, positive effect of the drug.

Long-term continuous administration of high doses of mitotane may lead to brain damage and impairment of function. Behavioural and neurological assessments should be made at regular intervals when continuous mitotane treatment exceeds two years.

Mitotane's safety in pregnancy or lactation has not been established. Treatment of women who are, or who may become pregnant, should be undertaken only after consideration of the benefits versus the possibility of harm to mother and child.

See Pregnancy.

Adrenal insufficiency may develop in patients treated with mitotane, and adrenal steroid replacement should be considered for these patients.

Since sedation, lethargy, vertigo, and other CNS adverse effects can occur, caution ambulatory patients about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.

Mitotane appears to induce drug metabolizing enzymes in both experimental animals and man. Consequently, the dosage of other drugs given concurrently with mitotane may require adjustment in order to achieve the desired therapeutic effect.

A very high percentage of patients treated with mitotane have shown at least one type of adverse effect. The main types of adverse reactions consist of the following:

Infrequently occurring adverse effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, albuminuria); cardiovascular system (hypertension, orthostatic hypotension, flushing); and some miscellaneous complaints including generalized aching, hyperpyrexia, and lowered PBI.

Two dosage regimens may be used. The patient may be started on 2-6 g a day, in divided doses q.i.d. or t.i.d. and the dosage increased as quickly as possible to as much drug as can be tolerated, preferably arriving at 8-10 g or more.

or

Start the patient at 9-10 g of mitotane per day in divided doses, either q.i.d. or t.i.d. since most patients will have side effects initially irrespective of starting dosage. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere.

Experience has shown that the maximum tolerated dose (MTD) will vary from 2 to 16 g/day, but has usually been 8 to 10 g/day. The highest doses used in the studies to date were 18 to 19 g/day.

Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred.

If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case may be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD.

Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response.

Each one-half inch, biconvex, round compressed white tablet, bisected on one side and impressed with “BL” over “L1" on the other side, contains: mitotane 500 mg. Nonmedicinal ingredients: microcrystalline cellulose, polyethylene glycol, silicon dioxide and starch. Bottles of 100.