Adrenal cortical carcinoma (ACC)

Active Ingredient: Mitotane

Indication for Mitotane

Population group: only adults (18 years old or older)

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma (ACC).

The effect of mitotane on non functional adrenal cortical carcinoma is not established.

For this indication, competent medicine agencies globally authorize below treatments:

2–6 g in 2-3 divided doses daily

Route of admnistration


Defined daily dose

2 - 6 g

Dosage regimen

From 0.667 To 2 g 3 time(s) per day every day

Detailed description

Treatment in adults should be started with 2-3 g mitotane per day and increased progressively (e.g. at two-week intervals) until mitotane plasma levels reach the therapeutic window 14–20 mg/L.

If it is urgent to control Cushing’s symptoms in highly symptomatic patients, higher starting doses between 4-6 g per day could be necessary and daily dose increased more rapidly (e.g. every week). A starting dose higher than 6 g/day is generally not recommended.

Dose adjustments, monitoring and discontinuation

Dose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14-20 mg/L) which ensures optimal use of mitotane with acceptable safety. Indeed, neurologic toxicity has been associated with levels above 20 mg/L and therefore this threshold should not be reached. There are some data suggesting that mitotane plasma above 14 mg/L may result in enhanced efficacy. Mitotane plasma levels higher than 20 mg/L may be associated with severe undesirable effects and offer no further benefit in terms of efficacy. Mitotane plasma levels should therefore be monitored in order to adjust the mitotane dose and to avoid reaching toxic levels.

Dosing should be individually adjusted based on mitotane plasma levels monitoring and clinical tolerance until mitotane plasma levels reach the therapeutic window 14-20 mg/L. The target plasma concentration is usually reached within a period of 3 to 5 months.

Mitotane plasma levels should be assessed after each dose adjustment and at frequent intervals (e.g. every two weeks), until the optimal maintenance dose is reached. Monitoring should be more frequent (e.g. every week) when a high starting dose has been used. It should be taken into account that dose adjustments do not produce immediate changes in plasma levels of mitotane. In addition, because of tissue accumulation, mitotane plasma levels should be monitored regularly (e.g. monthly) once the maintenance dose has been reached.

Regular monitoring (e.g. every two months) of mitotane plasma levels is also necessary after interruption of treatment. Treatment can be resumed when mitotane plasma levels will be ranged between 14-20 mg/L. Due to the prolonged half-life, significant serum concentrations may persist for weeks after cessation of therapy.

If serious adverse reactions occur, such as neurotoxicity, treatment with mitotane may need to be temporarily interrupted. In case of mild toxicity, the dose should be reduced until the maximum tolerated dose is attained.

Treatment with mitotane should be continued as long as clinical benefits are observed. If no clinical benefits are observed after 3 months at optimal dose, treatment should be permanently discontinued.

Dosage considerations

Mitotane should be taken with a glass of water during meals containing fat-rich food.

Active ingredient


Mitotane is an adrenal cytotoxic active substance, although it can apparently also cause adrenal inhibition without cellular destruction. Available data suggest that mitotane modifies the peripheral metabolism of steroids and that it also directly suppresses the adrenal cortex. The administration of mitotane alters the extra-adrenal metabolism of cortisol in humans, leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall.

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