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Precautions of Mitotane

1.Adrenal Insufficiency and Adrenal Crisis

Adrenal Insufficiency

Mitotane can cause adrenal insufficiency or worsen existing adrenal insufficiency in patients with adrenocortical carcinoma. 

Monitor for both glucocorticoid and mineralocorticoid insufficiency and replace systemic corticosteroids accordingly. Due to increased steroid clearance and increase of steroidbinding protein, high-dose replacement therapy may be required and free cortisol and corticotropin (ACTH) should be monitored to adapt the systemic corticosteroids.

Withhold, reduce the dose, or permanently discontinue Mitotane based on severity.

Adrenal Crisis in the Setting of Shock, Severe Trauma or Infection

Mitotane can cause adrenal suppression and adrenal crisis in the setting of shock, severe trauma or infection. 

Advise patients of the signs and symptoms of adrenal suppression and to contact their healthcare provider immediately if shock, trauma, infection, or adrenal suppression occurs. Withhold Mitotane before planned surgeries.

Temporarily withhold Mitotane during shock, trauma, infection or adrenal suppression.

Provide supportive care and administer systemic corticosteroids until recovery.

2.Central Nervous System Toxicity

Mitotane can cause central nervous system toxicity, including sedation, lethargy, and vertigo.

Monitor behavioral and neurologic assessments and mitotane plasma levels at regular intervals. Mitotane plasma levels exceeding 20 mg/L are associated with a greater incidence of toxicity. 

In cases of cognitive dysfunction, thyroid function should be evaluated as mitotane may induce hypothyroidism.

Mitotane can impair the ability to drive and operate machinery. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold, reduce the dose, or permanently discontinue Mitotane based on severity.

3.Ovarian Macrocysts in Premenopausal Women

Mitotane can cause non-malignant, multiple and bilateral ovarian macrocysts in premenopausal women.

Ovarian macrocysts can be symptomatic (e.g., pelvic pain or discomfort, or menstrual irregularities) or asymptomatic. 

Complications from these cysts, including adnexal torsion and hemorrhagic cyst rupture, have occurred. 

Advise female patients to contact their healthcare provider immediately for gynecological symptoms such as vaginal bleeding and/or pelvic pain.

Monitor pelvic imaging in premenopausal females at baseline and in regular intervals during treatment with Mitotane. 

Withhold, reduce the dose, or permanently discontinue Mitotane based on severity.

4.Hepatotoxicity

Mitotane can cause hepatoxicity, including liver injury or failure.

Monitor liver function tests prior to starting treatment with Mitotane, during dose  titration, and periodically during treatment as clinically indicated.

Isolated gamma-glutamyl transferase (GGT) elevation may occur.

Withhold,reduce the dose, or permanently discontinue Mitotane based on severity of hepatoxicity.

5.Hematologic toxicity

Mitotane can cause leukopenia, anemia and thrombocytopenia. Monitor complete blood counts including neutrophil count prior to starting treatment with Mitotane, during dose titration, and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue Mitotanebased on severity of cytopenia. 

6.Prolonged Bleeding Time

Mitotane can cause platelet function disorders due to abnormal adenosine diphosphate (ADP)-induced platelet aggregation. Some patients may have a prolonged bleeding time, while others may have a normal bleeding time. 

Routine in vitro bleeding time is not suitable to detect this platelet defect and to assess bleeding risk. 

Perform ADP-inducted platelet aggregometry testing prior to surgery or dental procedures to determine mitotane-induced bleeding risk. For patients with prolonged bleeding time, withhold or reduce the dose of Mitotane as clinically indicated.

7.Hormone binding protein

Mitotane has been shown to increase plasma levels of hormone binding proteins (e.g.,sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)). This should be taken into account when interpreting the results of hormonal assays and may result in gynecomastia. 

8.Embryo-Fetal Toxicity

Mitotane can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes, such as preterm births and early pregnancy loss, can occur in patients exposed to mitotane during pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception, during treatment with Mitotane and after discontinuation of treatment for as long as mitotane plasma levels are detectable, since Mitotane can render some hormonal contraceptives ineffective.

from FDA,2024.01