Table 8.

Mitotane Therapy Side Effects

Organ System	Symptoms and Signs	Frequency	Action Required
GI tract
General	Nausea, vomiting, diarrhea	Very common	Supportive therapy
Increased ALT and AST	None	Common	Hold mitotane and evaluate for causes with fast increase or enzymes >3- to 4-fold
Increased ALP and GGT	None	Very common	None
Autoimmune or drug-induced hepatitis	Cholestasis, liver failure	Rare	Stop mitotane
CYP3A4 induction	Increased hepatic drug metabolism	Very common	Evaluate all drugs for CYP3A4 metabolism, consider measuring levels
Central nervous system
General	Fatigue, somnolence, stupor, ataxia, balance disorder, decreased memory, depression, dysphasia	Very common	Obtain mitotane level and hold mitotane until symptoms resolve
Endocrine system
Adrenal insufficiency	Fatigue, nausea, abdominal pain, increased ACTH	Very common	Always start hydrocortisone with mitotane (minimum 30 mg/d, but may need substantially more); consider fludrocortisone
Hypogonadism	Loss of libido, fatigue, muscle weakness, low bioavailable testosterone	Common	Initiate testosterone replacement
Hypothyroidism	Weight gain, fatigue, dry skin, depression	Common	Initiate thyroid hormone replacement
Gynecomastia	Painful breast growth	Common	Consider radiation therapy or pharmacotherapy with aromatase inhibitor or antiestrogen. Replace testosterone in case of hypogonadism
Lab abnormalities	Increased SHBG, CBG, low TSH, low free T4	Very common	None
Hypercholesterolemia	High cholesterol	Very common	Treat with statin (choose statin not metabolized by CYP3A4, eg, pravastatin)
Skin
Rash	Rash	Common	Hold mitotane, may try restart depending on severity of reaction
Blood
Leukopenia, thromocytopenia		Rare	Depending on severity, hold mitotane