2.1 Recommended Dose

The recommended initial dose of LYSODREN is 2 g to 6 g orally, in three or four divided doses per day. Increase doses incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated.

LYSODREN is a cytotoxic drug. Follow applicable special handling and disposal procedures.

2.2 Dose Modifications

5.1 Adrenal Crisis in the Setting of Shock or Severe Trauma

In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock, and discontinue LYSODREN until recovery [see Dosage and Administration (2.2)].

5.2 CNS Toxicity

CNS toxicity, including sedation, lethargy, and vertigo, occurs with LYSODREN treatment. Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of toxicity.

5.3 Adrenal Insufficiency

Treatment with LYSODREN can cause adrenal insufficiency. Institute steroid replacement as clinically indicated. Measure free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement.

5.4 Embryo-Fetal Toxicity

LYSODREN 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 contraception during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable [see Use in Specific Populations (8.1, 8.3)].

5.5 Ovarian Macrocysts in Premenopausal Women

Ovarian macrocysts, often bilateral and multiple, have been reported in premenopausal patients receiving LYSODREN. Complications from these cysts, including adnexal torsion and hemorrhagic cyst rupture, have been reported. In some cases, improvement after mitotane discontinuation has been described. Advise female patients to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [seeAdverse Reactions (6)].

7.1 Certain CYP3A Substrates

Mitotane is a strong CYP3A inducer. Concomitant use of LYSODREN may decrease the concentrations of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid the concomitant use of LYSODREN with certain CYP3A4 substrates where minimal concentration changes may lead to therapeutic failure. If concomitant use cannot be avoided, increase the CYP3A substrate dosage in accordance with approved product labeling.

7.2 Warfarin

When administering coumarin-type anticoagulants to patients receiving LYSODREN, monitor coagulation tests and adjust the anticoagulant dose as needed.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Hepatic impairment may interfere with the metabolism of mitotane and the drug may accumulate. Administer LYSODREN with caution to patients with hepatic impairment.

12.1 Mechanism of Action

Mitotane is an adrenal cytotoxic agent with an unknown mechanism of action. Mitotane modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex. A reduction in 17-hydroxycorticosteroids in the absence of decreased corticosteroid concentrations and increased formation of 6-β-hydroxycortisol have been reported.

12.2 Pharmacodynamics

The pharmacodynamics of mitotane are unknown.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity and mutagenicity of mitotane are unknown.