What Is Mitotane (Lysodren)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes (Initial approval date: July 8, 1970)
• Brand Name: Lysodren
• Active Ingredient: Mitotane
• Route of Administration: Oral tablets
• Class: Adrenolytic agent
• Category: Chemotherapy medicine
• Manufacturer: HRA Pharma Rare Diseases
• Approved Cancer Indications: Inoperable, functional or nonfunctional adrenocortical carcinoma

What Is Lysodren? How Does It Work?

Lysodren, containing mitotane, is an oral adrenolytic agent used to treat adrenocortical cancer. It directly damages adrenal cortical cells, suppressing adrenal steroid production with the aim of slowing disease progression.

What Is an Adrenolytic Agent?

Adrenolytic agents target adrenal cortical cells, suppressing their function and reducing steroid production at the cellular level. In malignant tumors arising from the adrenal gland, these agents inhibit steroid synthesis to slow or stop tumor growth. This mechanism makes adrenolytic agents an effective treatment option for rare but aggressive cancers such as adrenocortical cancer.

How Does It Work?

• Mitotane is a dichloro derivative of the insecticide DDD.
• It directly damages mitochondria in adrenal cortical cells, inhibiting adrenal steroid production.
• It alters peripheral steroid metabolism and lowers 17-OH corticosteroid levels.
• Mitotane accumulates in adipose tissue, and its long half-life allows its effects to persist for weeks.

FDA (US Food and Drug Administration) Approval History

July 8, 1970: Mitotane (Lysodren) was approved by the FDA for treating inoperable, functional or nonfunctional adrenocortical carcinoma.

Licensing and Reimbursement in Turkey

Lysodren, containing mitotane, can be brought into Turkey with overseas medicine use authorization as a medicine not licensed by the Turkish Ministry of Health. This process is managed through the Turkish Pharmacists' Association (TEB).

Overseas Medicine Use Procedure

• For patients who need treatment, the treating specialist should request overseas medicine use authorization from the Turkish Ministry of Health.
• Once authorization is granted, Lysodren can be obtained from abroad through the Turkish Pharmacists' Association (TEB).
• This is an official process intended to facilitate and accelerate access to treatment for rare adrenocortical cancer.
• Lysodren is not covered by SGK (Social Security Institution) reimbursement; patients must finance it themselves. Exceptional individual applications may be submitted with specialized oncology reports.

Price: As of August 2025, the international selling price for Lysodren 500 mg tablets was 818.03 euros. 

Mechanisms of Resistance

• Inadequate intracellular drug levels because of excessive storage in adipose tissue.
• Adaptation of adrenal cortical cells to mitochondrial toxicity.
• Activation of alternative steroid synthesis pathways.
• Reduced levels of the active compound because of increased drug metabolism.

Absorption

• Approximately 35–45% of the oral dose is absorbed.
• Peak plasma levels are reached in 3–5 hours.

Distribution

• It is extensively distributed into tissues.
• It is highly fat-soluble and stored in large quantities in adipose tissue.
• Mitotane is released slowly, and drug levels may remain detectable for up to 10 weeks.
• It does not cross the blood-brain barrier.

Metabolism

• It is metabolized in the liver, producing both active and inactive metabolites.
• The parent compound and its metabolites are eliminated mainly through the hepatobiliary system in feces, approximately 60%.
• Only 10–25% is eliminated through the kidneys.
• Because the drug is stored in adipose tissue, its variable elimination half-life may extend to 160 hours.

Dosing Schedule 

• Initial dose:Treatment generally starts at 2 to 6 grams daily, divided into 3-4 doses.
• Maintenance dose: The usual goal is to maintain blood mitotane levels between 14-20 mg/L. After the initial dose, the dose may be increased as tolerated. Maintenance dosing is usually 2-4 grams daily.
• Maximum dose: The dose may be increased as tolerated, but because adverse effects, particularly gastrointestinal and neurological effects, can be serious, doses above 6-8 grams daily are generally not used.

Drug Interactions 

• Glucocorticoids (Cortisol Derivatives Such as Hydrocortisone and Prednisone): Mitotane increases the breakdown of these hormones. Hormone levels may fall, making dose increases necessary.
• Anticoagulants (Particularly Warfarin): Mitotane may reduce warfarin's effect. Coagulation parameters (INR) should be monitored more frequently.
• Anticonvulsants (Such as Phenytoin and Phenobarbital): Both medicines affect liver enzymes, making their interaction complex when used together. The risk of seizures or drug toxicity may increase.
• Chemotherapy Medicines (Such as Etoposide and Doxorubicin): Mitotane may accelerate the elimination of these medicines and reduce chemotherapy effectiveness.
• Sedatives and Sleeping Medicines (Such as Benzodiazepines): Because mitotane may increase central nervous system depression, adverse effects such as drowsiness and confusion may become more severe.
• Hormone Treatments (Such as Estrogen and Testosterone): Mitotane may reduce hormonal effects, so dose adjustment may be needed, particularly in patients receiving hormone replacement.

Precautions

• Use cautiously in patients with impaired liver function. Reduce the dose if necessary.
• Glucocorticoid and/or mineralocorticoid replacement may be needed because adrenal insufficiency can develop.
• Stress-dose IV steroids should be administered in cases of infection, stress, trauma, or shock.
• Because mitotane may cause lethargy and drowsiness, patients should be warned about driving and activities requiring alertness.
• When warfarin is used with mitotane, coagulation parameters (PT and INR) should be monitored carefully.
• Mitotane is pregnancy category C. Use during pregnancy is not recommended, and it should not be used while breastfeeding.
• Because mitotane may suppress the immune system, it may reduce the effectiveness of live vaccines or increase infection risk.
• Alcohol may increase the burden on the liver and intensify mitotane's depressant effects on the nervous system.

Adverse Effects 

• Loss of appetite 80%
• Nausea 77%
• Vomiting 48%
• Diarrhea 38%
• Weight loss 42%
• Abdominal pain 30%
• Dizziness 32%
• Headache 20%
• Drowsiness (sedation) 33%
• Confusion 26%
• Fatigue 22%
• Depression 15%
• Muscle weakness 15%
• Impaired coordination 12%
• Hand tremor 14%
• Skin rash 12%
• Dry skin 10%
• Itchy skin 9%
• Hypoadrenalism (adrenal insufficiency) 15%
• Hypothyroidism 8%
• Anemia 5%
• Leukopenia (low white blood cell count) 5%
• Hepatotoxicity (liver injury) 7%
• Hypercholesterolemia 9%
• Hypercalcemia 5%
• Upper respiratory tract infection 12%
• Cough 10%
• Taste disturbance 8%
• Low blood pressure (hypotension) 6%
• Fever 10%
• Muscle pain 9%
• Joint pain 7%
• Peripheral edema (swelling, particularly in the legs) 6%