Mitotane, also known by its brand name Lysodren, is a medication used in the treatment of adrenocortical carcinoma, a rare form of cancer that affects the adrenal glands. It is classified as an adrenolytic agent, meaning it destroys or suppresses the function of the adrenal glands.

Mitotane Uses:

• Adrenocortical carcinoma:

  • It is indicated to treat inoperable adrenocortical carcinoma

• Off Label Use of Mitotane in Adults:

  • Cushing syndrome

Mitotane Dose in Adults:

Note: Mitotane can make you feel nauseous and vomit, so you may need to take medicine to prevent this from happening.

Mitotane (Lysodren) Dose in the treatment of Adrenocortical carcinoma:

• In the treatment of adrenocortical carcinoma, the initial oral dose of Mitotane is typically 2 to 6 grams per day, divided into 3 to 4 doses.
• The dosage is then gradually increased to achieve a desired blood concentration of 14 to 20 micrograms/mL, or as tolerated by the patient.

Off-label dosing:

• The initial off-label dose is usually 1 to 2 grams per day, which can be increased by 1 to 2 grams per day at 1- to 2-week intervals as tolerated.
• The usual dose ranges from 4 to 6 grams per day, with a maximum dose of 6 to 10 grams per day as suggested in a study by Veytsman in 2009.

Mitotane (Lysodren) Dose in the treatment of Cushing syndrome (off-label):

• The initial oral dose is usually 500 milligrams (mg) taken three times daily.
• During the first 4 to 6 weeks, the dose may be increased rapidly up to a maximum of 4,000 to 8,000 mg per day, divided into three doses, with the largest dose given in the evening to minimize discomfort.
• Once control of cortisol secretion is achieved, the dose of Mitotane should be gradually tapered to the minimal dose required to maintain remission.

Mitotane Dose in Childrens:

Mitotane (Lysodren) Dose in the treatment of Adrenocortical carcinoma (stage III or IV):

• Children and Adolescents:
  • For children and adolescents, the initial oral dose of Mitotane is typically 0.5 to 1 gram per day, divided into three doses.
  • The dose should be titrated to achieve a target serum concentration range of 14 to 20 micrograms/mL.
  • In combination with the CED regimen (cisplatin, etoposide, and doxorubicin), Mitotane has been used with an initial dose of 0.5 to 1 gram per day, divided into three doses.
  • The dose was increased weekly to a target dose of 4 grams per square meter per day, divided into three doses.
  • However, it's important to note that the reported range for initially achieving a serum concentration of 14 ± 2 micrograms/mL was 1.6 to 7.3 grams per square meter per day.
  • Subsequent dose reductions to 1 to 5.3 grams per square meter per day were required to maintain therapeutic concentrations,

Mitotane (Lysodren) Dosing adjustment for toxicity:

When it comes to dosing adjustments for toxicity in adult patients receiving Mitotane, the following recommendations can be considered:

• Adrenal crisis in the setting of shock or severe trauma:
  • Mitotane should be discontinued until the patient has recovered.
• CNS toxicity:
  • If a patient experiences central nervous system (CNS) toxicity, Mitotane should be discontinued until the symptoms resolve.
  • After the symptoms have resolved (typically after 7 to 10 days), the medication can be restarted at a lower dose.
  • A reduction of 0.5 to 1 gram may be considered.
• Significant neuropsychiatric adverse effects:
  • In the case of significant neuropsychiatric adverse effects, treatment with Mitotane should be withheld for at least 1 week.
  • After this period, the medication can be restarted at a lower dose.

Mitotane Pregnancy Risk Category: D

• Mitotane has the ability to cross the placenta, as indicated by a study conducted by Gerl in 1992.
• Consequently, if administered during pregnancy, it can potentially cause harm to the fetus.
• Although the use of Mitotane during pregnancy is limited, reports have indicated instances of preterm birth and early pregnancy loss (as reported by Baszko-Błaszyk in 2011, Kojori in 2011, and Tripto-Shkolnik in 2013).
• It's important to note that Mitotane has a long elimination half-life.
• Therefore, women of reproductive potential should use effective contraception during treatment with Mitotane and for a period after treatment until plasma levels are no longer detectable.
• In the case of using Mitotane to treat Cushing's disease, available guidelines recommend avoiding pregnancy for several years after discontinuing Mitotane therapy, as stated in guidelines by Nieman in 2015.

Use of mitotane while breastfeeding

• Mitotane can be detected in breast milk, and there is a potential risk of serious adverse reactions in breastfed infants.
• Therefore, the manufacturer recommends discontinuing breastfeeding while taking Mitotane.
• Breastfeeding should be avoided until after Mitotane treatment is discontinued and plasma levels of the medication are no longer detectable.

Dose in Kidney Disease:

The manufacturer has not recommended any dose adjustment

Dose in Liver disease:

The manufacturer has not recommended any dose adjustment. However, use carefully in hepatic impairment

Common Side Effects of Mitotane (Lysodren):

• Central Nervous System:
  • Depression
  • Dizziness
  • Vertigo
• Dermatologic:
  • Skin Rash
• Gastrointestinal:
  • Anorexia
  • Diarrhea
  • Nausea
  • Vomiting

Less common side effects of Mitotane (Lysodren):

• Cardiovascular:
  • Flushing
  • Hypertension
  • Orthostatic Hypotension
• Central Nervous System:
  • Ataxia
  • Central Nervous System Toxicity
  • Confusion
  • Dysarthria
  • Generalized Ache
  • Headache
  • Mental Deficiency
• Endocrine & Metabolic:
  • Adrenocortical Insufficiency
  • Albuminuria
  • Altered Hormone Level
  • Decreased Plasma Testosterone
  • Growth Suppression
  • Gynecomastia
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Hypothyroidism
  • Increased Sex Hormone Binding Globulin
  • Ovarian Cyst
• Genitourinary:
  • Hematuria
  • Hemorrhagic Cystitis
• Hematologic & Oncologic:
  • Neutropenia
  • Prolonged Bleeding Time
• Hepatic:
  • Hepatitis
  • Increased Liver Enzymes
• Neuromuscular & Skeletal:
  • Weakness
• Ophthalmic:
  • Blurred Vision
  • Cataract
  • Diplopia
  • Maculopathy
  • Retinopathy
• Miscellaneous:
  • Fever

Contraindications to Mitotane (Lysodren):

In the United States, the manufacturer's labeling does not specify any contraindications for Mitotane. However, it is important to note that individual patient factors and specific circumstances may still influence the decision to use Mitotane.

In Canada, according to the Canadian labeling, Mitotane is contraindicated in individuals with hypersensitivity to Mitotane or any component of the formulation.

Warnings and precautions

Adrenal crisis: [US Boxed Warning]

• Adrenal crisis is a potential serious adverse effect associated with mitotane use, and it is included in the US Boxed Warning for the drug.
• In the setting of shock or severe trauma, patients taking mitotane may experience impaired response to shock, and adrenal crisis may occur.
• The recommended management includes administering hydrocortisone, monitoring for signs of shock, and discontinuing mitotane until recovery occurs.

Insufficiency of the adrenals:

• Mitotane treatment can cause adrenal insufficiency due to its inhibitory effect on the adrenal cortex.
• Patients receiving mitotane therapy should be monitored for signs and symptoms of adrenal insufficiency, such as fatigue, weakness, weight loss, and hypotension.
• If adrenal insufficiency is suspected, appropriate steroid replacement therapy should be initiated.
• Monitoring of free cortisol and ACTH levels can help to optimize steroid replacement therapy.

Toxicity to the CNS:

• CNS toxicity is a potential adverse effect of mitotane, and patients should be closely monitored for symptoms such as lethargy, sedation, and vertigo.
• Mitotane plasma concentrations above 20 mcg/mL have been associated with a higher incidence of CNS toxicity.
• Patients should also be advised to avoid tasks that require mental alertness, such as operating machinery or driving, until it is determined that they can safely perform such activities while on the medication.
• If CNS toxicity occurs, mitotane should be discontinued until the symptoms resolve, and then restarted at a lower dose.

Gastrointestinal toxicities:

• Mitotane can cause nausea and vomiting.
• To prevent these symptoms, you may need to take anti-nausea medications.

Ovarian macrocysts

• Mitotane may cause ovarian macrocysts, which are cysts that can develop in the ovaries of premenopausal women who are taking the medication.
• These cysts can be multiple and appear on both sides of the body.
• In some cases, complications have been reported, including twisting of the ovary and rupture of the cyst with bleeding.
• Discontinuation of mitotane has resulted in improvement in some cases.
• Women taking mitotane should seek medical attention if they experience vaginal bleeding or pelvic pain.

Extended bleeding time

• Mitotane may rarely cause prolonged bleeding time.
• Patients who are about to undergo any surgical procedure should be evaluated for their bleeding risk.
• If the patient is currently on anticoagulant therapy, their coagulation parameters should be monitored and their anticoagulant dose adjusted as needed.

Hepatic impairment

• In patients with liver problems, mitotane should be used with caution.
• This is because the liver may not be able to break down mitotane properly, leading to increased levels of the drug in the body.

Mitotane: Drug Interaction

Monitoring parameters:

Monitor for therapeutic mitotane levels:

• Adults: Monitor mitotane levels using gas chromatography-flame ionization assay.
  • Initially, monitor every 4 to 8 weeks until target levels are achieved.
  • Once target levels are attained, monitor every 3 months.
• Pediatrics (adrenocortical carcinoma): Monitor mitotane serum concentrations.
  • Initially, monitor every 2 to 4 weeks until a serum concentration of 10 mcg/mL is reached.
  • After reaching the target concentration of 14 to 20 mcg/mL, continue monitoring every 1 to 2 weeks due to drug accumulation and a narrow therapeutic window.
• Monitor free cortisol and corticotropin levels to assess adrenal function.
• Watch for signs and symptoms of CNS toxicity, such as lethargy, sedation, and vertigo.
• Monitor for signs and symptoms of ovarian macrocysts in premenopausal females, such as vaginal bleeding and/or pelvic pain.
• Ensure patient adherence to the prescribed treatment regimen.

Additional Monitoring Recommendations:

• Monitor urinary free cortisol levels regularly.
• Assess thyroid function by monitoring thyroid-stimulating hormone (TSH) and free thyroxine levels every few months in adults (Veytsman, 2009).

How to administer Mitotane (Lysodren)?

Mitotane Dosage and Emetic Potential:

• Mitotane is associated with a moderate emetic potential, meaning it can cause nausea and vomiting in some patients.
• To prevent or manage these symptoms, antiemetic medications may be prescribed alongside mitotane treatment.
• Mitotane is typically administered in 3 to 4 divided doses throughout the day.
• The specific dosing schedule will be based on individual patient factors and treatment response.

Mechanism of action of Mitotane (Lysodren):

Mitotane is a medication that works by suppressing the adrenal cortex, which is responsible for producing steroids in the body. It also affects how steroids are processed in other parts of the body.

The beginning of action:

• Antitumor Response: At serum concentrations greater than 14 mcg/mL
• Children: Patients with adenocarcinoma may take between 1.5 and 12.5 months to reach 10 mg/mL. However, if the patient is a child, a clinical response can be seen sooner.

Duration:

• After discontinuation of mitotane, detectable serum levels may persist for months

Absorption:

• Oral: ~40%

Distribution:

• Stored mainly in fat tissue but can be found in all body tissues

Metabolism:

• Mainly Hepatic and other tissues

Half-life elimination:

• 18 -159 days

Excretion:

• Urine (~10%, as metabolites)
• Feces (1% -17%, as metabolites)

International Brand Names of Mitotane:

• Lysodren
• Lisodren
• Opeprim

Mitotane Brand Names in Pakistan:

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