Lysodren (Mitotane)
Antineoplastic Agent for Adrenocortical Carcinoma
Quick Facts About Lysodren
Key Takeaways About Lysodren
- Only approved drug for adrenocortical carcinoma: Lysodren (mitotane) is the sole drug specifically approved for treating advanced, inoperable, metastatic, or recurrent malignant adrenal cortex tumours
- Requires blood level monitoring: Plasma mitotane levels must be regularly checked to achieve the therapeutic window of 14–20 mg/L for optimal efficacy while minimising toxicity
- Causes adrenal insufficiency: Mitotane suppresses adrenal cortex function, meaning most patients require corticosteroid replacement therapy (hydrocortisone or equivalent) throughout treatment
- Must be taken with fatty food: Absorption is significantly improved when tablets are taken with fat-containing meals such as milk, chocolate, or oil
- Cytotoxic handling required: Lysodren tablets should be handled with disposable gloves; the drug must not be handled by pregnant women due to risk of foetal harm
What Is Lysodren and What Is It Used For?
Lysodren (mitotane) is an antineoplastic agent specifically indicated for the treatment of advanced adrenocortical carcinoma (ACC) that cannot be completely removed by surgery, has spread to other parts of the body (metastatic), or has returned after prior treatment (recurrent).
Adrenocortical carcinoma is a rare and aggressive malignancy arising from the cortex (outer layer) of the adrenal glands, which are small organs located above each kidney. The adrenal cortex normally produces essential hormones including cortisol, aldosterone, and androgens. When cancer develops in these cells, the tumour may produce excessive amounts of these hormones (functioning tumour) or may not produce hormones at all (non-functioning tumour). The annual incidence of adrenocortical carcinoma is approximately 0.7–2 cases per million people worldwide, making it one of the rarest solid organ cancers.
Mitotane, the active substance in Lysodren, exerts a direct cytotoxic (cell-killing) effect on adrenocortical cells. It causes destruction of the mitochondria within these cells and inhibits key enzymes involved in steroid hormone production, including 11-beta-hydroxylase and cholesterol side-chain cleavage enzyme. This dual mechanism means that mitotane both kills tumour cells and reduces the excessive hormone production that often accompanies adrenocortical carcinoma. The European Society for Medical Oncology (ESMO) and the European Network for the Study of Adrenal Tumours (ENSAT) recommend mitotane as the cornerstone of medical treatment for advanced adrenocortical carcinoma.
Lysodren is used in two primary clinical settings. First, as adjuvant therapy after surgical removal of the tumour, particularly in patients at high risk of recurrence (based on tumour stage, grade, and completeness of resection). Second, as the primary medical therapy for patients with advanced, inoperable, or metastatic disease, either alone or in combination with cytotoxic chemotherapy regimens such as etoposide, doxorubicin, and cisplatin (the EDP-M protocol).
Due to the rarity and complexity of adrenocortical carcinoma, Lysodren treatment should always be initiated and supervised by a specialist oncologist or endocrinologist with experience in managing this disease. Treatment requires regular blood monitoring to achieve and maintain therapeutic drug levels, and ongoing management of adrenal insufficiency.
Mitotane was first synthesised in the 1940s as an insecticide (DDD, a metabolite of DDT). Its adrenolytic properties were discovered when dogs exposed to the compound developed adrenal cortex destruction. This led to the development of mitotane as a pharmaceutical treatment for adrenocortical carcinoma. It has been used clinically since the 1960s and was granted orphan drug designation by the European Medicines Agency (EMA) due to the rarity of the condition it treats.
What Should You Know Before Taking Lysodren?
Before starting Lysodren, your doctor will assess your overall health, liver and kidney function, and all current medications. Lysodren is contraindicated during breastfeeding and must not be combined with spironolactone. It requires special handling precautions and causes adrenal insufficiency that needs hormonal replacement.
Contraindications
You should not take Lysodren if any of the following apply to you:
- Allergy to mitotane or any of the other ingredients in the tablet (maize starch, microcrystalline cellulose, macrogol 3350, colloidal anhydrous silica)
- Breastfeeding – mitotane may pass into breast milk and cause serious adverse effects in the nursing infant. You must not breastfeed while taking Lysodren or after treatment has ended
- Concurrent use of spironolactone – spironolactone (a potassium-sparing diuretic used for heart, liver, or kidney conditions) blocks the adrenolytic action of mitotane and must not be used together
Warnings and Precautions
Talk to your doctor or pharmacist before taking Lysodren if you have or have had any of the following conditions, or if any of these situations arise during treatment:
- Trauma, shock, or severe infection: In the event of a significant physical injury, surgery, severe infection, or other physiological stress, inform your doctor immediately. Mitotane suppresses adrenal function, and your body may not be able to produce adequate stress hormones. Your doctor may temporarily discontinue Lysodren and/or increase your corticosteroid replacement dose
- Liver problems: Tell your doctor if you develop any signs of liver damage including itching, yellowing of the skin or eyes (jaundice), dark-coloured urine, or pain in the upper right abdomen. Your doctor will perform blood tests to monitor liver function before and during treatment
- Severe kidney impairment: Lysodren should be used with caution in patients with significantly reduced kidney function
- Gynaecological symptoms: Mitotane can affect sex hormone levels and cause vaginal bleeding, menstrual disturbances, and/or pelvic pain. Ovarian macrocysts have been reported. Inform your doctor of any new gynaecological symptoms
Lysodren is a cytotoxic (cell-damaging) drug. It should not be handled by anyone other than the patient and their caregivers. Caregivers should always wear disposable gloves when handling the tablets. Pregnant women must not handle Lysodren tablets under any circumstances, as mitotane may cause harm to the developing foetus.
Adrenal Insufficiency During Treatment
One of the most important aspects of Lysodren therapy is that it intentionally suppresses adrenal cortex function. This means your adrenal glands will produce insufficient amounts of cortisol and potentially other steroid hormones. Your doctor will prescribe corticosteroid replacement therapy (typically hydrocortisone) to compensate for this deficit. The replacement dose may need to be adjusted over time based on your symptoms and blood test results.
During periods of physical stress such as illness, injury, or surgery, your body normally increases cortisol production. Because Lysodren prevents this, you may need a temporary increase in your corticosteroid dose during such events. This is known as “stress dosing.” It is essential that you understand this concept and communicate with your healthcare team whenever you face a stressful physical situation.
Prolonged Bleeding Time
Lysodren can cause prolonged bleeding time, meaning that cuts and wounds may take longer than usual to stop bleeding. If you require surgery or dental procedures while on Lysodren treatment, your healthcare team will perform blood tests to assess your bleeding risk beforehand. Always inform surgeons and dentists that you are taking Lysodren.
Patient Card
You should always carry your Lysodren patient card (included with the medication packaging) with you at all times. This card informs emergency healthcare providers that you are taking mitotane, that you may have adrenal insufficiency, and that you may require emergency corticosteroid treatment. The card also alerts medical staff to the risk of prolonged bleeding time.
Pregnancy and Breastfeeding
Lysodren may cause serious harm to a developing foetus. If you are pregnant, suspect you may be pregnant, or are planning to become pregnant, inform your doctor immediately so that a decision can be made about whether to continue or discontinue treatment. Women of childbearing potential must use effective contraception during Lysodren treatment and for a prolonged period after treatment ends, as mitotane has an extremely long elimination half-life (18–159 days) and persists in body fat for months after the last dose.
Breastfeeding is strictly contraindicated during and after Lysodren treatment due to the risk of serious adverse effects in the nursing infant. Consult your doctor about the appropriate duration to avoid breastfeeding after stopping treatment.
Driving and Operating Machinery
Lysodren has a significant impact on the ability to drive and use machines. Common neurological side effects include dizziness, drowsiness, confusion, and coordination disturbances. You should discuss with your doctor whether it is safe for you to drive or operate machinery during treatment. If you experience any neurological symptoms, do not drive or operate hazardous equipment.
How Does Lysodren Interact with Other Drugs?
Lysodren has clinically significant interactions with many medications because it is a potent inducer of liver enzymes (particularly CYP3A4). This means it can substantially reduce the effectiveness of many other drugs. The combination with spironolactone is absolutely contraindicated.
Mitotane is a potent inducer of several cytochrome P450 liver enzymes, particularly CYP3A4. This enzyme induction accelerates the metabolism of many other drugs, reducing their blood levels and potentially their effectiveness. Additionally, mitotane alters peripheral steroid metabolism and can affect the protein binding of other medications. Because of these widespread pharmacokinetic interactions, it is critical that your doctor knows about all medications you are taking, including over-the-counter drugs, herbal remedies, and dietary supplements.
Contraindicated and Major Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Spironolactone | Potassium-sparing diuretic | Blocks the adrenolytic action of mitotane, potentially rendering treatment ineffective | Absolutely contraindicated – do not combine under any circumstances |
| Warfarin and other anticoagulants | Blood thinners | Mitotane induces warfarin metabolism via CYP enzymes, reducing anticoagulant effect; combined with mitotane's own effect on bleeding time | Monitor INR closely and frequently; significant dose adjustment of anticoagulant likely needed |
| Sunitinib | Anticancer (tyrosine kinase inhibitor) | Mitotane significantly reduces sunitinib blood levels through CYP3A4 induction | Avoid combination if possible; if used together, monitor sunitinib levels and consider dose increase |
| Etoposide | Anticancer (topoisomerase inhibitor) | Mitotane may reduce etoposide levels through enhanced metabolism | Dose adjustments may be required; monitor clinical response |
| Midazolam | Sedative (benzodiazepine) | Mitotane significantly reduces midazolam blood levels through CYP3A4 induction | Higher doses of midazolam may be needed; monitor sedative effect |
Moderate Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Antiepileptics (phenytoin, carbamazepine, phenobarbital) | Seizure medications | Both mitotane and these drugs are CYP inducers; unpredictable mutual effects on drug levels | Monitor blood levels of both drugs; dose adjustments likely required |
| Rifampicin / Rifabutin | Antibiotics (TB treatment) | Additional CYP3A4 induction may alter mitotane metabolism and reduce effectiveness of co-administered drugs | Use with caution; close monitoring of both drug levels |
| Griseofulvin | Antifungal | CYP inducer that may interact with mitotane metabolism | Monitor treatment response; consider alternative antifungal |
| St. John’s Wort (Hypericum perforatum) | Herbal supplement | Additional CYP3A4 induction may reduce effectiveness of many co-administered drugs | Avoid concurrent use |
| Hormonal contraceptives | Birth control | Mitotane may reduce effectiveness of hormonal contraceptives through enzyme induction | Use additional non-hormonal contraception (e.g., barrier methods) during treatment |
Because mitotane suppresses adrenal function, you will require corticosteroid replacement therapy (e.g., hydrocortisone). However, mitotane also accelerates cortisol metabolism through CYP3A4 induction. This means higher-than-normal replacement doses of hydrocortisone may be needed. Your doctor will adjust your replacement dose based on clinical symptoms and blood cortisol levels.
Food Interactions
Lysodren should preferably be taken with meals containing fatty food, such as milk, chocolate, or oil. Mitotane is a highly lipophilic compound, and its gastrointestinal absorption is significantly enhanced when taken with dietary fat. Taking the tablets without fat-containing food may result in reduced drug absorption and lower blood levels, potentially compromising treatment effectiveness.
What Is the Correct Dosage of Lysodren?
The usual starting dose for adults is 2–3 g (4–6 tablets) per day. The dose is individually adjusted based on regular plasma mitotane level monitoring, aiming for a therapeutic concentration of 14–20 mg/L. The total daily dose is usually divided into two or three doses taken with fat-containing meals.
Always take Lysodren exactly as your doctor has prescribed. Your oncologist will determine the optimal dose for you based on regular blood tests measuring your plasma mitotane levels. The goal is to achieve and maintain a plasma concentration within the therapeutic window of 14–20 mg/L. Levels below 14 mg/L may be insufficient for tumour control, while levels above 20 mg/L are associated with increased toxicity, particularly neurological side effects.
Adults
Standard Starting Dose
Starting dose: 2–3 g per day (4–6 tablets of 500 mg)
Some protocols may start higher: 4–6 g per day (8–12 tablets) under close medical supervision
The total daily dose should be divided into two or three doses, taken with meals containing fatty food. Your doctor will increase or decrease the dose based on your blood mitotane levels and how well you tolerate the medication.
Dose Adjustment and Monitoring
Target plasma level: 14–20 mg/L
Monitoring frequency: Blood levels checked regularly (typically every 2–4 weeks initially, then less frequently once stable)
Due to mitotane’s extremely long half-life and accumulation in fat tissue, it may take several weeks to months to reach steady-state plasma levels. Your doctor may temporarily suspend treatment or reduce the dose if you experience significant side effects.
Children and Adolescents
Paediatric Dosing
Starting dose: 1.5–3.5 g/m2 body surface area per day
The body surface area is calculated by your doctor based on the child’s weight and height. Experience with Lysodren in the paediatric population is very limited, and treatment should only be undertaken by specialist centres with expertise in paediatric oncology and endocrinology.
In children and adolescents, additional monitoring for thyroid function, neuropsychological effects, and growth is particularly important, as these have been reported as specific concerns in the younger patient population.
How to Take the Tablets
Swallow the tablets whole with a glass of water during meals that contain fatty food. The total daily dose should be divided into two or three doses spread throughout the day. Do not crush or chew the tablets. Remember to wear disposable gloves if you are a caregiver handling the tablets for a patient.
Missed Dose
If you accidentally miss a dose, simply take your next dose at the scheduled time. Do not take a double dose to compensate for the missed one. Due to mitotane’s extremely long half-life, missing a single dose is unlikely to significantly affect your plasma levels. However, consistent daily dosing is important for maintaining therapeutic levels over time.
Overdose
If you accidentally take more Lysodren than prescribed, or if a child accidentally swallows any tablets, contact your doctor or go to your nearest emergency department immediately. Take the medication packaging with you so that medical staff can identify the drug. Symptoms of overdose may include severe nausea, vomiting, diarrhoea, confusion, dizziness, and neurological disturbances. There is no specific antidote for mitotane overdose; treatment is supportive.
What Are the Side Effects of Lysodren?
Lysodren causes side effects in the majority of patients. The most common include gastrointestinal symptoms (nausea, vomiting, diarrhoea), neurological disturbances (dizziness, confusion, coordination problems), fatigue, skin rash, elevated cholesterol and liver enzymes, and adrenal insufficiency. Serious side effects requiring immediate medical attention include signs of liver damage, severe neurological symptoms, and anaemia.
Like all medicines, Lysodren can cause side effects, although not everybody gets them. Many side effects are dose-related and may improve with dose reduction. Your oncologist will regularly monitor you for side effects and adjust your treatment accordingly. It is important to report any new or worsening symptoms to your medical team promptly.
Adrenal crisis: Severe fatigue, abdominal pain, nausea, vomiting, diarrhoea, confusion – may indicate acute adrenal insufficiency requiring emergency corticosteroid treatment.
Liver damage: Yellowing of skin or eyes, dark urine, severe itching, persistent nausea or fatigue.
Severe neurological symptoms: Loss of coordination, severe memory problems, difficulty speaking, persistent dizziness.
Anaemia: Unusual paleness, severe fatigue, shortness of breath, dizziness when standing.
Very Common
- Nausea, vomiting, diarrhoea, abdominal pain
- Loss of appetite (anorexia)
- Abnormal sensations such as numbness and tingling (paraesthesia)
- Movement and coordination disturbances (ataxia)
- Dizziness, confusion
- Drowsiness, fatigue, muscle weakness
- Mucous membrane inflammation, skin rash
- Prolonged bleeding time
- Elevated cholesterol, triglycerides, and liver enzymes (in blood tests)
- Decreased white blood cell count (leukopenia)
- Gynaecomastia (breast development in males)
- Adrenal insufficiency
Common
- Dizziness, headache
- Peripheral neuropathy (numbness, weakness, pain in extremities)
- Psychological disturbances (memory loss, concentration difficulties)
- Movement disorders
- Anaemia (low red blood cells), thrombocytopenia (low platelets)
- Autoimmune hepatitis (liver inflammation)
- Muscle coordination difficulties
Not Known Frequency
- Fever, generalised aches
- Flushing, high or low blood pressure, orthostatic hypotension
- Increased salivation
- Visual disturbances (blurred vision, double vision, image distortion)
- Opportunistic infections
- Liver damage (hepatotoxicity)
- Decreased uric acid levels
- Haemorrhagic cystitis (bladder inflammation with bleeding)
- Blood or protein in urine
- Balance disorders, altered taste
- Digestive problems
- Ovarian macrocysts (with or without pelvic pain, vaginal bleeding, menstrual changes)
- Hormonal changes: decreased androstenedione, decreased testosterone in women, increased sex hormone-binding globulin, hypogonadism in males
- Allergic reactions, itching
Additional Side Effects in Children and Adolescents
In children and adolescents, additional adverse effects have been observed that warrant particular attention. These include thyroid function abnormalities, neuropsychological problems (including cognitive difficulties and behavioural changes), and growth retardation. One case of encephalopathy (brain dysfunction) has been reported. Hormonal changes including gynaecomastia in males and vaginal bleeding or premature breast development in females have also been observed. These findings underscore the importance of comprehensive monitoring in paediatric patients receiving mitotane therapy.
It is important to report suspected side effects after the medicine has been authorised. This allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients are encouraged to report any suspected adverse reactions to their national pharmacovigilance authority or through the European Medicines Agency (EMA) reporting system.
How Should You Store Lysodren?
Store Lysodren in the original container, out of sight and reach of children. Once opened, the tablets should be used within 1 year. Do not use after the expiry date printed on the container. Dispose of unused tablets according to local guidelines for cytotoxic waste.
Lysodren tablets should be kept in their original plastic container to protect them from environmental factors. There are no special temperature storage requirements beyond normal room temperature. Once the container has been opened, the tablets remain usable for 1 year. After this period, any remaining tablets should be discarded appropriately.
Always check the expiry date (marked “EXP”) on the container and outer carton before taking a tablet. Do not use Lysodren after this date has passed.
Lysodren is a cytotoxic drug. Unused tablets and waste material must be disposed of in accordance with local regulations for cytotoxic medicines. Do not flush down the toilet or throw in household rubbish. Return unused tablets to your pharmacist for safe disposal. These measures protect both the environment and other people from accidental exposure to this potent medication.
What Does Lysodren Contain?
Each Lysodren tablet contains 500 mg of mitotane as the active ingredient, along with inactive excipients including maize starch, microcrystalline cellulose, macrogol 3350, and colloidal anhydrous silica.
Active Ingredient
The active substance is mitotane. Each tablet contains exactly 500 mg of mitotane. Mitotane (also known as o,p’-DDD) is a derivative of the insecticide DDT and has a unique adrenolytic mechanism of action. Its chemical name is 1,1-(dichlorodiphenyl)-2,2-dichloroethane, and it is a white crystalline powder with a molecular weight of 320.04 g/mol.
Other Ingredients (Excipients)
- Maize starch – acts as a binder and disintegrant to help the tablet hold together and break apart in the stomach
- Microcrystalline cellulose (E 460) – a filler and binder that gives the tablet its structure
- Macrogol 3350 – a lubricant that aids in tablet manufacture
- Colloidal anhydrous silica – a flow agent that ensures uniform drug distribution within the tablet
Appearance and Packaging
Lysodren tablets are white, biconvex (curved on both sides), round, and scored (with a line across one face for easier breaking if needed). They are supplied in plastic containers containing 100 tablets. The marketing authorisation holder is Esteve Pharmaceuticals S.A. (Barcelona, Spain).
Frequently Asked Questions About Lysodren
Lysodren (mitotane) is used to treat advanced adrenocortical carcinoma – a rare cancer of the adrenal gland cortex. It is indicated when the tumour cannot be completely removed by surgery, has spread to other parts of the body (metastatic disease), or has recurred after previous treatment. Lysodren is the only drug specifically approved for this condition and works by destroying adrenal cortex cells and reducing excessive hormone production.
The most common side effects (affecting more than 1 in 10 patients) include gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and loss of appetite; neurological effects including numbness, tingling, dizziness, confusion, drowsiness, and coordination problems; fatigue and muscle weakness; skin rash; prolonged bleeding time; elevated cholesterol, triglycerides, and liver enzymes; and adrenal insufficiency. Most side effects are dose-related and may improve with dose reduction.
Mitotane is a highly lipophilic (fat-loving) compound, meaning it dissolves much better in fat than in water. Taking Lysodren tablets with meals that contain fatty food (such as milk, chocolate, butter, or cooking oil) significantly improves the absorption of the drug from the gastrointestinal tract into the bloodstream. Without adequate dietary fat, a substantial proportion of the drug passes through the body unabsorbed, leading to lower blood levels and potentially reduced treatment effectiveness.
Mitotane has an extremely long elimination half-life, ranging from 18 to 159 days (approximately 3 weeks to over 5 months). This is because the drug is highly lipophilic and accumulates extensively in adipose (fat) tissue throughout the body. Even after stopping treatment, measurable blood levels of mitotane can persist for weeks to months. This prolonged presence is an important consideration for drug interactions, pregnancy planning, and breastfeeding decisions.
The Lysodren patient card is a vital safety measure. It informs any healthcare professional who treats you in an emergency that you are taking mitotane and may have impaired adrenal function. In stressful situations such as accidents, surgery, or severe illness, your body normally produces extra cortisol – but Lysodren prevents this. Without the card, emergency doctors might not know to give you life-saving corticosteroid treatment. The card also warns about your increased bleeding risk, which is important for any urgent surgical or dental procedures.
No. Lysodren may cause serious harm to a developing baby and is not safe during pregnancy. Women of childbearing age must use effective contraception during treatment and for a prolonged period after stopping, because the drug stays in the body for months due to its very long half-life. Breastfeeding is also strictly prohibited during and after treatment, as the drug can pass into breast milk and potentially harm the nursing infant. Always discuss family planning with your oncologist if you are receiving Lysodren treatment.
References and Sources
- European Medicines Agency (EMA). Lysodren (mitotane) – Summary of Product Characteristics. EMA/EPAR. Available at: ema.europa.eu. Last updated April 2025.
- Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1–G46. doi:10.1530/EJE-18-0608.
- Berruti A, Baudin E, Gelderblom H, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii131–vii138. doi:10.1093/annonc/mds231.
- Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356(23):2372–2380. doi:10.1056/NEJMoa063360.
- Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189–2197. doi:10.1056/NEJMoa1200966.
- World Health Organization (WHO). WHO Model List of Essential Medicines. 23rd edition. Geneva: WHO; 2023.
- Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282–326. doi:10.1210/er.2013-1029.
- Megerle F, Herrmann W, Gretschel W, et al. Mitotane monotherapy in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab. 2018;103(4):1686–1695. doi:10.1210/jc.2017-02591.
About the Medical Editorial Team
This article was written and reviewed by the iMedic Medical Editorial Team, comprising licensed physicians with specialisations in oncology, endocrinology, and clinical pharmacology. Our team follows the GRADE evidence framework and adheres to guidelines from the European Society for Medical Oncology (ESMO), the European Network for the Study of Adrenal Tumours (ENSAT), and the World Health Organization (WHO).
Written by specialists in oncology and clinical pharmacology with experience in rare endocrine tumour management.
Independently reviewed by the iMedic Medical Review Board to ensure accuracy, completeness, and adherence to current evidence-based guidelines.
Conflict of interest: The iMedic Medical Editorial Team has no financial relationships with pharmaceutical companies. All content is independently produced with no commercial funding or sponsorship.
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