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Mitotane

Also known as Lysodren, o,p'-DDD

An oral drug related to the insecticide DDT that damages the adrenal cortex. The label lists inoperable adrenocortical carcinoma, functional or nonfunctional.

From discovery to approval

  1. 1959 · Earliest report found

    The EMA says mitotane has been used in Europe for adrenal cortical carcinoma since 1959, and a 2018 review gives the same year for inoperable disease. The review adds that it derives from the insecticide DDT and was recognised about 70 years before the review as selectively damaging adrenocortical tissue. A 1960 paper reported chemotherapy of adrenocortical cancer with o,p'-DDD.[2][3][1][4]

  2. 1959 · First use in people

    The EMA's EPAR summary says mitotane has been used in the treatment of adrenal cortical carcinoma in Europe since 1959, and a 2018 review says it has been used for inoperable adrenocortical carcinoma since 1959. The earliest report found is a 1960 Annals of Internal Medicine paper titled as chemotherapy of adrenocortical cancer with o,p'-DDD (no abstract available).[4]

  3. 1970-07-08 · FDA regular

    Original approval, classed as a Type 1 new molecular entity with priority review in the Drugs@FDA history; the EMA procedural document independently lists the USA marketing authorisation as 8 July 1970. The 1970 label and letter are not available, so the original indication is not stated here (the 2025 label lists inoperable, functional or nonfunctional adrenocortical carcinoma). The type regular is an inference: no accelerated-approval wording was found.[5]

  4. 2004-04-28 · EMA regular

    European Commission decision of 28 April 2004 (EMA procedural-steps document; CPMP positive opinion 21 January 2004): symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma; the effect on non-functional carcinoma is not established (EPAR page). The document mentions a letter of undertaking on follow-up measures but no conditional or exceptional wording, so 'regular' is an inference.[6]

How it works

The label calls it an adrenal cytotoxic agent with an unknown mechanism of action. It modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex.[1]

Where it came from and why

The review says mitotane's toxic effects were widely studied in dogs, a particularly sensitive species; in humans high doses cause adrenal atrophy, while rats, mice, rabbits and monkeys are relatively unresponsive. No source read says why it was first tried in adrenal cancer.

Cancers

  • Adrenocortical carcinoma

    The 2025 US label lists inoperable, functional or nonfunctional adrenocortical carcinoma.[1]

  • Adrenocortical carcinoma (EU authorisation)

    The EU authorisation covers symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma and says the effect on non-functional carcinoma is not established.[4]

Worth knowing

  • Before its EU authorisation, the EMA procedural document lists marketing authorisations for Lysodren in Canada (14 December 1978), Malaysia (15 December 1986), Brazil (25 July 1988), Hong Kong (20 June 1989), South Korea (9 October 2001), the USA (8 July 1970) and Singapore (no date given).[6]
  • In the FIRM-ACT trial of 304 patients with advanced adrenocortical carcinoma, mitotane was given in both arms; etoposide, doxorubicin and cisplatin plus mitotane had a higher response rate than streptozocin plus mitotane (23.2% versus 9.2%), with no significant difference in overall survival.[7]
  • In ADIUVO, which randomised 91 patients and was stopped early, 5-year recurrence-free survival was 79% with adjuvant mitotane and 75% with surveillance (hazard ratio 0.74, 95% CI 0.30 to 1.85).[8]
  • The label advises titrating the dose to a plasma level of 14 to 20 mg/L and notes that mitotane is lipophilic and accumulates in adipose tissue.[1]

References

  1. HRA Pharma Rare Diseases. Lysodren (mitotane tablets): prescribing information. DailyMed, set ID f0cd76e9-460c-450e-b094-172e636f340a, published 17 November 2025. Source
  2. Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A, Corsello SM. Role of Mitotane in Adrenocortical Carcinoma - Review and State of the art. Eur Endocrinol. 2018;14(2):62-66. PubMedDOI
  3. Bergenstal DM, Hertz R, Lipsett MB, Moy RH. Chemotherapy of adrenocortical cancer with o,p'-DDD. Ann Intern Med. 1960;53(4):672-82. DOI
  4. European Medicines Agency. Lysodren (mitotane): European public assessment report (EPAR) page; marketing authorisation issued 28/04/2004. Page read 2026-10-29. Source
  5. U.S. Food and Drug Administration. Drugs@FDA: approval date(s) and history, letters, labels for NDA 016885 (Lysodren, mitotane). Page read 2026-10-29. Source
  6. European Medicines Agency. Lysodren (mitotane): EPAR procedural steps taken before authorisation, CPMP/712/04 (CPMP positive opinion of 21 January 2004; European Commission decision of 28 April 2004). Source
  7. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189-97. PubMedDOI
  8. Terzolo M, Fassnacht M, Perotti P, Libé R, Kastelan D, Lacroix A, et al. Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol. 2023;11(10):720-730. PubMedDOI