Mitotane (Specialist drug)

SOURCE: UK SPC for Mitotane Esteve 500 mg Tablets (https://www.medicines.org.uk/emc/product/101074/smpc), §4.2. Treatment should be initiated and followed by a suitably experienced specialist. URGENT CUSHING'S CONTROL (§4.2): 'If it is urgent to control Cushing's symptoms in highly symptomatic patients, higher starting doses between 4 - 6 g per day could be necessary and daily dose increased more rapidly (e.g. every week).' MONITORING AND TITRATION (§4.2): dosing should be individually adjusted on mitotane plasma level monitoring and clinical tolerance until levels reach 14-20 mg/L; the target plasma concentration is usually reached within 3 to 5 months; assess plasma levels after each dose adjustment and at frequent intervals (e.g. every two weeks) until the optimal maintenance dose is reached, more frequently (e.g. every week) when a high starting dose has been used; because of tissue accumulation, monitor regularly (e.g. monthly) once the maintenance dose is reached, and every two months after interruption of treatment. Dose adjustments do not produce immediate changes in plasma levels. Treatment can be resumed when levels range between 14-20 mg/L. Because of the prolonged half-life, significant serum concentrations may persist for weeks after cessation. TOXICITY (§4.2): if serious adverse reactions occur, such as neurotoxicity, treatment may need to be temporarily interrupted; in mild toxicity the dose should be reduced until the maximum tolerated dose is attained. DURATION (§4.2): continue as long as clinical benefits are observed; if no clinical benefits are observed after 3 months at optimal dose, discontinue permanently. HANDLING (§4.2): patients should not use any tablets showing signs of deterioration, and caregivers should wear disposable gloves when handling the tablets. HEPATIC IMPAIRMENT (§4.2): no experience — data insufficient for a dose recommendation; use in severe hepatic impairment is not recommended; in mild to moderate impairment exercise caution, monitor liver function and monitor mitotane plasma levels. ELDERLY (§4.2, 65 years and over): no experience — data insufficient for a dose recommendation; exercise caution and monitor mitotane plasma levels frequently. PAEDIATRIC (§4.2, quoted): 'The experience in children is limited. The paediatric posology of mitotane has not been well characterised but appears equivalent to that of adults after correction for body surface area. Treatment should be initiated at 1.5 to 3.5 g/m2/day in children and adolescents with the objective of reaching 4 g/m2/day. Mitotane plasma levels should be monitored as for adults, with particular attention when plasma levels reach 10 mg/L as a quick increase in plasma levels may be observed. Dose may be reduced after 2 or 3 months according to the mitotane plasma levels or in case of serious toxicity.' This is a body-surface-area dose, NOT a per-kg dose, so paedDose is left null rather than forced into a per-kg field — verify any under-18 use against a children's formulary. US CROSS-CHECK (LYSODREN, ESTEVE Pharmaceuticals S.A., label date 2026-03-03, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=58257b74-15bb-d5d5-e063-6394a90accc7) §2.3: 'The recommended initial dose of LYSODREN is 2000 mg to 6000 mg orally, in three or four divided doses per day', titrated to a plasma level of 14 to 20 mg/L; in case of plasma levels above 20 mg/L without toxicities, consider reducing the dose by 50 to 75%; the recommended dosage reduction for adverse reactions is to decrease the usual daily dose by 500-1000 mg; swallow tablets whole, do not crush, chew or split, take with food and keep the timing of the dose relative to meals consistent. Note the US initial range (2000-6000 mg/day) is wider than the UK SPC starting dose (2-3 g/day, or 4-6 g/day only where urgent control of Cushing's symptoms is needed). BEFORE STARTING (§4.4): large metastatic masses should be surgically removed as far as possible before starting, to minimise the risk of infarction and haemorrhage in the tumour. ADRENAL INSUFFICIENCY (§4.4): all patients with non-functional tumour and 75% of patients with functional tumour show signs of adrenal insufficiency, so steroid replacement may be necessary; free cortisol and corticotropin (ACTH) determinations are needed for optimal steroid dosing because mitotane increases plasma levels of steroid binding proteins. Mitotane should be temporarily discontinued immediately following shock, severe trauma or infection, with exogenous steroids administered; instruct patients to contact their physician immediately if injury, infection or other concomitant illness occurs. HEPATOTOXICITY (§4.4): monitor ALT, AST, bilirubin and ALP periodically, especially in the first months and when increasing the dose — if AST and/or ALT are increased above 5x ULN, or ALP or bilirubin above 2x ULN, there is risk of liver injury/failure and treatment should be interrupted. The fetched §4.4 and §4.8 texts were truncated at the source-fetch limit.