Mitotane

Mitotane is an adrenal cytotoxic active substance that can apparently also inhibit the adrenal gland without destroying cells. The EU SmPC notes that mitotane has not been studied in a comprehensive clinical development programme; the clinical information comes mainly from published data in patients with inoperable or metastatic adrenal carcinoma.

Mechanism of Action

• Adrenal cytotoxicity: the biochemical mechanism of action is unknown. Available data suggest that mitotane changes the peripheral metabolism of steroids and also suppresses the adrenal cortex directly.
• Selectivity: its specificity for the adrenal cortex may arise from conversion to an active form by an enzyme system found only in adrenocortical tissue.
• Cortisol metabolism: mitotane alters the extra-adrenal metabolism of cortisol, lowering measurable 17-hydroxycorticosteroids even though plasma corticosteroid levels do not fall.
• Clinical evidence: four studies concluded that mitotane does not improve overall survival and five found an improvement; in three of those five the improvement was seen only in patients with plasma mitotane above 14 mg/L. In the FIRM-ACT trial (304 patients on first-line mitotane combined with either etoposide, doxorubicin and cisplatin or streptozotocin), reaching a level of 14 mg/L or more at least once within 6 months could suggest a better disease control rate (62.9% versus 33.5%).

Pharmacokinetics

• Absorption: oral bioavailability is about 40%, and fat-rich food enhances absorption. In 8 patients with adrenal carcinoma given 2 to 3 g daily, the plasma level correlated closely with the total dose; the 14 mg/L target was reached in every patient within 3 to 5 months, after a total of 283 to 387 g (median 363 g), and 20 mg/L was reached at a cumulative dose of about 500 g. With a rapid escalation protocol (3 g on day 1 rising to 9 g on day 5) in 3 patients, two exceeded 14 mg/L within 15 days and one exceeded 20 mg/L within about 30 days. In some patients the level kept rising despite a constant or reduced dose.
• Distribution: mitotane is found in most tissues, and fat is the main storage site. Binding to plasma proteins is low (about 6%).
• Metabolism: extensive, in the liver and elsewhere. The main circulating metabolite is the acid o,p’-DDA, with smaller amounts of the o,p’-DDE analogue. No unchanged mitotane is found in bile or urine, where o,p’-DDA predominates together with hydroxylated metabolites. Mitotane also induces cytochrome P450 enzymes (see Drug Interactions).
• Elimination: after intravenous administration, 25% of the dose was excreted as metabolites within 24 hours, and about 10% of a dose appears in urine as water-soluble metabolites. After treatment stops, mitotane is released slowly from fat; reported terminal plasma half-lives range from 18 to 159 days (median 53 days).
• Special populations: because mitotane is mainly metabolised in the liver, plasma levels are expected to rise in hepatic impairment. There is no experience in renal impairment or in elderly patients.

• Advanced adrenocortical carcinoma (ACC): symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenocortical carcinoma.
• Non-functional tumours: the effect of Lysodren on non-functional adrenocortical carcinoma has not been established.

• Hypersensitivity to mitotane or to any of the excipients.
• Lactation (breastfeeding is also contraindicated after treatment stops, for as long as mitotane plasma levels are detectable).
• Concomitant use with spironolactone.

Safety data come from the literature, mainly retrospective studies. More than 80% of patients treated with mitotane had at least one type of undesirable effect. Very common reactions include adrenal insufficiency, gastrointestinal and nervous system effects, raised liver enzymes and raised cholesterol and triglycerides.

Very common (≥1/10): leukopenia, prolonged bleeding time, adrenal insufficiency, decreased appetite, hypercholesterolaemia, hypertriglyceridaemia, confusional state, ataxia, paraesthesia, vertigo, somnolence, mucosal inflammation, vomiting, diarrhoea, nausea, epigastric discomfort, elevated liver enzymes, skin rash, muscular weakness, gynaecomastia, asthenia, increased blood cholesterol, increased serum triglycerides.

Common (≥1/100 to <1/10): anaemia, thrombocytopenia, mental impairment, polyneuropathy, movement disorder, dizziness, headache, autoimmune hepatitis.

Not known: opportunistic infection, hypersensitivity reactions, thyroid disorder, hypogonadism (in males), hypouricaemia, balance disorder, maculopathy, retinal toxicity, diplopia, lenticular opacities, visual impairment, blurred vision, hypertension, orthostatic hypotension, flushing, salivary hypersecretion, dysgeusia, dyspepsia, liver injury (hepatocellular, cholestatic or mixed), pruritus, haemorrhagic cystitis, haematuria, proteinuria, ovarian macrocysts, hyperpyrexia, generalised pain, decreased blood uric acid, decreased androstenedione and testosterone in women, decreased free testosterone in men, and increased sex hormone-binding, corticosteroid-binding and thyroxine-binding globulins.

Important serious reactions are adrenal insufficiency (including acute adrenocortical insufficiency after shock, severe trauma or infection), neurotoxicity at high plasma levels, liver injury and autoimmune hepatitis, severe hypertriglyceridaemia (a potential cause of acute pancreatitis), and complicated ovarian cysts in premenopausal women.

• Spironolactone: must not be combined with mitotane, because it may block the action of mitotane.
• Warfarin and coumarin-like anticoagulants: mitotane speeds up warfarin metabolism by hepatic microsomal enzyme induction and raises the dose requirement. Patients need close monitoring for changes in anticoagulant dose.
• Cytochrome P450 substrates: mitotane induces cytochrome P450 enzymes, including CYP3A4, so plasma concentrations of other medicines may change. Caution is advised with anticonvulsants, rifabutin, rifampicin, griseofulvin and St John’s wort, and with CYP3A4 substrates such as sunitinib, etoposide and midazolam, whose dose should be adjusted as appropriate. Enzyme induction is likely to persist after mitotane is stopped.
• Medicines acting on the central nervous system: mitotane can cause central nervous system effects at high concentrations. No specific interaction data exist, but this should be borne in mind when it is combined with CNS depressant medicines.
• Fat-rich food: enhances absorption, so tablets are taken with fat-rich meals, consistently in relation to food.
• Hormone-binding proteins: mitotane raises plasma levels of sex hormone-binding globulin and corticosteroid-binding globulin. This should be taken into account when interpreting hormonal assays and may result in gynaecomastia.

Treatment must be started and followed by a suitably experienced specialist. The total daily dose can be divided into two or three doses, and the tablets are taken with a glass of water during meals that contain fat-rich food.

Starting Dose and Titration

• Adults: start with 2 to 3 g of mitotane a day and increase progressively (for example at two-week intervals) until the plasma level reaches the therapeutic window of 14 to 20 mg/L.
• Urgent control of Cushing’s symptoms: in highly symptomatic patients, higher starting doses of 4 to 6 g a day may be necessary, with faster increases (for example every week). A starting dose above 6 g a day is generally not recommended.
• Target level: some data suggest that a plasma level above 14 mg/L may give enhanced efficacy. Levels above 20 mg/L may be associated with severe undesirable effects, including neurological toxicity, and offer no further benefit, so this threshold should not be exceeded. The target level is usually reached within 3 to 5 months.

Plasma-Level Monitoring

• Plasma levels are assessed after each dose adjustment and at frequent intervals (for example every two weeks) until the optimal maintenance dose is reached, and more often (for example every week) after a high starting dose. Dose changes do not alter plasma levels at once.
• Once the maintenance dose is reached, levels are monitored regularly (for example monthly) because of tissue accumulation.
• Levels are also monitored regularly (for example every two months) after treatment is interrupted. Treatment can be resumed when levels are back within 14 to 20 mg/L. Significant serum concentrations may persist for weeks after treatment stops.
• For information on sample testing, contact the Marketing Authorisation Holder or its local representative.

Adverse Reactions and Duration

• If serious reactions such as neurotoxicity occur, treatment may need to be interrupted temporarily. For mild toxicity the dose is reduced until the maximum tolerated dose is reached.
• Treatment continues for as long as clinical benefit is seen. If there is no clinical benefit after 3 months at the optimal dose, treatment should be stopped permanently.

Special Populations

• Children and adolescents: experience is limited and the posology is not well characterised, but it appears equivalent to that of adults after correction for body surface area. Start at 1.5 to 3.5 g/m² a day with the aim of reaching 4 g/m² a day. Plasma levels are monitored as in adults, with particular attention once levels reach 10 mg/L, because a quick rise may occur. The dose may be reduced after 2 or 3 months according to plasma levels or in case of serious toxicity.
• Hepatic impairment: no experience, so no dose recommendation. Plasma levels are expected to rise. Use is not recommended in severe impairment; in mild to moderate impairment use caution, monitor liver function and monitor plasma levels especially closely.
• Renal impairment: no experience, so no dose recommendation. Use is not recommended in severe impairment; in mild to moderate impairment use caution and monitor plasma levels especially closely.
• Elderly (65 years and over): no experience, so no dose recommendation. Use caution and monitor plasma levels frequently.

Plasma-Level Monitoring

Treatment with mitotane requires monitoring of plasma levels. The SmPC states that levels must be monitored to adjust the dose and avoid toxic levels, within the window of 14 to 20 mg/L. Monitoring is especially recommended in patients with hepatic or renal impairment, in elderly patients, and in overweight patients or those with recent weight loss. It continues after treatment is interrupted, because mitotane is released slowly from fat tissue and levels may rise despite a constant dose.

Adrenal Insufficiency

• Steroid replacement: all patients with a non-functional tumour and 75% of patients with a functional tumour show signs of adrenal insufficiency, so steroid replacement may be necessary. Because mitotane raises the plasma levels of steroid-binding proteins, free cortisol and corticotropin (ACTH) measurements are needed to dose the steroid substitution optimally. Glucocorticoid insufficiency is more frequent, but mineralocorticoid insufficiency may also be present, and the substitution may need to be adapted accordingly.
• Shock, severe trauma or infection: mitotane should be stopped temporarily and immediately after shock, severe trauma or infection, because adrenal suppression is its main action. Exogenous steroids should be given in these situations, since the suppressed adrenal gland may not start producing steroids at once. Because of the increased risk of acute adrenocortical insufficiency, patients must contact their physician immediately if injury, infection or any other illness occurs.

Before Starting Treatment

Large metastatic masses should be removed surgically as far as possible before treatment, to minimise the risk of infarction and haemorrhage in the tumour from the rapid cytotoxic effect of mitotane.

Liver

Liver damage (hepatocellular, cholestatic and mixed) and autoimmune hepatitis have been observed. Liver function tests (ALT, AST, bilirubin and ALP) should be checked periodically, especially during the first months or when the dose is raised. If AST or ALT rise above 5 times the upper limit of normal, or ALP or bilirubin above 2 times that limit, there is a risk of liver injury or failure and treatment should be interrupted. It can be resumed at the physician’s discretion according to the severity of the event and the patient’s condition.

Lipids

Triglycerides should be monitored regularly whatever the dose, especially in patients with or at risk of dyslipidaemia. In severe hypertriglyceridaemia, which can cause acute pancreatitis, triglyceride-lowering treatment and discontinuation of mitotane may be considered.

Central Nervous System

Long-term continuous high doses may lead to reversible brain damage and impairment of function. Behavioural and neurological assessments should be made at regular intervals, especially when plasma levels exceed 20 mg/L.

Blood Counts and Bleeding

All blood cells can be affected. Leukopenia (including neutropenia), anaemia and thrombocytopenia are reported frequently, so red cell, white cell and platelet counts should be monitored. Prolonged bleeding time has been reported; in some patients the in vitro bleeding time is normal but platelet aggregation induced by ADP is abnormal. This should be considered when surgery is planned.

Premenopausal Women

Non-malignant ovarian macrocysts, often bilateral and multiple, are seen more often in this group. They may cause pelvic pain or discomfort, vaginal bleeding or menstrual disorders, or no symptoms. Isolated cases of complicated cysts (adnexal torsion, haemorrhagic cyst rupture) have been reported, and improvement followed discontinuation. Women should seek medical advice for gynaecological symptoms such as bleeding or pelvic pain, and periodic ovarian ultrasound is recommended.

Children and Adolescents

Neuro-psychological retardation can be observed during treatment. In that case thyroid function should be investigated for a possible thyroid impairment linked to mitotane.

Handling

Patients should not use tablets that show signs of deterioration, and caregivers should wear disposable gloves when handling the tablets.

Pregnancy and Breastfeeding

• Contraception: women of childbearing potential must use effective contraception during treatment and after it stops for as long as mitotane plasma levels are detectable, which may take several months.
• Pregnancy: limited data indicate abnormalities of the foetal adrenals after exposure, and mitotane has been detected in foetal cord blood. Pregnant women should be told of the potential risk to the foetus. Animal reproduction studies have not been conducted, but similar substances have shown reproductive toxicity. Lysodren is not recommended during pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: because of its lipophilic nature mitotane is likely to be excreted in breast milk. Breastfeeding is contraindicated during treatment and after it stops for as long as plasma levels are detectable.

Effect on Driving

Lysodren has a major influence on the ability to drive and use machines. Ambulatory patients should be warned not to drive or use machines.

Store the tablets in the original package; the SmPC sets no temperature limit, and no cold chain is needed. They are supplied in a square, opaque white HDPE bottle with a threaded mouth, containing 100 tablets (one bottle per pack).

3 years in the unopened pack. After opening: 1 year.

Prescription only (Rx). Lysodren is a medicinal product subject to restricted medical prescription (Annex II B), and treatment is started and followed by a suitably experienced specialist. Dosing depends on plasma-level monitoring, which the treating specialist arranges throughout treatment. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.