4.1. Therapeutic indications

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenocortical carcinoma (ACC).

The effect of Mitotane Esteve on non functional adrenal cortical carcinoma is not established.

4.2. Posology and method of administration

Treatment should be initiated and followed by a suitably experienced specialist.

Posology

Treatment in adults should be started with 2 - 3 g mitotane per day and increased progressively (e.g. at two‑week intervals) until mitotane plasma levels reach the therapeutic window 14 – 20 mg/L.

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). A starting dose higher than 6 g/day is generally not recommended.

Dose adjustments, monitoring and discontinuation

Dose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14 - 20 mg/L) which ensures optimal use of Mitotane Esteve with acceptable safety. There are some data suggesting that a mitotane plasma level above 14 mg/L may result in enhanced efficacy (see section 5.1). Mitotane plasma levels higher than 20 mg/L may be associated with severe undesirable effects, including neurological toxicity, and offer no further benefit in terms of efficacy, therefore this threshold should not be exceeded. Mitotane plasma levels should therefore be monitored in order to adjust the Mitotane Esteve dose and to avoid reaching toxic levels. For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).

Dosing should be individually adjusted based on mitotane plasma levels monitoring and clinical tolerance until mitotane plasma levels reach the therapeutic window 14 - 20 mg/L. The target plasma concentration is usually reached within a period of 3 to 5 months.

Mitotane plasma levels should be assessed after each dose adjustment and at frequent intervals (e.g. every two weeks), until the optimal maintenance dose is reached. Monitoring should be more frequent (e.g. every week) when a high starting dose has been used. It should be taken into account that dose adjustments do not produce immediate changes in plasma levels of mitotane (see section 4.4). In addition, because of tissue accumulation, mitotane plasma levels should be monitored regularly (e.g. monthly) once the maintenance dose has been reached.

Regular monitoring (e.g. every two months) of mitotane plasma levels is also necessary after interruption of treatment. Treatment can be resumed when mitotane plasma levels range between 14 - 20 mg/L. Due to the prolonged half-life, significant serum concentrations may persist for weeks after cessation of therapy.

If serious adverse reactions occur, such as neurotoxicity, treatment with mitotane may need to be temporarily interrupted. In case of mild toxicity, the dose should be reduced until the maximum tolerated dose is attained.

Treatment with Mitotane Esteve should be continued as long as clinical benefits are observed. If no clinical benefits are observed after 3 months at optimal dose, treatment should be permanently discontinued.

Special populations

Paediatric population

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.

Hepatic impairment

There is no experience in the use of mitotane in patients with hepatic impairment, so data are insufficient to give a dose recommendation in this group. Since mitotane is mainly metabolised through the liver, mitotane plasma levels are expected to increase if liver function is impaired. The use of mitotane in patients with severe hepatic impairment is not recommended. In patients with mild to moderate hepatic impairment, caution should be exercised and monitoring of liver function should be performed. Monitoring of mitotane plasma levels is specially recommended in these patients (see section 4.4).

Renal impairment

There is no experience in the use of mitotane in patients with renal impairment, so data are insufficient to give a dose recommendation in this group. The use of mitotane in patients with severe renal impairment is not recommended and, in cases of mild to moderate renal impairment, caution should be exercised. Monitoring of mitotane plasma levels is specially recommended in these patients (see section 4.4).

Elderly patients (≥ 65 years old)

There is no experience on the use of mitotane in elderly patients, so data are insufficient to give a dose recommendation in this group. Caution should be exercised and frequent monitoring of mitotane plasma levels is especially recommended in these patients.

Method of administration

The total daily dose may be divided in two or three doses according to patient's convenience. Tablets should be taken with a glass of water during meals containing fat-rich food (see section 4.5). Patients should be advised not to use any tablets showing signs of deterioration, and caregivers to wear disposable gloves when handling the tablets.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Lactation (see section 4.6)

Concomitant use with spironolactone (see section 4.5)

4.4. Special warnings and precautions for use

Before the initiation of the treatment: Large metastatic masses should be surgically removed as far as possible before starting mitotane treatment, in order to minimise the risk of infarction and haemorrhage in the tumour due to a rapid cytotoxic effect of mitotane.

Risk of adrenal insufficiency: All patients with non functional tumour and 75% of patients with functional tumour show signs of adrenal insufficiency. Therefore, steroid replacement may be necessary in these patients. Since mitotane increases plasma levels of steroid binding proteins, free cortisol and corticotropin (ACTH) determinations are necessary for optimal dosing of steroid substitution (see section 4.8). Glucocorticoid insufficiency is more frequent, but mineralocorticoid insufficiency may also be associated and the steroid substitution may need to be adapted accordingly.

Shock, severe trauma or infection: Mitotane should be temporarily discontinued immediately following shock, severe trauma or infection, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal gland may not immediately start to secrete steroids. Because of an increased risk of acute adrenocortical insufficiency, patients should be instructed to contact their physician immediately if injury, infection, or any other concomitant illness occurs.

Monitoring of plasma levels: Mitotane plasma levels should be monitored in order to adjust the mitotane dose, particularly if high starting doses are considered necessary. Dose adjustments may be necessary to achieve the desired therapeutic levels in the window between 14 - 20 mg/L and avoid specific adverse reactions (see section 4.2). For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).

Hepatic or renal impairment: There are insufficient data to support the use of mitotane in patients with severe hepatic or renal impairment. In patients with mild or moderate hepatic or renal impairment, caution should be exercised and monitoring of mitotane plasma levels is particularly recommended (see section 4.2).

Hepatotoxicity has been observed in patients treated with mitotane. Cases of liver damage (hepatocellular, cholestatic and mixed) and autoimmune hepatitis were observed. Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin, and alkaline phosphatase [ALP] levels) should be periodically monitored, especially during the first months of treatment or when it is necessary to increase the dose. If AST and/or ALT are increased > 5 ULN, or ALP or bilirubin > 2 ULN, there is risk of liver injury/failure. In this case, Mitotane Esteve treatment should be interrupted. Treatment can be resumed at physician's discretion depending on the severity of the event as well as the patient's clinical condition.

Metabolism and nutrition disorders: Regardless of Mitotane Esteve dosage, triglycerides should be monitored regularly especially in patients with or at risk of dyslipidemia (such as metabolic syndrome, alcohol abuse, high fat diet…). Triglyceride-lowering therapy and discontinuation of Mitotane Esteve may be considered in case of severe hypertriglyceridemia as it is a potential cause of acute pancreatitis.

Mitotane tissue accumulation: Fat tissue can act as a reservoir for mitotane, resulting in a prolonged half-life and potential accumulation of mitotane. Consequently, despite a constant dose, mitotane levels may increase. Therefore, monitoring of mitotane plasma levels (e.g. every two months) is also necessary after interruption of treatment, as prolonged release of mitotane can occur. Caution and close monitoring of mitotane plasma levels are highly recommended when treating overweight patients and patients with recent weight loss.

Central nervous system disorders: Long-term continuous administration of high doses of mitotane may lead to reversible brain damage and impairment of function. Behavioural and neurological assessments should be made at regular intervals, especially when mitotane plasma levels exceed 20 mg/L (see section 4.8).

Blood and lymphatic system disorders: All blood cells can be affected with mitotane treatment. Leucopenia (including neutropenia), anemia and thrombocytopenia have been reported frequently during mitotane treatment (see section 4.8). Red blood cell, white blood cell and platelet counts should be monitored during mitotane treatment.

Bleeding time: Prolonged bleeding time has been reported in patients treated with mitotane. In some patients, in vitro bleeding time may be normal but with pathologic adenosine diphosphate (ADP)-induced platelet aggregation. This should be taken into account when surgery is considered (see section 4.8).

Warfarin and coumarin-like anticoagulants: When administering mitotane to patients on coumarin-like anticoagulants, patients should be closely monitored for a change in anticoagulant dose requirements (see section 4.5).

Substances metabolised through cytochrome P450 and particularly cytochrome 3A4: Mitotane is a hepatic enzyme inducer and it should be used with caution in case of concomitant use of medicinal products influenced by hepatic metabolism (see section 4.5).

Premenopausal women: Non-malignant ovarian macrocysts, often bilateral and multiple, have been observed with higher incidence in this population. The ovarian macrocysts may be symptomatic (e.g., pelvic pain or discomfort, vaginal bleeding or menstrual disorders) or asymptomatic. Isolated cases of complicated cysts have been reported (adnexal torsion and haemorrhagic cyst rupture). Improvement after mitotane discontinuation has been observed. Women should be urged to seek medical advice if they experience gynaecological symptoms such as bleeding and/or pelvic pain. Periodic ovarian ultrasound monitoring is recommended in premenopausal women treated with mitotane.

Paediatric population: In children and adolescents, neuro-psychological retardation can be observed during mitotane treatment. In such cases, thyroid function should be investigated in order to identify a possible thyroid impairment linked to mitotane treatment.

4.5. Interaction with other medicinal products and other forms of interaction

Spironolactone: Mitotane must not be given in combination with spironolactone, since this active substance may block the action of mitotane (see section 4.3).

Warfarin and coumarin-like anticoagulants: Mitotane has been reported to accelerate the metabolism of warfarin through hepatic microsomal enzyme induction, leading to an increase in dose requirements for warfarin. Therefore, patients should be closely monitored for a change in anticoagulant dose requirements when mitotane is administered to patients on coumarin‑like anticoagulants.

Substances metabolised through cytochrome P450: Mitotane has been shown to have an inductive effect on cytochrome P450 enzymes. Therefore, the plasma concentrations of the substances metabolised via cytochrome P450 may be modified. In the absence of information on the specific P450 isoenzymes involved, caution should be taken when co-prescribing active substances metabolised by this route such as, among others, anticonvulsants, rifabutin, rifampicin, griseofulvin and St. John's wort (Hypericum perforatum). Particularly, mitotane has been shown to have an inductive effect on cytochrome 3A4. Therefore, the plasma concentrations of the substances metabolised via cytochrome 3A4 may be modified. Caution should be taken when co-prescribing active substances metabolised by this pathway such as, among others, sunitinib, etoposide and midazolam and dose should be adjusted as appropriate when coadministered with mitotane.

Enzyme induction is likely to persist after discontinuation of mitotane treatment.

Medicinal products active on central nervous system: Mitotane can cause central nervous system undesirable effects at high concentrations (see section 4.8). Although no specific information on pharmacodynamic interactions in the central nervous system is available, this should be borne in mind when co-prescribing medicinal products with central nervous system depressant action.

Fat-rich food: Data with various mitotane formulations suggest that administration with fat-rich food enhances absorption of mitotane.

Hormone binding protein: Mitotane has been shown to increase plasma levels of hormone binding proteins (e.g. sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)). This should be taken into account when interpreting the results of hormonal assays and may result in gynaecomastia.

4.6. Fertility, pregnancy and lactation

Pregnancy

Data, based on a limited number of exposed pregnancies indicate abnormalities on the adrenals of the foetus after exposure to mitotane. Mitotane has been detected in foetal cord blood. Pregnant women should be advised of a potential risk to the foetus. Animal reproduction studies have not been conducted with mitotane. Animal studies with similar substances have shown reproductive toxicity (see section 5.3). Mitotane Esteve is not recommended during pregnancy and in women of childbearing potential not using contraception.

Women of childbearing potential

Women of childbearing potential must use an effective contraception during treatment and after discontinuation of treatment as long as mitotane plasma levels are detectable, which may require several months. The prolonged elimination of mitotane from the body after discontinuation of Mitotane Esteve should be considered (see section 5.2).

Breast-feeding

Due to the lipophilic nature of mitotane, it is likely to be excreted in breast milk. Because of the potential for serious adverse reactions in the breastfed infant, breast‑feeding is contraindicated while taking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levels are detectable.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Safety data are based on literature (mainly retrospective studies). More than 80 % of patients treated with mitotane have shown at least one type of undesirable effect. Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Frequency of adverse reactions

System Organ Class

Adverse reaction

Very common

Common

Not Known

Infections and infestations

Opportunistic infection

Blood and lymphatic system disorders

Leukopenia

Bleeding time prolonged

Anaemia

Thrombocytopenia

Immune system disorders

Hypersensitivity reactions

Endocrine disorders

Adrenal insufficiency

Thyroid disorder

Hypogonadism (in males)

Metabolism and nutrition disorders

Decreased appetite

Hypercholesterolemia

Hypertriglyceridaemia

Hypouricaemia

Psychiatric disorders

Confusional state

Nervous system disorders

Ataxia

Paraesthesia

Vertigo

Somnolence

Mental impairment

Polyneuropathy

Movement disorder

Dizziness

Headache

Balance disorder

Eye disorders

Maculopathy

Retinal toxicity

Diplopia

Lenticular opacitiesVisual impairment

Vision blurred

Vascular disorders

Hypertension

Orthostatic hypotension

Flushing

Gastrointestinal disorders

Mucosal inflammation

Vomiting

Diarrhoea

Nausea

Epigastric discomfort

Salivary hypersecretion

Dysgeusia

Dyspepsia

Hepatobiliary disorders

Elevated liver enzymes

Autoimmune hepatitis

Liver injury (hepatocellular/cholestatic/mixed)

Skin and subcutaneous tissue disorders

Skin rash

Pruritus

Muscoloskeletal and connective tissue disorders

Muscular weakness

Renal and urinary disorders

Cystitis haemorrhagic

Haematuria

Proteinuria

Reproductive system and breast disorders

Gynaecomastia

Ovarian macrocysts

General disorders and administration site conditions

Asthenia

Hyperpyrexia

Generalised aching

Investigations

Blood cholesterol increased

Blood triglycerides increased

Blood uric acid decreased

Blood androstenedione decreased (in females)

Blood testosterone decreased (in females)

Sex hormone binding globulin increased

Blood testosterone free decreased (in males)

Corticosteroid binding globulin increased

Thyroxin binding globulin increased

Description of selected adverse reactions

Gastrointestinal disorders are the most frequently reported (10 to 100 % of patients) and are reversible when the dose is reduced. Some of these effects (anorexia) may constitute the hallmark of initial central nervous system impairment.

Nervous system undesirable effects occur in approximately 40 % of patients. Other undesirable central nervous effects have been reported in literature such as memory defects, aggressiveness, central vestibular syndrome, dysarthria, or Parkinson syndrome. Serious undesirable effects appear linked to the cumulative exposure to mitotane and are most likely to occur when mitotane plasma levels are at 20 mg/L or above. At high doses and after prolonged utilization, brain function impairment can occur. Nervous system undesirable effects appear reversible after cessation of mitotane treatment and decrease in plasma levels (see section 4.4).

Skin rashes which have been reported in 5 to 25 % of patients do not seem to be dose related.

Leucopoenia has been reported in 8 to 12 % of patients. Prolonged bleeding time appears a frequent finding (90 %): although the exact mechanism of such an effect is unknown and its relation with mitotane or with the underlying disease is uncertain, it should be taken into account when surgery is considered.

The activity of liver enzymes (gamma-GT, aminotransferase, alkaline phosphatase) is commonly increased. Liver enzymes levels usually normalize when the mitotane dose is decreased or temporarily interrupted or discontinued. However, autoimmune hepatitis has been reported in 7 % of patients with no other information on mechanism. Very rare serious cases of liver injury (acute hepatic failure and hepatic encephalopathy) have been observed.

Hypogonadism: Hypogonadism in males (with symptoms such as gynaecomastia, libido decreased, erectile dysfunction, fertility disorders) has been described.

Premenopausal women

Non-malignant ovarian macrocysts (with symptoms such as pelvic pain, vaginal bleeding, menstrual disorders or asymptomatic) have been described.

Paediatric population

Neuro-psychological retardation may be observed during mitotane treatment. In such cases, thyroid function should be investigated in order to identify a possible thyroid impairment linked to mitotane treatment. Hypothyroidism and growth retardation may be also observed. One case of encephalopathy has been observed in a paediatric patient five months after initiation of the treatment; this case was considered to be related to an increased mitotane plasma level of 34.5 mg/L. After six months mitotane plasma levels were undetectable and the patient recovered clinically.

Oestrogenic-like effects (such as gynaecomastia in male patients and breast development and/or vaginal bleeding in female patients) have been observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Mitotane overdose may lead to central nervous system impairment especially if mitotane plasma levels are above 20 mg/L. No proven antidotes have been established for mitotane overdose. Temporary interruption of Mitotane Esteve should be considered. The patient should be followed closely, taking into account that impairment is reversible, but given the long half‑life and the lipophilic nature of mitotane, it may take weeks to return to normal. Other effects should be treated symptomatically. Because of its lipophilic nature, mitotane is not likely to be dialysable.

It is recommended to increase frequency of mitotane plasma level monitoring (e.g. every two weeks) in patients at risk of overdose (e.g. in case of renal or hepatic impairment, obese patients or patients with a recent weight loss).