Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: HRA Pharma Rare Diseases, 200 avenue de Paris, 92320, CHATILLON, France
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).
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.
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).
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. Patients should carry with them the Lysodren Patient Card provided with the package leaflet indicating that they are prone to adrenal insufficiency and that, in case of emergency care, adequate precautionary measures should be taken.
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).
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 levels) should be periodically monitored, especially during the first months of treatment or when it is necessary to increase the dose.
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.
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).
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.
Prolonged bleeding time has been reported in patients treated with mitotane and this should be taken into account when surgery is considered (see section 4.8).
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).
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).
Women of childbearing potential must use effective contraception during treatment with mitotane (see section 4.6).
Ovarian macrocysts have been observed with higher incidence in this population. 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.
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.
Mitotane must not be given in combination with spironolactone, since this active substance may block the action of mitotane (see section 4.3).
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.
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 and midazolam.
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.
Data with various mitotane formulations suggest that administration with fat-rich food enhances absorption of mitotane.
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.
Data on a limited number of exposed pregnancies indicate abnormalities on the adrenals of the foetus after exposure to mitotane. Animal reproduction studies have not been conducted with mitotane. Animal studies with similar substances have shown reproductive toxicity (see section 5.3). Lysodren should be given to pregnant women only if clearly needed and if the clinical benefit clearly outweighs any potential risk to the foetus.
Women of childbearing potential must use an effective contraception during treatment and after discontinuation of treatment as long as mitotane plasma levels are detectable. The prolonged elimination of mitotane from the body after discontinuation of Lysodren should be considered.
Due to the lipophilic nature of mitotane, it is likely to be excreted in breast milk. Breast-feeding is contraindicated while taking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levels are detectable.
Lysodren has a major influence on the ability to drive and use machines. Ambulatory patients should be warned not to drive or use machines.
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 identified from literature data:
Very common: Elevated liver enzymes, Plasma cholesterol increased, Plasma triglycerides increased
Not Known: Blood uric acid decreased, Blood androstenedione decreased (in females), Blood testosterone decreased (in females), Sex hormone binding globulin increased, Blood free testosterone decreased (in males)
Very common: Leucopoenia, Bleeding time prolonged
Common: Anaemia, Thrombocytopenia
Very common: Ataxia, Paresthesia, Vertigo, Sleepiness
Common: Mental impairment, Polyneuropathy, Movement disorder, Dizziness, Headache
Not Known: Balance disorders
Not Known: Maculopathy, Retinal toxicity, Diplopia, Lens opacity, Visual impairment, Vision blurred
Very common: Mucositis, Vomiting, Diarrhoea, Nausea, Epigastric discomfort
Not Known: Salivary hypersecretion, Dysgeusia, Dyspepsia
Not Known: Haemorrhagic cystitis, Haematuria, Proteinuria
Very common: Skin rash
Very common: Myasthenia
Very common: Adrenal insufficiency
Not Known: Thyroid impairment
Very common: Anorexia, Hypercholesterolemia, Hypertriglyceridaemia
Not Known: Hypouricaemia
Not Known: Opportunistic mycosis
Not Known: Hypertension, Orthostatic hypotension, Flushing
Very common: Asthenia
Not Known: Hyperpyrexia, Generalised aching
Common: Autoimmune hepatitis
Not Known: Liver damage (hepatocellular/cholestatic/mixed)
Very common: Gynaecomastia
Not Known: Ovarian macrocysts
Very common: Confusion
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. Autoimmune hepatitis has been reported in 7% of patients with no other information on mechanism. Liver enzymes levels normalize when the mitotane dose is decreased. A case of cholestatic hepatitis has been reported. Therefore, the possibility of mitotane-induced liver damage cannot be excluded.
Non-malignant ovarian macrocysts (with symptoms such as pelvic pain, bleeding) have been described.
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.
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 the national reporting system listed in Appendix V.
Not applicable.
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