Leitlinien & Arzneimittelsicherheit

HOS-093696 · has-adverse-reaction-information · PDF-Seite 6

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. 6 Table 1: Frequency of adverse reactions Adverse reaction System Organ Class Very common Common Not Known Infections and Opportunistic infection infestations Blood and lymphatic Leukopenia Anaemia system disorders Bleeding time prolonged Thrombocytopenia Immune system Hypersensitivity reactions disorders Endocrine disorders Adrenal insufficiency Thyroid disorder Hypogonadism (in males) Metabolism and Decreased appetite Hypouricaemia nutrition disorders Hypercholesterolemia Hypertriglyceridaemia Psychiatric disorders Confusional state Nervous system Ataxia Mental impairment Balance disorder disorders Paraesthesia Polyneuropathy Vertigo Movement disorder Somnolence Dizziness Headache Eye disorders Maculopathy Retinal toxicity Diplopia Lenticular opacities Visual impairment

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HOS-093692 · has-contraindication-information · PDF-Seite 4

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).

HOS-093691 · has-indication-information · PDF-Seite 2

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenocortical carcinoma (ACC). The effect of Lysodren on non functional adrenocortical carcinoma is not established.

HOS-093694 · has-interaction-information · PDF-Seite 5

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. 5 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.

HOS-093695 · has-pregnancy-information · PDF-Seite 6

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). Lysodren 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 Lysodren 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.

HOS-093693 · has-warning-information · PDF-Seite 4

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 pe

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