Lysodren

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Lysodren 500 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 500 mg of mitotane. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet.  
 
White, biconvex, round, scored tablets. 
They are bisected on one side and impressed "BL" over "L1" on the other side. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma 
(ACC).  
 
The effect of Lysodren 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 Lysodren with acceptable safety. Indeed, neurologic toxicity has been 
associated with levels above 20 mg/L and therefore this threshold should not be reached. There are 
some data suggesting that mitotane plasma 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 and offer no further benefit in terms of efficacy. Mitotane plasma levels should therefore be 
monitored in order to adjust the Lysodren 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. 
 



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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 will be ranged 
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 Lysodren 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. 
 
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). 
 
Older patients (≥ 65 years old) 
There is no experience on the use of mitotane in older 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 



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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). 
 
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. 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. 
 
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 levels) should be periodically 
monitored, especially during the first months of treatment or when it is necessary to increase the dose. 

 
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. 
 
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 



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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 and 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). 
 
Women of childbearing potential: Women of childbearing potential must use effective contraception 
during treatment with mitotane (see section 4.6). 
 
Premenopausal women: 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.  
 
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 and midazolam. 
 
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 



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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 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. 
 
Breast-feeding 
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. 
 
4.7 Effects on ability to drive and use machines 
 
Lysodren 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 identified from literature data  
 Adverse reaction  

 
System Organ Class Very common 

 
Common 

 
Not Known 

Investigations Elevated liver enzymes 
Plasma cholesterol 
increased 
Plasma triglycerides 
increased 

 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) 
 

Blood and lymphatic 
system disorders 

Leucopoenia 
Bleeding time prolonged 

Anaemia 
Thrombocytopenia 

 



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Nervous system 
disorders 

Ataxia 
Paresthesia 
Vertigo 
Sleepiness 
 

Mental impairment 
Polyneuropathy 
Movement disorder 
Dizziness 
Headache 
 

Balance disorders 

Eye disorders   Maculopathy 
Retinal toxicity  
Diplopia 
Lens opacity 
Visual impairment 
Vision blurred 

Gastrointestinal 
disorders 

Mucositis  
Vomiting  
Diarrhoea 
Nausea 
Epigastric discomfort 

 Salivary hypersecretion 
Dysgeusia 
Dyspepsia 

Renal and urinary 
disorders 

  Haemorrhagic cystitis 
Haematuria 
Proteinuria 

Skin and subcutaneous 
tissue disorders 

Skin rash   

Muscoloskeletal and 
connective tissue 
disorders 

Myasthenia   

Endocrine disorders Adrenal insufficiency  Thyroid impairment 
Metabolism and 
nutrition disorders 

Anorexia 
Hypercholesterolemia 
Hypertriglyceridaemia 

 Hypouricaemia 

Infections and 
infestations 

  Opportunistic mycosis 

Vascular disorders   Hypertension 
Orthostatic hypotension 
Flushing 

General disorders and 
administration site 
conditions 

Asthenia  Hyperpyrexia 
Generalised aching 

Hepatobiliary disorders  Autoimmune hepatitis Liver damage 
(hepatocellular/cholestatic
/mixed) 

Reproductive system 
and breast disorders 

Gynaecomastia  Ovarian macrocysts 
 

Psychiatric disorders Confusion   
 
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).  



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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. 
 
Premenopausal women  
Non-malignant ovarian macrocysts (with symptoms such as pelvic pain, bleeding) 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. 
 
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 the national reporting system 
listed in Appendix V. 
 
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. 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). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX23 
 
Mechanism of action 
Mitotane is an adrenal cytotoxic active substance, although it can apparently also cause adrenal 
inhibition without cellular destruction. Its biochemical mechanism of action is unknown. Available 
data suggest that mitotane modifies the peripheral metabolism of steroids and that it also directly 
suppresses the adrenal cortex. The administration of mitotane alters the extra-adrenal metabolism of 



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cortisol in humans, leading to a reduction in measurable 17-hydroxy corticosteroids, even though 
plasma levels of corticosteroids do not fall. Mitotane apparently causes increased formation of 6-beta-
hydroxy cholesterol. 
 
Clinical efficacy 
Mitotane has not been studied in a comprehensive clinical development program. Available clinical 
information comes mainly from published data in patients with inoperable or metastatic adrenal 
carcinoma. In terms of overall survival, four studies conclude that mitotane treatment does not 
increase the survival rate whereas five find an increase in the survival rate. Among the latter, three 
studies find such an increase only in patients in whom mitotane plasma is above 14 mg/L.  
 
Mitotane plasma levels and the possible relationship with its efficacy were studied in the FIRM ACT 
trial, a randomized, prospective, controlled, open–label, multicenter, parallel-group study to compare 
the efficacy of etoposide, doxorubicin and cisplatin plus mitotane (EDP/M) to that of streptozotocin 
plus mitotane (Sz/M) as first-line treatment in 304 patients. The analysis of patients who achieved 
mitotane levels ≥ 14 mg/L at least once in 6 six months versus patients who mitotane levels were 
< 14 mg/L could suggest that patients with mitotane plasma levels ≥ 14 mg/L could have an 
improvement in disease control rate (62.9% versus 33.5%; p< 0. 0001). However, this result should be 
cautiously taken since the examination of the mitotane effects was not the primary endpoint of the 
study. 
 
In addition, mitotane induces a state of adrenal insufficiency which leads to the disappearance of 
Cushing syndrome in patients with secreting adrenal carcinoma and necessitates substitution 
hormonotherapy. 
 
Paediatric population 
Clinical information comes mainly from a prospective trial (n= 24 patients) in children and 
adolescents aged at diagnosis from 5 months to 16 years (median age: 4 years) who had an 
unresectable primary tumour or who presented a tumour recurrence or a metastasic disease; most of 
the children (75%) presented with endocrine symptoms. Mitotane was given alone or combined with 
chemotherapy with various agents. Overall, the disease-free interval was 7 months (2 to 16 months). 
There were recurrences in 40% of children; the survival rate at 5 years was 49%.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
In a study performed in 8 patients with adrenal carcinoma treated with 2 to 3 g daily of mitotane, a 
highly significant correlation was found between plasma mitotane concentration and the total mitotane 
dose. The target plasma mitotane concentration (14 mg/L) was reached in all patients within 3 to 5 
months and the total mitotane dose ranged between 283 and 387 g (median value: 363 g). The 
threshold of 20 mg/L was reached for cumulative amounts of mitotane of approximately 500 g. In 
another study, 3 patients with adrenal carcinoma received Lysodren according to a precise protocol 
allowing fast introduction of a high dose if the product was well tolerated: 3 g (as 3 intakes) on day 1, 
4.5 g on day 2, 6 g on day 3, 7.5 g on day 4 and 9 g on day 5. This dose of Lysodren was continued or 
decreased in function of side effects and plasma mitotane levels. There was a positive linear 
correlation between the cumulative dose of Lysodren and the plasma levels of mitotane. In two of the 
3 patients, plasma levels of more than 14 mg/L were achieved within 15 days and in one of them 
levels above 20 mg/L were achieved within approximately 30 days. In addition, in both studies, in 
some patients, the plasma mitotane levels continued to rise despite maintenance or a decrease of the 
daily dose of mitotane.  
 
Distribution 
Autopsy data from patients show that mitotane is found in most tissues of the body, with fat as the 
primary site of storage. 
 
Biotransformation 
Metabolism studies in man have identified the corresponding acid, 1,1-(o,p'-dichlorodiphenyl) acetic 



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acid (o,p’-DDA), as the major circulating metabolite, together with smaller quantities of the 1,1-(o,p'-
dichlorodiphenyl)-2,2 dichloroethene (o,p’-DDE) analogue of mitotane. No unchanged mitotane has 
been found in bile or in urine, where o,p’-DDA predominates, together with several of its 
hydroxylated metabolites. For induction with cytochrome P450, see section 4.5. 
 
Elimination 
After intravenous administration, 25% of the dose was excreted as metabolites within 24 hours. 
Following discontinuation of mitotane treatment, it is slowly released from storage sites in fat, leading 
to reported terminal plasma half-lives ranging from 18 to 159 days. 
 
5.3 Preclinical safety data 
 
Non-clinical data on the general toxicity of mitotane is limited.  
 
Reproductive toxicity studies have not been performed with mitotane. However, 
dichlorodiphenyltrichlorethane (DDT) and other polychlorinated biphenyl analogues are known to 
have deleterious effects on fertility, pregnancy and development, and mitotane could be expected to 
share these properties.  
 
The genotoxic and carcinogenic potential of mitotane has not been investigated. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Maize starch  
Microcrystalline cellulose (E 460) 
Macrogol 3350 
Silica colloidal anhydrous 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
After opening: 1 year. 
 
6.4 Special precautions for storage 
 
Store in the original packaging. 
 
6.5 Nature and contents of container 
 
Square opaque white HDPE bottle having a thread on the mouth containing 100 tablets.  
Pack size of 1 bottle. 
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product should not be handled by persons other than the patient and his/her caregivers, 
and especially not by pregnant women. Caregivers should wear disposable gloves when handling the 
tablets. 
 
Any unused product or waste material should be disposed of in accordance with local requirements for 



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cytotoxic medicinal products. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
HRA Pharma Rare Diseases 
200 avenue de Paris 
92320 CHATILLON 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/273/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 April 2004 
Date of last renewal: 28 April 2009 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMEA) http://www.emea.europa.eu/  



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ANNEX II 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
 
Name and address of the manufacturer responsible for batch release 
 
Corden Pharma Latina S.p.A. 
Via del Murillo Km. 2.800  
04010 Sermoneta (Latina) 
Italy 
 
or 
 
CENTRE SPECIALITES PHARMACEUTIQUES 
76-78, avenue du Midi 
63800 COURNON D’AUVERGNE 
FRANCE  
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 
• Periodic safety update reports (PSURs)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 
 
Not applicable. 

 
 
 



 14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



 15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON 
BOTTLE LABEL 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Lysodren 500 mg tablets 
mitotane 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 500 mg of mitotane. 
 
 
3. LIST OF EXCIPIENTS  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet. 
Bottle of 100 tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 

 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

  
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING (S), IF NECESSARY   
 
Cytotoxic. 
To be handled only by patients, or caregivers wearing gloves.  
 
 
8.  EXPIRY DATE 
 
EXP 
 
After opening: 1 year 
 
 



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9. SPECIAL STORAGE CONDITIONS  
 

Store in the original container. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused product or waste material should be disposed of in accordance with local requirements  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTORISATION HOLDER 
 
HRA Pharma Rare Diseases 
200 avenue de Paris 
92320 CHATILLON 
France 

 
 
12. MARKETING AUTORISATION NUMBER 
 
EU/1/04/273/001 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS FOR USE 

 
 

16. INFORMATION IN BRAILLE  
 

Lysodren (Braille applies only to outer carton) 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



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B. PACKAGE LEAFLET



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Package leaflet: Information for the user 
 

Lysodren 500 mg tablets 
mitotane 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
Always keep with you the Lysodren Patient Card included at the end of this leaflet.  
 
 
What is in this leaflet:  
1. What Lysodren is and what it is used for 
2. What you need to know before you take Lysodren 
3. How to take Lysodren 
4. Possible side effects 
5. How to store Lysodren 
6. Contents of the pack and other information 
 
 
1. What Lysodren is and what it is used for 
 
Lysodren is an antitumoral medicine. 
 
This medicine is used for the treatment of symptoms of advanced non operable, metastatic or recurrent 
malignant tumours of the adrenal glands. 
 
 
2. What you need to know before you take Lysodren 
 
Do not take Lysodren 
- if you are allergic to mitotane or any of the other ingredients of this medicine (listed in 

section 6). 
- if you are breast-feeding. You must not breast-feed while taking Lysodren. 
- if you are being treated with medicines containing spironolactone (see "Other medicines and 

Lysodren"). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Lysodren. 
You should tell your doctor if any of the following applies to you: 
- if you have an injury (shock, severe trauma), an infection or if you have any illness while you 

are taking Lysodren. Tell your doctor immediately, who may decide to temporarily stop 
treatment. 

- -if you have liver problems: Tell your doctor if you develop any of the following signs and 
symptoms of liver problems during Lysodren treatment: itching, yellow eyes or skin, dark urine, 
and pain or discomfort in the right upper stomach area. Your doctor should do blood tests to 
check your liver function before and during treatment with Lysodren, and as clinically 
indicated. 



 20 

- if you have severe kidney problems 
- if you are using any medicines mentioned below (see "Other medicines and Lysodren") 
- if you have gynaecological problems such as bleeding and/ or pelvic pain.  
This medicine should not be handled by persons other than the patient and his/her caregivers, and 
especially not by pregnant women. Caregivers should wear disposable gloves when handling the 
tablets. 
 
Your doctor may prescribe you some hormonal treatment (steroids) while you are taking Lysodren. 
 
Always keep with you the Lysodren Patient Card included at the end of this leaflet. 
 
Other medicines and Lysodren 
Please tell your doctor or pharmacist if you are using or have recently used any other medicines, 
including medicines obtained without a prescription. 
 
You must not use Lysodren with medicines containing spironolactone, often used as a diuretic for 
heart, liver or kidney diseases. 
 
Lysodren may interfere with several medicines. Therefore, you should tell your doctor if you are using 
medicines containing any of the following active substances: 
- warfarin or other anticoagulants (blood thinners), used to prevent blood clots. The dose of your 

anticoagulant may need adjustment. 
- antiepileptics 
- rifabutin or rifampicin, used to treat tuberculosis 
- griseofulvin, used in the treatment of fungal infections 
- herbal preparations containing St. John’s wort (Hypericum perforatum) 
- Sunitinib: to treat cancer 

 
 
Lysodren with food and drink 
Lysodren should preferably be taken during meals containing fat-rich food such as milk, chocolate, 
oil. 
 
Pregnancy, breast-feeding and fertility 
Lysodren may harm the foetus. If you are pregnant or planning to become pregnant, tell your doctor. 
If you may become pregnant, you should use an effective contraception during treatment with 
Lysodren and even after stopping it, ask your doctor for advice.  
 
You must not breast-feed while taking Lysodren and even after stopping it. Ask your doctor for 
advice. 
 
Driving and using machines 
Lysodren has a major influence on your ability to drive and use machines. Ask your doctor for advice. 
 
 
3. How to take Lysodren 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Dose and schedule 
The usual starting dose for adults is 2 to 3 g (4 to 6 tablets) per day. 
Your doctor may start treatment at higher doses such as 4 to 6 g (8 to 12 tablets). 
 
In order to find the optimal dose for you, your doctor will monitor regularly the levels of Lysodren in 
your blood. Your doctor may decide to stop treatment with Lysodren temporarily or to lower the dose 
if you experience certain side effects. 



 21 

 
Use in children and adolescents  
The starting daily dose of Lysodren is 1.5 to 3.5 g/m2 body surface (this will be calculated by your 
doctor according to the weight and the size of the child). The experience in patients in this age group is 
very limited. 
 
Method of administration 
You should swallow the tablets with a glass of water during meals containing fat-rich food. You can 
divide the total daily dose in two or three intakes. 
 
If you take more Lysodren than you should 
Tell your doctor immediately if you have taken accidentally more Lysodren than you should or if a 
child has accidentally swallowed some. 
 
If you forget to take Lysodren 
If you accidentally miss a dose, just take the next dose as scheduled. Do not take a double dose to 
make up for the forgotten one. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Lysodren can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately if you experience any of the following side effects: 
- Adrenal insufficiency: fatigue, abdominal pain, nausea, vomiting, diarrhoea, confusion 
- Anaemia: cutaneous pallor, muscular fatigability, feeling breathless, vertigo especially when 

standing up 
- Liver damage: yellowing of the skin and eyes, itching, nausea, diarrhoea, fatigue, dark coloured 

urine 
- Neurological disorders: movement and coordination disorders, abnormal sensations like pins 

and needles, memory loss, concentration difficulty, difficulty to talk, vertigo 
 
These symptoms may reveal complications for which specific medication could be appropriate. 
 
Side effects may occur with certain frequencies, which are defined as follows: 
- very common: may affect more than 1 in 10 people 
- common: may affect up to 1 in 10 people  
- not known: frequency cannot be estimated from the available data 
 
Very common side effects 
- vomiting, nausea (feeling sick), diarrhoea, belly pain 
- lack of appetite 
- abnormal sensations like pins and needles 
- movement and coordination disorders, vertigo, confusion 
- feeling sleepy, fatigue, muscle weakness (fatigue of muscle during effort) 
- inflammation (swelling, heat, pain) of mucosa, skin rash 
- blood disorders (bleeding time prolonged)  
- increase of cholesterol, triglycerides (fats) and liver enzymes (in blood tests) 
- decrease in white blood cells count  
- breast overdevelopment in men 
- adrenal insufficiency 
 
Common side effects  
- dizziness, headache 



 22 

- peripheral nervous system disorders (association of sensory disorders, muscular weakness and 
atrophy, decrease of tendon reflex and vasomotor symptoms such as hot flushes, sweat and 
sleep disorders) 

- mental impairment (such as memory loss, concentration difficulty) 
- movement disorder 
- decrease of red blood cells (anaemia, with symptoms such as skin pallor and fatigue), decrease 

in blood platelets (may make you more prone to bruising and bleeding) 
- hepatitis (auto-immune) (may cause yellowing of the skin and eyes, dark coloured urine) 
- difficulty of coordinating muscles 
 
 
Frequency Not Known 
- fever 
- general aching 
- flushing, high or low blood pressure, feeling of dizziness/vertigo when you suddenly stand up 
- increased production of saliva 
- eye disorders: visual impairment, vision blurred, double vision, distortion of images, complain 

of glare 
- fungal infection 
- liver damage (may cause yellowing of the skin and eyes, dark coloured urine) 
- decreased uric acid in blood tests  
- bladder inflammation with bleeding 
- presence of blood in urine, presence of proteins in urine 
- balance disorder 
- distortion of the sense of taste 
- impaired digestion 
- ovarian macrocysts (with symptoms such as pelvic pain, bleeding) 
- decreased androstenedione (precursor of sex hormones) in blood tests in females 
- decreased testosterone (sex hormone) in blood tests in females 
- sex hormone binding globulin (a protein which binds sex hormones) increased in blood tests 
- decreased free testosterone (sex hormone) in blood tests in males 
 
In children and adolescents, thyroid problems, neuro-psychological, growth retardation and one case 
of encephalopathy have been observed. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
the medicine. 
 
 
5. How to store Lysodren 
 
Keep out of the sight and reach of children. 
 
Store in the original packaging. After opening: 1 year. 
 
Do not use after the expiry date which is stated on the carton and the bottle after EXP. 
 
Any unused product or waste material should be disposed of in accordance with local requirements for 
cytotoxic medicines. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 



 23 

6. Contents of the pack and other information 
 
What Lysodren contains 
- The active substance is mitotane. Each tablet contains 500 mg of mitotane. 
- The other ingredients are maize starch, microcrystalline cellulose (E 460), macrogol 3350 and 

silica colloidal anhydrous. 
 
What Lysodren looks like and contents of the pack 
Lysodren tablets are white, biconvex, round and scored. 
Lysodren is available in plastic bottles of 100 tablets. 
 
Marketing Authorisation Holder 
HRA Pharma Rare Diseases 
200 avenue de Paris 
92320 CHATILLON 
France 
 
Manufacturer  
Corden Pharma Latina S.p.A. 
Via del Murillo Km. 2.800  
04010 Sermoneta (Latina) 
Italy 
 
or  
 
CENTRE SPECIALITES PHARMACEUTIQUES 
76-78, avenue du Midi 
63800 COURNON D’AUVERGNE 
FRANCE  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.emea.europa.eu/. There are also links to other websites about rare diseases and 
treatments. 
  
This leaflet is available in all European languages on the EMA website. 
 
 
─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─  
 

LYSODREN   PATIENT   CARD 
 
 

I am on Lysodren (mitotane) treatment 
 

 
I am prone to acute adrenal insufficiency 

 
In case I need emergency care,  

 
The name of my Doctor is: 

 
……………………………………….. 
Phone: ………………………………. 

 
For information on the product, 



 24 

adequate precautionary measures 
should be taken 

 
 
 
 

 please contact: 
 HRA Pharma Rare Diseases 

Tel: + 33 1 40 33 11 30 
lysodren@hra-pharma.com 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET