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.

Mitotane plasma levels should be assessed after each dose adjustment and at frequent intervals (e.g.
2
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
should be advised not to use any tablets showing signs of deterioration, and caregivers to wear

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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
20 mg/L (see section 4.8).

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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, etoposide 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

Infections and Opportunistic mycosis

infestations
Blood and lymphatic Leucopoenia Anaemia
system disorders Bleeding time prolonged Thrombocytopenia
Immune system Hypersensitivity reactions
disorders
Endocrine disorders Adrenal insufficiency Thyroid impairment
Hypogonadism (in males)
Metabolism and Anorexia Hypouricaemia
nutrition disorders Hypercholesterolemia
Hypertriglyceridaemia

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Psychiatric disorders Confusion
Nervous system Ataxia Mental impairment Balance disorders
disorders Paresthesia Polyneuropathy
Vertigo Movement disorder
Sleepiness Dizziness
Headache
Eye disorders Maculopathy
Retinal toxicity
Diplopia
Lens opacity
Visual impairment
Vision blurred
Vascular disorders Hypertension
Orthostatic hypotension
Flushing
Gastrointestinal Mucositis Salivary hypersecretion
disorders Vomiting Dysgeusia
Diarrhoea Dyspepsia
Nausea
Epigastric discomfort
Hepatobiliary disorders Autoimmune hepatitis Liver damage
(hepatocellular/cholestatic
/mixed)
Skin and subcutaneous Skin rash Pruritus
tissue disorders
Muscoloskeletal and Myasthenia
connective tissue
disorders
Renal and urinary Haemorrhagic cystitis
disorders Haematuria
Proteinuria
Reproductive system Gynaecomastia Ovarian macrocysts
and breast disorders
General disorders and Asthenia Hyperpyrexia
administration site Generalised aching
conditions
Investigations Elevated liver enzymes Blood uric acid decreased
Plasma cholesterol Blood androstenedione
increased decreased (in females)
Plasma triglycerides Blood testosterone
increased decreased (in females)
Sex hormone binding
globulin increased
Blood free testosterone
decreased (in males)

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

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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.

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, 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.
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 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).

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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
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 and safety

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

9
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
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.

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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
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

Latina Pharma S.p.A.

Via Murillo, 7
04013 Sermoneta (LT)
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.

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 ANNEX III

LABELLING AND PACKAGE LEAFLET

14
A. LABELLING

15
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 AUTHORISATION NUMBER

EU/1/04/273/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON 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

17
B. PACKAGE LEAFLET

18
 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.
- if you have severe kidney problems.

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- 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, etoposide: 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.

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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

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- 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
- hypogonadism in males (with symptoms such as breast overdevelopment, libido decreased,
erectile dysfunction, fertility disorders)
- allergic reactions, itching

In children and adolescents, thyroid problems, neuro-psychological, growth retardation and one case
of encephalopathy have been observed. In addition, some signs of hormonal changes (such as breast
overdevelopment in males and vaginal bleeding and/or early breast development in females) 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
this medicine.

5. How to store Lysodren

Keep this medicine out of the sight and reach of children.

Store in the original packaging. After opening: 1 year.

Do not use this medicine 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.

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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.

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
Latina Pharma S.p.A.
Via Murillo, 7
04013 Sermoneta (LT)
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.

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LYSODREN PATIENT CARD

I am on Lysodren (mitotane) treatment The name of my Doctor is:

………………………………………..
I am prone to acute adrenal insufficiency Phone: ……………………………….

In case I need emergency care, For information on the product,

adequate precautionary measures please contact:
should be taken HRA Pharma Rare Diseases
Tel: + 33 1 40 33 93 14
[email protected]

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