ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Lysodren 500 mg tablets
2.
Each tablet contains 500 mg of mitotane.
For a full list of excipients, see section 6.1.
3.
Tablet.
White, biconvex, round, scored tablets.
4.
4.1
Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma.
The effect of Lysodren on non-functional adrenal cortical carcinoma is not established.
4.2
Treatment should be initiated and followed by a suitably experienced specialist.
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 daily 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 between 14 and
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.
Weaker evidence has suggested that mitotane plasma levels above 14 mg/l may result in enhanced
efficacy. 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.
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 (e.g. every two
weeks) intervals, 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 (section 4.4). In addition,
because of tissue accumulation, mitotane plasma levels should be monitored regularly (e.g. monthly)
1
Posology
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
transiently 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
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/m
2
/day in children and adolescents with the objective of
reaching 4 g/m
2
/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
Since mitotane is mainly metabolised through the liver, mitotane plasma levels are expected to
increase if liver function is impaired. 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. The use of
mitotane in patients with severe hepatic impairment is not recommended. In patients with mild or
moderate hepatic impairment, caution should be exercised and monitoring of liver biochemistry
should be performed. Monitoring of mitotane plasma levels is specially recommended in these patients
(see section 4.4).
Renal impairment
There is no experience in the use of mitotane in patients with renal impairment, so data are insufficient
to give a dose recommendation in this group. The use of mitotane in patients with severe renal
impairment is not recommended and, in cases of mild to moderate renal impairment, caution should be
exercised. Monitoring of mitotane plasma levels is specially recommended in these patients (see
section 4.4).
Elderly patients (≥ 65 years old)
There is no experience on the use of mitotane in elderly patients, so data are insufficient to give a dose
recommendation in this group. Caution should be exercised and frequent monitoring of mitotane
plasma levels is highly recommended.
The total daily dose may be divided in two or three doses according to patient’s convenience. Tablets
should be taken with water during meals containing fat-rich food (see section 4.5). Patients should be
advised not to use any tablets showing signs of deterioration, and caregivers to wear disposable gloves
when handling the tablets.
4.3
Hypersensitivity to the active substance or to any of the excipients
2
Paediatric patients
Method of administration
Lactation (see section 4.6)
Concomitant use with spironolactone (see section 4.5)
4.4
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).
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 and 20 mg/l and avoid
specific adverse reactions (see section 4.2).
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).
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).
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:
Physicians should closely monitor patients for a change
in anticoagulant dose requirements when administering mitotane to patients on coumarin-like
anticoagulants (see section 4.5).
Substances metabolised through cytochrome P450
: Mitotane is a hepatic enzyme inducer and it should
be used with caution in case of concomitant use of medicinal products influenced by hepatic enzyme
3
induction (see section 4.5).
Women of childbearing potential
: Women of childbearing potential must use effective contraception
during treatment with mitotane (see section 4.6).
Paediatric patients:
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
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, physicians should closely monitor patients for a change in anticoagulant dose
requirements when administering mitotane 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
).
Medicinal products active on central nervous system:
Mitotane can cause central nervous system
undesirable effects at high concentrations (see section 4.8). Although no specific information on
pharmacodynamic interactions in the central nervous system is available, this should be borne in mind
when co-prescribing medicinal products with central nervous system depressant action.
Fat-rich food:
Data with various mitotane formulations suggest that administration with fat-rich food
enhances absorption of mitotane.
Hormone binding protein:
Mitotane has been shown to increase plasma levels of hormone binding
proteins (e.g. sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)). This
should be taken into account when interpreting the results of hormonal assays and may result in
gynaecomastia.
4.6
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 a pregnant woman only if clearly needed and if the clinical benefit clearly
outweighs any potential risk to the foetus.
Women of childbearing potential must use 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.
Lactation
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
4.7
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
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 and lymphatic
system disorders
Leucopoenia
Bleeding time prolonged
Anaemia
Thrombocytopenia
Nervous system
disorders
Ataxia
Paresthesia
Vertigo
Sleepiness
Mental impairment
Polyneuropathy
Movement disorder
Dizziness
Headache
Eye disorders
Maculopathy
Retinal toxicity
Diplopia
Lens opacity
Visual impairment
Vision blurred
Gastrointestinal
disorders
Mucositis
Vomiting
Diarrhoea
Nausea
Epigastric discomfort
Salivary hypersecretion
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
5
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
Psychiatric disorders
Confusion
Gastrointestinal disorders are the most frequently reported (10 to 100 % of patients) and are reversible
when the dose is reduced. Some of these effects (anorexia) may constitute the hallmark of initial
central nervous system impairment.
Nervous system undesirable effects occur in approximately 40 % of patients. Other undesirable central
nervous effects have been reported in literature such as memory defects, aggressiveness, central
vestibular syndrome, dysarthria, or Parkinson syndrome. Serious undesirable effects appear linked to
the cumulative exposure to mitotane and are most likely to occur when mitotane plasma levels are at
20 mg/l or above. At high doses and after prolonged utilization, brain function impairment can occur.
Nervous system undesirable effects appear reversible after cessation of mitotane treatment and
decrease in plasma levels (see section 4.4).
Skin rashes which have been reported in 5 to 25 % of patients do not seem to be dose related.
Leucopoenia has been reported in 8 to 12 % of patients. Prolonged bleeding time appears a frequent
finding (90 %): although the exact mechanism of such an effect is unknown and its relation with
mitotane or with the underlying disease is uncertain, it should be taken into account when surgery is
considered.
The activity of liver enzymes (gamma-GT, aminotransferase, alkaline phosphatase) is commonly
increased. Autoimmune hepatitis has been reported in 7 % of patients with no other information on
mechanism. Liver enzymes levels normalize when the mitotane dose is decreased. A case of
cholestatic hepatitis has been reported. Therefore, the possibility of mitotane-induced liver damage
cannot be excluded.
Paediatric patients
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.
4.9
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).
6
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX23
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.
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. In terms of
total or partial tumour and/or metastasis regression, eleven studies have shown some degree of
improvement and sometimes occasional prolonged remissions. However, in several studies, the
objective criteria for evaluating tumour response are missing or not reported. There are nevertheless
some studies which provide accurate information on tumour regression or disappearance and
demonstrate that the threshold of 14 mg/l appears necessary to induce an objective tumour regression.
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 patients
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.
7
Mechanism of action
Clinical efficacy
Distribution
Autopsy data from patients show that mitotane is found in most tissues of the body, with fat as the
primary site of storage.
Metabolism
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.
Excretion
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.
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 container.
6.5
Nature and contents of container
Square opaque white HDPE bottle containing 100 tablets.
Pack size of 1 bottle.
8
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.
Laboratoire HRA Pharma
15 rue Béranger
75003 Paris
France
8.
EU/1/04/273/001
9.
Date of first autorisation : 28/04/2004
Date of last renewal : 28/04/2009
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/
9
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
10
A
MANUFACTURING AUTHORISATION HOLDER 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 OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
Not applicable.
11
ANNEX III
LABELLING AND PACKAGE LEAFLET
12
A. LABELLING
13
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE
PACKAGING
OUTER CARTON
BOTTLE LABEL
Lysodren 500 mg tablets
Mitotane
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 500 mg of mitotane.
3. LIST OF EXCIPIENTS
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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
14
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
Laboratoire HRA Pharma
15 rue Béranger
75003 Paris
France
12.
MARKETING AUTORISATION NUMBER
13.
BATCH NUMBER
Batch
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)
15
B. PACKAGE LEAFLET
16
PACKAGE LEAFLET: INFORMATION FOR THE USER
Lysodren 500 mg tablets
Mitotane
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
Always keep with you the
Lysodren Patient Card included at the end of this leaflet.
In this leaflet
:
1. What Lysodren is and what it is used for
2. Before you take Lysodren
3. How to take Lysodren
4. Possible side effects
5. How to store Lysodren
6. Further 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.
BEFORE YOU TAKE LYSODREN
Do not take Lysodren
-
if you are allergic (hypersensitive) to mitotane or any of the other ingredients of Lysodren
-
if you are being treated with medicines containing spironolactone (see "Using other
medicines").
Take special care with 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 severe liver or kidney problems.
-
if you are using any medicines mentioned below (see "Using other medicines").
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.
17
-
If you have further questions, please ask your doctor or pharmacist.
-
if you are breast-feeding. You must not breast-feed while taking Lysodren.
Using other medicines
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
)
Taking Lysodren with food and drink
Lysodren should preferably be taken during meals containing fat-rich food such as milk, chocolate,
oil.
Pregnancy and breast-feeding
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 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 Lysodren exactly as your doctor has told you. You should 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.
Children and adolescents
The starting daily dose of Lysodren is 1.5 to 3.5 g/m
2
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 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
18
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.
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: affects more than 1 user in 10
-
common: affects 1 to 10 users in 100
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data
Very common side effects
-
vomiting, nausea (feeling sick), diarrhoea, belly pain
-
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
-
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)
-
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)
19
-
lack of appetite
-
movement disorder
Frequency Not Known
-
fever
-
general aching
-
flushing, high or low blood pressure, feeling of dizziness/vertigo when you suddenly stand up
-
eye disorders : visual impairment, vision blurred, double vision
-
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,
In children and adolescents, thyroid problems, neuro-psychological and growth retardation have been
observed.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, tell your
doctor or your pharmacist.
5.
HOW TO STORE LYSODREN
Keep out of the reach and sight of children.
Store in the original container.
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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Lysodren contains
-
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
Laboratoire HRA Pharma
15 rue Béranger
F - 75003 Paris
France
Manufacturer
Corden Pharma Latina S.p.A.
Via del Murillo Km. 2.800
04010 Sermoneta (Latina)
Italy
20
-
increased production of saliva
-
The active substance is mitotane. Each tablet contains 500 mg of mitotane.
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:
België/Belgique/Belgien
Laboratoire HRA Pharma
Tél/Tel: + 33 (0)1 40 33 11 30
Luxembourg/Luxemburg
Laboratoire HRA Pharma
Tél/Tel: + 33 (0)1 40 33 11 30
България
Laboratoire HRA Pharma
Teл.: + 33 (0)1 40 33 11 30
Magyarország
Laboratoire HRA Pharma
Tel.: + 33 (0)1 40 33 11 30
Česká republika
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Malta
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Danmark
Laboratoire HRA Pharma
Tlf: + 33 (0)1 40 33 11 30
Nederland
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Deutschland
HRA Pharma Deutschland GmbH
Tel: + 49 (0) 234 516 592-0
Norge
Laboratoire HRA Pharma
Tlf: + 33 (0)1 40 33 11 30
Eesti
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Österreich
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Ελλάδα
Laboratoire HRA Pharma
Τηλ: + 33 (0)1 40 33 11 30
Polska
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
España
Laboratorios HRA Pharma España SL
Tel: + 34 902 107 428
Portugal
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
France
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
România
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Ireland
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Slovenija
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Ísland
Laboratoire HRA Pharma
Sími: + 33 (0)1 40 33 11 30
Slovenská republika
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
21
Italia
HRA Pharma Italia srl
Tel: + 39 06 541 44 60
Suomi/Finland
Laboratoire HRA Pharma
Puh/Tel: + 33 (0)1 40 33 11 30
Κύπρος
Laboratoire HRA Pharma
Τηλ: + 33 (0)1 40 33 11 30
Sverige
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
Latvija
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
United Kingdom
HRA Pharma UK Ltd.
Tel: + 44 (0) 800 917 9548
Lietuva
Laboratoire HRA Pharma
Tel: + 33 (0)1 40 33 11 30
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu/
. There are also links to other websites about rare diseases and
treatments.
─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─
LYSODREN PATIENT CARD
I am on Lysodren (mitotane) treatment
The name of my Doctor is:
………………………………………..
Phone: ……………………………….
For information on the product,
please contact:
Laboratoire HRA Pharma
Tel: + 33 1 40 33 11 30
lysodren@hra-pharma.com
I am prone to acute adrenal insufficiency
In case I need emergency care,
adequate precautionary measures
should be taken
22
Source: European Medicines Agency
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