ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Afinitor 5 mg tablets
2.
Each tablet contains 5 mg everolimus.
Excipients
Each tablet contains 149 mg lactose.
For a full list of excipients, see section 6.1.
3.
Tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on
one side and “NVR” on the other.
4.
Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease
has progressed on or after treatment with VEGF-targeted therapy.
Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of
anticancer therapies.
Posology
The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical
benefit is observed or until unacceptable toxicity occurs.
Dose adjustment due to adverse reactions
Management of severe and/or intolerable suspected adverse reactions may require dose alterations.
Afinitor may be dose reduced or temporarily withheld (e.g. for one week) followed by reintroduction
at 5 mg daily. If dose reduction is required, the suggested dose is 5 mg daily (see also section 4.4).
Special populations
Paediatric population
The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data
are available.
Elderly patients (≥65 years)
No dose adjustment is required (see section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
2
Hepatic impairment
For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to
5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh
class C) and is not recommended for use in this patient population (see sections 4.4 and 5.2).
Method of administration
Afinitor should be administered orally once daily at the same time every day, consistently either with
or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water.
The tablets should not be chewed or crushed.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next
dose.
Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
Non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Non-
infectious pneumonitis (including interstitial lung disease) was described in 12% of patients taking
Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was
observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea,
and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of
appropriate investigations. Patients should be advised to report promptly any new or worsening
respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or
no symptoms may continue Afinitor therapy without dose adjustments If symptoms are moderate,
consideration should be given to interruption of therapy until symptoms improve. The use of
corticosteroids may be indicated. Afinitor may be re-initiated at 5 mg daily.
For cases where symptoms of non-infectious pneumonitis are severe, Afinitor therapy should be
discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy
with Afinitor may be re-initiated at 5 mg daily depending on the individual clinical circumstances.
Infections
Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or
protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised
and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections
such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus,
have been described in patients taking Afinitor. Some of these infections have been severe (e.g.
leading to respiratory or hepatic failure) and occasionally fatal.
Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing
infections should be treated appropriately and should have resolved fully before starting treatment
with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of
infection is made, institute appropriate treatment promptly and consider interruption or discontinuation
of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, Afinitor treatment should be promptly and
permanently discontinued and the patient treated with appropriate antifungal therapy.
3
Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis,
dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without
respiratory impairment) have been observed with everolimus (see section 4.3).
Oral ulceration
Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see
section 4.8). In such cases topical treatments are recommended, but alcohol- or peroxide-containing
mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not
be used unless fungal infection has been diagnosed (see section 4.5).
Laboratory tests and monitoring
Renal function
Elevations of serum creatinine, usually mild, have been reported in clinical trials (see section 4.8).
Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum
creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood glucose and lipids
Hyperglycaemia, hyperlipidaemia and hypertrigylceridaemia have been reported in clinical trials (see
section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy
and periodically thereafter. When possible optimal glycaemic control should be achieved before
starting a patient on Afinitor.
Haematological parameters
Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in clinical trials
(see section 4.8). Monitoring of complete blood count is recommended prior to the start of Afinitor
therapy and periodically thereafter.
Interactions
Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-
glycoprotein (PgP) should be avoided. If co-administration of a
moderate
CYP3A4 and/or PgP
inhibitor or inducer cannot be avoided, dose adjustments of Afinitor can be taken into consideration
based on predicted AUC (see section 4.5).
Concomitant treatment with
potent
CYP3A4 inhibitors result in dramatically increased plasma
concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing
recommendations in this situation. Hence, concomitant treatment of Afinitor and
potent
inhibitors is
not recommended.
Hepatic impairment
Afinitor should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see
sections 4.2 and 5.2).
Vaccinations
The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).
Lactose
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.
Wound healing complications
Impaired wound healing is a class effect of rapamycin derivatives, including Afinitor. Caution should
therefore be exercised with the use of Afinitor in the peri-surgical period.
4
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore,
absorption and subsequent elimination of everolimus may be influenced by products that affect
CYP3A4 and/or PgP.
In vitro
, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor
of CYP2D6.
Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are
listed in Table 1 below.
CYP3A4 and PgP inhibitors increasing everolimus concentrations
Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by
decreasing metabolism or the efflux of everolimus from intestinal cells.
CYP3A4 and PgP inducers decreasing everolimus concentrations
Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by
increasing metabolism or the efflux of everolimus from intestinal cells.
Table 1
Effects of other active substances on everolimus
Active substance by
interaction
Interaction – Change in
Everolimus AUC/C
max
Geometric mean ratio
(observed range)
Recommendations concerning co-
administration
Potent
CYP3A4/PgP inhibitors
Ketoconazole
AUC ↑15.3-fold
(range 11.2-22.5)
C
max
↑4.1-fold
(range 2.6-7.0)
Concomitant treatment of Afinitor
and potent inhibitors is not
recommended.
Itraconazole,
posaconazole,
voriconazole
Telithromycin,
clarithromycin
Nefazodone
Ritonavir, atazanavir,
saquinavir, darunavir,
indinavir, nelfinavir
Not studied. Large increase in
everolimus concentration is
expected.
5
Moderate CYP3A4/PgP inhibitors
Erythromycin
AUC ↑4.4-fold
(range 2.0-12.6)
C
max
↑2.0-fold
(range 0.9-3.5)
Use caution when co-administration
of moderate CYP3A4 inhibitors or
PgP inhibitors cannot be avoided. If
patients require co-administration of a
moderate CYP3A4 or PgP inhibitor,
dose reduction to 5 mg daily or 5 mg
every other day may be considered.
However, there are no clinical data
with this dose adjustment. Due to
between subject variability the
recommended dose adjustments may
not be optimal in all individuals,
therefore close monitoring of side
effects is recommended.
Verapamil
AUC ↑3.5-fold
(range 2.2-6.3)
C
max
↑2.3-fold
(range1.3-3.8)
Ciclosporin oral
AUC ↑2.7-fold
(range 1.5-4.7)
C
max
↑1.8-fold
(range 1.3-2.6)
Fluconazole
Diltiazem
Not studied. Increased exposure
expected.
Amprenavir,
fosamprenavir
Not studied. Increased exposure
expected.
Grapefruit juice or other
food affecting
CYP3A4/PgP
Not studied. Increased exposure
expected (the effect varies
widely).
Combination should be avoided.
Potent
CYP3A4 inducers
Rifampicin
AUC ↓63%
(range 0-80%)
C ↓58%
Avoid the use of concomitant potent
CYP3A4 inducers. If patients require
co-administration of a potent
CYP3A4 inducer, an Afinitor dose
increase from 10 mg daily up to
20 mg daily should be considered
using 5 mg increments applied on
Day 4 and 8 following start of the
inducer. This dose of Afinitor is
predicted to adjust the AUC to the
range observed without inducers.
However, there are no clinical data
with this dose adjustment. If
treatment with the inducer is
discontinued, the Afinitor dose should
be returned to the dose used prior to
initiation of the co-administration.
max
(range 10-70%)
Corticosteroids
(e.g. dexamethasone,
prednisone,
prednisolone)
Not studied. Decreased exposure
expected.
Carbamazepine,
phenobarbital, phenytoin
Not studied. Decreased exposure
expected.
Efavirenz, nevirapine
Not studied. Decreased exposure
expected.
St John’s Wort
(
Hypericum perforatum
)
Not studied. Large decrease in
exposure expected.
Preparations containing St John’s
Wort should not be used during
treatment with everolimus
Agents whose plasma concentration may be altered by everolimus
Based on
in vitro
results, the systemic concentrations obtained after oral daily doses of 10 mg make
inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the
gut cannot be excluded; hence everolimus may affect the bioavailability of co-administered drugs
which are CYP3A4 and/or PgP substrates.
6
Vaccinations
The immune response to vaccination may be affected and, therefore, vaccination may be less effective
during treatment with Afinitor. The use of live vaccines should be avoided during treatment with
Afinitor (see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps,
rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid
vaccines.
Fertility
Based on non-clinical findings, male fertility may be compromised by treatment with everolimus (see
section 5.3).
Women of childbearing potential
Women of childbearing potential must use an effective method of contraception while receiving
everolimus.
Pregnancy
There are no or limited amount of data from the use of everolimus in pregnant women. Studies in
animals have shown reproductive toxicity effects (see section 5.3).
Everolimus is not recommended during pregnancy and in women of childbearing potential not using
contraception.
Lactation
It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its
metabolites readily pass into the milk. Therefore, women taking everolimus should not breast-feed.
No studies on the effects on the ability to drive and use machines have been performed. Patients
should be advised to be cautious when driving or using machines if they experience fatigue during
treatment with Afinitor.
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a
randomised phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 patients
were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients was 61 years (range
27-85).
The most frequent grade 3-4 adverse reactions (incidence ≥2%) were lymphocytes decreased, glucose
increased, haemoglobin decreased, phosphate decreased, cholesterol increased, infections, stomatitis,
fatigue, and pneumonitis.
The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving
Afinitor and 60 days (range 21-295) for those receiving placebo. The rates of adverse reactions
resulting in permanent discontinuation were 7% and 0% for the Afinitor and placebo treatment groups,
respectively. Most adverse reactions were grade 1 or 2 in severity.
Table 2 shows the incidence of adverse reactions reported for patients receiving everolimus
10 mg/day. Adverse reactions in Table 2 are listed according to MedDRA system organ class and
frequency category. Frequency categories are defined using 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, adverse reactions are presented in order of decreasing seriousness.
7
Table 2
Adverse reactions
Infections and infestations
Very common Infections
a
Blood and lymphatic system disorders
Very common Lymphocytes decreased
b
, haemoglobin decreased
b
, platelets decreased
b
, neutrophils
decreased
b
Immune system disorders
Not known Hypersensitivity
Metabolism and nutrition disorders
Very common Glucose increased
b
, cholesterol increased
b
, triglycerides increased
b
, phosphate
decreased
b
, anorexia
Common Dehydration
Uncommon New-onset diabetes mellitus
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Abnormal taste
Common
Headache
Eye disorders
Common Conjunctivitis, eyelid oedema
Cardiac disorders
Uncommon Congestive cardiac failure
Vascular disorders
Common Hypertension
Not known Haemorrhage
Respiratory, thoracic and mediastinal disorders
Very common Pneumonitis
c
, dyspnoea, epistaxis, cough
Common Haemoptysis
Gastrointestinal disorders
Very common Stomatitis
d
, diarrhoea, mucosal inflammation, vomiting, nausea
Common Dry mouth, abdominal pain, dysphagia, dyspepsia
Hepatobiliary disorders
Very common Alanine aminotransferase increased
b
, aspartate aminotransferase increased
b
Common Bilirubin increased
b
Skin and subcutaneous tissue disorders
Very common Rash, dry skin, pruritus
Common Palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, nail
disorder, acneiform dermatitis, onychoclasis
Uncommon Angioedema
Renal and urinary disorders
Very common Creatinine increased
b
General disorders and administration site conditions
Very common Fatigue, asthenia, peripheral oedema
Common
Chest pain, pyrexia
Uncommon
Impaired wound healing
Investigations
C
omm
Weight decreased
a
Includes all events within the ‘infections and infestations’ system organ class (such as
pneumonia, sepsis, and opportunistic infections [e.g. aspergillosis and candidiasis (see also
section 4.4)])
b
Frequency based on determination of abnormal laboratory value (as part of routine laboratory
assessment)
c
Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar
haemorrhage, pulmonary toxicity, and alveolitis
d
Includes stomatitis and aphthous stomatitis, and mouth and tongue ulceration
8
on
Information from further clinical studies
In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation,
including fatal outcome. Reactivation of infection is an expected event during periods of
immunosuppression.
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been
given with acceptable acute tolerability. General supportive measures should be initiated in all cases of
overdose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protein kinase inhibitors, ATC code: L01XE10
Mechanism of action
Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-
threonine kinase, the activity of which is known to be upregulated in a number of human cancers.
Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR
complex-1 (mTORC1) activity.
Inhibition of the mTORC1 signalling pathway interferes with the
translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1)
and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the
cell cycle, angiogenesis and glycolysis. Everolimus reduces levels of vascular endothelial growth
factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the
growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated
smooth muscle cells and has been shown to reduce glycolysis in solid tumours
in vitro
and
in vivo
.
Clinical efficacy and safety
A phase III, international, multicentre, randomised, double-blind study comparing everolimus
10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with
metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI
(vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or
both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted.
Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic
score (favourable-
vs.
intermediate-
vs.
poor-risk groups) and prior anticancer therapy (1
vs.
2 prior
VEGFR-TKIs).
Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid
Tumours) and assessed via a blinded, independent central review, was the primary endpoint.
Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related
symptoms, and quality of life. After documented radiological progression, patients could be unblinded
by the investigator: those randomised to placebo were then able to receive open-label everolimus
10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the
time of the second interim analysis as the primary endpoint had been met.
In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139).
Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88%
Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]).
9
Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a
statistically significant 67% reduction in the risk of progression or death (see Table 3 and Figure 1).
Table 3
Progression-free survival results
Population
n
Afinitor
n=277
Placebo
n=139
Hazard ratio
(95%CI)
p-value
Median progression-free
survival (months) (95% CI)
Primary analysis
All (blinded independent
central review)
416
4.9
(4.0-5.5)
1.9
(1.8-1.9)
0.33
(0.25-0.43)
<0.0001
a
Supportive/sensitivity analyses
All (local review by
investigator)
416
5.5
(4.6-5.8)
1.9
(1.8-2.2)
0.32
(0.25-0.41)
<0.0001
a
MSKCC prognostic score (blinded independent central review)
Favourable risk
120
5.8
(4.0-7.4)
1.9
(1.9-2.8)
0.31
(0.19-0.50)
<0.0001
Intermediate risk
235
4.5
(3.8-5.5)
1.8
(1.8-1.9)
0.32
(0.22-0.44)
<0.0001
Poor risk
61
3.6
(1.9-4.6)
1.8
(1.8-3.6)
0.44
(0.22-0.85)
0.007
a
Stratified log-rank test
Figure 1 KaplanMeier progression-free survival curves
Censoring Times
Everolimus (n/N = 155/277)
Placebo (n/N = 111/139)
Hazard Ratio = 0.33
95% CI [0.25, 0.43]
Kaplan-Meier medians
Everolimus: 4.90 months
Placebo: 1.87 months
Logrank p value = <0.0001
Time (months)
No. of patients still at risk
Time (months)
Afinitor
Placebo
Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.
10
Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while
none were observed in patients receiving placebo. Therefore, the progression-free survival advantage
primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor
treatment group).
No statistically significant treatment-related difference in overall survival was noted (hazard
ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following
disease progression for patients allocated to placebo confounded the detection of any treatment-related
difference in overall survival.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Afinitor in all subsets of the paediatric population in renal cell carcinoma
(see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
In patients with advanced solid tumours, peak everolimus concentrations (C
max
) are reached at a
median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions
or with a light fat-free snack. C
max
is dose-proportional between 5 and 10 mg. Everolimus is a substrate
and moderate inhibitor of PgP.
Food effect
:
In healthy subjects, high fat meals reduced systemic exposure to Afinitor 10 mg (as measured by
AUC) by 22% and the peak plasma concentration C
max
by 54%. Light fat meals reduced AUC by 32%
and C
max
by 42%. Food, however, had no apparent effect on the post absorption phase concentration-
time profile.
Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to
5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is
confined to plasma of cancer patients given Afinitor 10 mg/day. Plasma protein binding is
approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In
patients with advanced solid tumours, V
d
was 191 l for the apparent central compartment and 517 l for
the apparent peripheral compartment.
Metabolism
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main
circulating component in human blood. Six main metabolites of everolimus have been detected in
human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products,
and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal
species used in toxicity studies, and showed approximately 100 times less activity than everolimus
itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological
activity.
Elimination
Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h.
The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available
from the studies in transplant patients. Following the administration of a single dose of radiolabelled
everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces,
while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
11
Steady-state pharmacokinetics
After administration of everolimus in patients with advanced solid tumours, steady-state AUC
0-τ
was
dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two
weeks. C
max
is dose-proportional between 5 and 10 mg. t
max
occurs at 1 to 2 hours post-dose. There
was a significant correlation between AUC
0-τ
and pre-dose trough concentration at steady-state.
Special populations
Hepatic impairment
The average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh class B)
was twice that found in 8 subjects with normal hepatic function. AUC was positively correlated with
serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated
with serum albumin concentration. The impact of severe hepatic impairment (Child-Pugh class C) on
the pharmacokinetics of everolimus has not been assessed (see sections 4.2 and 4.4).
Renal impairment
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant
influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant
renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of
everolimus in transplant patients.
Elderly patients
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age
(27-85 years) on oral clearance of everolimus was detected.
Ethnicity
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.
Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in
black transplant patients.
5.3 Preclinical safety data
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits.
The major target organs were male and female reproductive systems (testicular tubular degeneration,
reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased
alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in
monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular
anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of
age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of
background lesions). There was no indication of kidney toxicity in monkeys or minipigs.
Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats,
coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal
tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at
systemic exposure levels within the range of therapeutic exposure or above, with the exception of the
findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm
motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is
within the range of therapeutic exposure and which caused a reduction in male fertility. There was
evidence of reversibility. Female fertility was not affected, but everolimus crossed the placenta and
was toxic to the foetus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below
the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of
skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits,
embryotoxicity was evident in an increase in late resorptions.
12
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or
mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic
potential in mice and rats up to the highest doses, corresponding respectively to 4.3 and 0.2 times the
estimated clinical exposure.
6.
6.1 List of excipients
Butylated hydroxytoluene (E321)
Magnesium stearate
Lactose monohydrate
Hypromellose
Crospovidone type A
Lactose anhydrous
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/polyamide/aluminium/PVC blister containing 10 tablets.
Packs containing 10, 30, 60 or 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
13
8.
EU/1/09/538/001
EU/1/09/538/002
EU/1/09/538/003
EU/1/09/538/007
9.
03.08.2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
14
1.
Afinitor 10 mg tablets
2.
Each tablet contains 10 mg everolimus.
Excipients
Each tablet contains 297 mg lactose.
For a full list of excipients, see section 6.1.
3.
Tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE”
on one side and “NVR” on the other.
4.
Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease
has progressed on or after treatment with VEGF-targeted therapy.
Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of
anticancer therapies.
Posology
The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical
benefit is observed or until unacceptable toxicity occurs.
Dose adjustment due to adverse reactions
Management of severe and/or intolerable suspected adverse reactions may require dose alterations.
Afinitor may be dose reduced or temporarily withheld (e.g. for one week) followed by reintroduction
at 5 mg daily. If dose reduction is required, the suggested dose is 5 mg daily (see also section 4.4).
Special populations
Paediatric population
The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data
are available.
Elderly patients (≥65 years)
No dose adjustment is required (see section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
15
Hepatic impairment
For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to
5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh
class C) and is not recommended for use in this patient population (see sections 4.4 and 5.2).
Method of administration
Afinitor should be administered orally once daily at the same time every day, consistently either with
or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water.
The tablets should not be chewed or crushed.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next
dose.
Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
Non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Non-
infectious pneumonitis (including interstitial lung disease) was described in 12% of patients taking
Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was
observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea,
and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of
appropriate investigations. Patients should be advised to report promptly any new or worsening
respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or
no symptoms may continue Afinitor therapy without dose adjustments If symptoms are moderate,
consideration should be given to interruption of therapy until symptoms improve. The use of
corticosteroids may be indicated. Afinitor may be re-initiated at 5 mg daily.
For cases where symptoms of non-infectious pneumonitis are severe, Afinitor therapy should be
discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy
with Afinitor may be re-initiated at 5 mg daily depending on the individual clinical circumstances.
Infections
Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or
protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised
and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections
such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus,
have been described in patients taking Afinitor. Some of these infections have been severe (e.g.
leading to respiratory or hepatic failure) and occasionally fatal.
Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing
infections should be treated appropriately and should have resolved fully before starting treatment
with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of
infection is made, institute appropriate treatment promptly and consider interruption or discontinuation
of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, Afinitor treatment should be promptly and
permanently discontinued and the patient treated with appropriate antifungal therapy.
16
Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis,
dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without
respiratory impairment) have been observed with everolimus (see section 4.3).
Oral ulceration
Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see
section 4.8). In such cases topical treatments are recommended, but alcohol- or peroxide-containing
mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not
be used unless fungal infection has been diagnosed (see section 4.5).
Laboratory tests and monitoring
Renal function
Elevations of serum creatinine, usually mild, have been reported in clinical trials (see section 4.8).
Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum
creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood glucose and lipids
Hyperglycaemia, hyperlipidaemia and hypertrigylceridaemia have been reported in clinical trials (see
section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy
and periodically thereafter. When possible optimal glycaemic control should be achieved before
starting a patient on Afinitor.
Haematological parameters
Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in clinical trials
(see section 4.8). Monitoring of complete blood count is recommended prior to the start of Afinitor
therapy and periodically thereafter.
Interactions
Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-
glycoprotein (PgP) should be avoided. If co-administration of a
moderate
CYP3A4 and/or PgP
inhibitor or inducer cannot be avoided, dose adjustments of Afinitor can be taken into consideration
based on predicted AUC (see section 4.5).
Concomitant treatment with
potent
CYP3A4 inhibitors result in dramatically increased plasma
concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing
recommendations in this situation. Hence, concomitant treatment of Afinitor and
potent
inhibitors is
not recommended.
Hepatic impairment
Afinitor should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see
sections 4.2 and 5.2).
Vaccinations
The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).
Lactose
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicinal product.
Wound healing complications
Impaired wound healing is a class effect of rapamycin derivatives, including Afinitor. Caution should
therefore be exercised with the use of Afinitor in the peri-surgical period.
17
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore,
absorption and subsequent elimination of everolimus may be influenced by products that affect
CYP3A4 and/or PgP.
In vitro
, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor
of CYP2D6.
Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are
listed in Table 1 below.
CYP3A4 and PgP inhibitors increasing everolimus concentrations
Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by
decreasing metabolism or the efflux of everolimus from intestinal cells.
CYP3A4 and PgP inducers decreasing everolimus concentrations
Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by
increasing metabolism or the efflux of everolimus from intestinal cells.
Table 1
Effects of other active substances on everolimus
Active substance by
interaction
Interaction – Change in
Everolimus AUC/C
max
Geometric mean ratio
(observed range)
Recommendations concerning co-
administration
Potent
CYP3A4/PgP inhibitors
Ketoconazole
AUC ↑15.3-fold
(range 11.2-22.5)
C
max
↑4.1-fold
(range 2.6-7.0)
Concomitant treatment of Afinitor
and potent inhibitors is not
recommended.
Itraconazole,
posaconazole,
voriconazole
Telithromycin,
clarithromycin
Nefazodone
Ritonavir, atazanavir,
saquinavir, darunavir,
indinavir, nelfinavir
Not studied. Large increase in
everolimus concentration is
expected.
18
Moderate CYP3A4/PgP inhibitors
Erythromycin
AUC ↑4.4-fold
(range 2.0-12.6)
C
max
↑2.0-fold
(range 0.9-3.5)
Use caution when co-administration
of moderate CYP3A4 inhibitors or
PgP inhibitors cannot be avoided. If
patients require co-administration of a
moderate CYP3A4 or PgP inhibitor,
dose reduction to 5 mg daily or 5 mg
every other day may be considered.
However, there are no clinical data
with this dose adjustment. Due to
between subject variability the
recommended dose adjustments may
not be optimal in all individuals,
therefore close monitoring of side
effects is recommended.
Verapamil
AUC ↑3.5-fold
(range 2.2-6.3)
C
max
↑2.3-fold
(range1.3-3.8)
Ciclosporin oral
AUC ↑2.7-fold
(range 1.5-4.7)
C
max
↑1.8-fold
(range 1.3-2.6)
Fluconazole
Diltiazem
Not studied. Increased exposure
expected.
Amprenavir,
fosamprenavir
Not studied. Increased exposure
expected.
Grapefruit juice or other
food affecting
CYP3A4/PgP
Not studied. Increased exposure
expected (the effect varies
widely).
Combination should be avoided.
Potent
CYP3A4 inducers
Rifampicin
AUC ↓63%
(range 0-80%)
C ↓58%
Avoid the use of concomitant potent
CYP3A4 inducers. If patients require
co-administration of a potent
CYP3A4 inducer, an Afinitor dose
increase from 10 mg daily up to
20 mg daily should be considered
using 5 mg increments applied on
Day 4 and 8 following start of the
inducer. This dose of Afinitor is
predicted to adjust the AUC to the
range observed without inducers.
However, there are no clinical data
with this dose adjustment. If
treatment with the inducer is
discontinued, the Afinitor dose should
be returned to the dose used prior to
initiation of the co-administration.
max
(range 10-70%)
Corticosteroids
(e.g. dexamethasone,
prednisone,
prednisolone)
Not studied. Decreased exposure
expected.
Carbamazepine,
phenobarbital, phenytoin
Not studied. Decreased exposure
expected.
Efavirenz, nevirapine
Not studied. Decreased exposure
expected.
St John’s Wort
(
Hypericum perforatum
)
Not studied. Large decrease in
exposure expected.
Preparations containing St John’s
Wort should not be used during
treatment with everolimus
Agents whose plasma concentration may be altered by everolimus
Based on
in vitro
results, the systemic concentrations obtained after oral daily doses of 10 mg make
inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the
gut cannot be excluded; hence everolimus may affect the bioavailability of co-administered drugs
which are CYP3A4 and/or PgP substrates.
19
Vaccinations
The immune response to vaccination may be affected and, therefore, vaccination may be less effective
during treatment with Afinitor. The use of live vaccines should be avoided during treatment with
Afinitor (see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps,
rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid
vaccines.
Fertility
Based on non-clinical findings, male fertility may be compromised by treatment with everolimus (see
section 5.3).
Women of childbearing potential
Women of childbearing potential must use an effective method of contraception while receiving
everolimus.
Pregnancy
There are no or limited amount of data from the use of everolimus in pregnant women. Studies in
animals have shown reproductive toxicity effects (see section 5.3).
Everolimus is not recommended during pregnancy and in women of childbearing potential not using
contraception.
Lactation
It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its
metabolites readily pass into the milk. Therefore, women taking everolimus should not breast-feed.
No studies on the effects on the ability to drive and use machines have been performed. Patients
should be advised to be cautious when driving or using machines if they experience fatigue during
treatment with Afinitor.
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a
randomised phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 patients
were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients was 61 years (range
27-85).
The most frequent grade 3-4 adverse reactions (incidence ≥2%) were lymphocytes decreased, glucose
increased, haemoglobin decreased, phosphate decreased, cholesterol increased, infections, stomatitis,
fatigue, and pneumonitis.
The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving
Afinitor and 60 days (range 21-295) for those receiving placebo. The rates of adverse reactions
resulting in permanent discontinuation were 7% and 0% for the Afinitor and placebo treatment groups,
respectively. Most adverse reactions were grade 1 or 2 in severity.
Table 2 shows the incidence of adverse reactions reported for patients receiving everolimus
10 mg/day. Adverse reactions in Table 2 are listed according to MedDRA system organ class and
frequency category. Frequency categories are defined using 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, adverse reactions are presented in order of decreasing seriousness.
20
Table 2
Adverse reactions
Infections and infestations
Very common Infections
a
Blood and lymphatic system disorders
Very common Lymphocytes decreased
b
, haemoglobin decreased
b
, platelets decreased
b
, neutrophils
decreased
b
Immune system disorders
Not known Hypersensitivity
Metabolism and nutrition disorders
Very common Glucose increased
b
, cholesterol increased
b
, triglycerides increased
b
, phosphate
decreased
b
, anorexia
Common Dehydration
Uncommon New-onset diabetes mellitus
Psychiatric disorders
Common Insomnia
Nervous system disorders
Very common Abnormal taste
Common
Headache
Eye disorders
Common Conjunctivitis, eyelid oedema
Cardiac disorders
Uncommon Congestive cardiac failure
Vascular disorders
Common Hypertension
Not known Haemorrhage
Respiratory, thoracic and mediastinal disorders
Very common Pneumonitis
c
, dyspnoea, epistaxis, cough
Common Haemoptysis
Gastrointestinal disorders
Very common Stomatitis
d
, diarrhoea, mucosal inflammation, vomiting, nausea
Common Dry mouth, abdominal pain, dysphagia, dyspepsia
Hepatobiliary disorders
Very common Alanine aminotransferase increased
b
, aspartate aminotransferase increased
b
Common Bilirubin increased
b
Skin and subcutaneous tissue disorders
Very common Rash, dry skin, pruritus
Common Palmar-plantar erythrodysaesthesia syndrome, erythema, skin exfoliation, nail
disorder, acneiform dermatitis, onychoclasis
Uncommon Angioedema
Renal and urinary disorders
Very common Creatinine increased
b
General disorders and administration site conditions
Very common Fatigue, asthenia, peripheral oedema
Common
Chest pain, pyrexia
Uncommon
Impaired wound healing
Investigations
C
omm
Weight decreased
a
Includes all events within the ‘infections and infestations’ system organ class (such as
pneumonia, sepsis, and opportunistic infections [e.g. aspergillosis and candidiasis (see also
section 4.4)])
b
Frequency based on determination of abnormal laboratory value (as part of routine laboratory
assessment)
c
Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar
haemorrhage, pulmonary toxicity, and alveolitis
d
Includes stomatitis and aphthous stomatitis, and mouth and tongue ulceration
21
on
Information from further clinical studies
In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation,
including fatal outcome. Reactivation of infection is an expected event during periods of
immunosuppression.
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been
given with acceptable acute tolerability. General supportive measures should be initiated in all cases of
overdose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protein kinase inhibitors, ATC code: L01XE10
Mechanism of action
Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-
threonine kinase, the activity of which is known to be upregulated in a number of human cancers.
Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR
complex-1 (mTORC1) activity.
Inhibition of the mTORC1 signalling pathway interferes with the
translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1)
and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the
cell cycle, angiogenesis and glycolysis. Everolimus reduces levels of vascular endothelial growth
factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the
growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated
smooth muscle cells and has been shown to reduce glycolysis in solid tumours
in vitro
and
in vivo
.
Clinical efficacy and safety
A phase III, international, multicentre, randomised, double-blind study comparing everolimus
10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with
metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI
(vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or
both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted.
Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic
score (favourable-
vs.
intermediate-
vs.
poor-risk groups) and prior anticancer therapy (1
vs.
2 prior
VEGFR-TKIs).
Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid
Tumours) and assessed via a blinded, independent central review, was the primary endpoint.
Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related
symptoms, and quality of life. After documented radiological progression, patients could be unblinded
by the investigator: those randomised to placebo were then able to receive open-label everolimus
10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the
time of the second interim analysis as the primary endpoint had been met.
In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139).
Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88%
Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]).
22
Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a
statistically significant 67% reduction in the risk of progression or death (see Table 3 and Figure 1).
Table 3
Progression-free survival results
Population
n
Afinitor
n=277
Placebo
n=139
Hazard ratio
(95%CI)
p-value
Median progression-free
survival (months) (95% CI)
Primary analysis
All (blinded independent
central review)
416
4.9
(4.0-5.5)
1.9
(1.8-1.9)
0.33
(0.25-0.43)
<0.0001
a
Supportive/sensitivity analyses
All (local review by
investigator)
416
5.5
(4.6-5.8)
1.9
(1.8-2.2)
0.32
(0.25-0.41)
<0.0001
a
MSKCC prognostic score (blinded independent central review)
Favourable risk
120
5.8
(4.0-7.4)
1.9
(1.9-2.8)
0.31
(0.19-0.50)
<0.0001
Intermediate risk
235
4.5
(3.8-5.5)
1.8
(1.8-1.9)
0.32
(0.22-0.44)
<0.0001
Poor risk
61
3.6
(1.9-4.6)
1.8
(1.8-3.6)
0.44
(0.22-0.85)
0.007
a
Stratified log-rank test
Figure 1 KaplanMeier progression-free survival curves
Censoring Times
Everolimus (n/N = 155/277)
Placebo (n/N = 111/139)
Hazard Ratio = 0.33
95% CI [0.25, 0.43]
Kaplan-Meier medians
Everolimus: 4.90 months
Placebo: 1.87 months
Logrank p value = <0.0001
Time (months)
No. of patients still at risk
Time (months)
Afinitor
Placebo
Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.
23
Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while
none were observed in patients receiving placebo. Therefore, the progression-free survival advantage
primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor
treatment group).
No statistically significant treatment-related difference in overall survival was noted (hazard
ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following
disease progression for patients allocated to placebo confounded the detection of any treatment-related
difference in overall survival.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Afinitor in all subsets of the paediatric population in renal cell carcinoma
(see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
In patients with advanced solid tumours, peak everolimus concentrations (C
max
) are reached at a
median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions
or with a light fat-free snack. C
max
is dose-proportional between 5 and 10 mg. Everolimus is a substrate
and moderate inhibitor of PgP.
Food effect
:
In healthy subjects, high fat meals reduced systemic exposure to Afinitor 10 mg (as measured by
AUC) by 22% and the peak plasma concentration C
max
by 54%. Light fat meals reduced AUC by 32%
and C
max
by 42%. Food, however, had no apparent effect on the post absorption phase concentration-
time profile.
Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to
5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is
confined to plasma of cancer patients given Afinitor 10 mg/day. Plasma protein binding is
approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In
patients with advanced solid tumours, V
d
was 191 l for the apparent central compartment and 517 l for
the apparent peripheral compartment.
Metabolism
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main
circulating component in human blood. Six main metabolites of everolimus have been detected in
human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products,
and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal
species used in toxicity studies, and showed approximately 100 times less activity than everolimus
itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological
activity.
Elimination
Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h.
The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available
from the studies in transplant patients. Following the administration of a single dose of radiolabelled
everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces,
while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
24
Steady-state pharmacokinetics
After administration of everolimus in patients with advanced solid tumours, steady-state AUC
0-τ
was
dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two
weeks. C
max
is dose-proportional between 5 and 10 mg. t
max
occurs at 1 to 2 hours post-dose. There
was a significant correlation between AUC
0-τ
and pre-dose trough concentration at steady-state.
Special populations
Hepatic impairment
The average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh class B)
was twice that found in 8 subjects with normal hepatic function. AUC was positively correlated with
serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated
with serum albumin concentration. The impact of severe hepatic impairment (Child-Pugh class C) on
the pharmacokinetics of everolimus has not been assessed (see sections 4.2 and 4.4).
Renal impairment
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant
influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant
renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of
everolimus in transplant patients.
Elderly patients
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age
(27-85 years) on oral clearance of everolimus was detected.
Ethnicity
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.
Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in
black transplant patients.
5.3 Preclinical safety data
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits.
The major target organs were male and female reproductive systems (testicular tubular degeneration,
reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased
alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in
monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular
anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of
age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of
background lesions). There was no indication of kidney toxicity in monkeys or minipigs.
Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats,
coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal
tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at
systemic exposure levels within the range of therapeutic exposure or above, with the exception of the
findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm
motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is
within the range of therapeutic exposure and which caused a reduction in male fertility. There was
evidence of reversibility. Female fertility was not affected, but everolimus crossed the placenta and
was toxic to the foetus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below
the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of
skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits,
embryotoxicity was evident in an increase in late resorptions.
25
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or
mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic
potential in mice and rats up to the highest doses, corresponding respectively to 4.3 and 0.2 times the
estimated clinical exposure.
6.
6.1 List of excipients
Butylated hydroxytoluene (E321)
Magnesium stearate
Lactose monohydrate
Hypromellose
Crospovidone type A
Lactose anhydrous
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/polyamide/aluminium/PVC blister containing 10 tablets.
Packs containing 10, 30, 60 or 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
26
8.
EU/1/09/538/004
EU/1/09/538/005
EU/1/09/538/006
EU/1/09/538/008
9.
03.08.2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
27
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Novartis Pharma GmbH
Roonstrasse 25
D-90429 Nuremberg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 8.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.3 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities.
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached.
•
At the request of the EMEA.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Afinitor 5 mg tablets
Everolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg everolimus.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
10 tablets
30 tablets
60 tablets
90 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
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/09/538/007
10 tablets
EU/1/09/538/001
30 tablets
EU/1/09/538/003
90 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Afinitor 5 mg
33
EU/1/09/538/002
60 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Afinitor 5 mg tablets
Everolimus
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Afinitor 10 mg tablets
Everolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg everolimus.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
10 tablets
30 tablets
60 tablets
90 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
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
35
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/09/538/008
10 tablets
EU/1/09/538/004
30 tablets
EU/1/09/538/006
90 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Afinitor 10 mg
36
EU/1/09/538/005
60 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Afinitor 10 mg tablets
Everolimus
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
Afinitor 5 mg tablets
Afinitor 10 mg tablets
Everolimus
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
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.
In this leaflet
:
1.
What Afinitor is and what it is used for
2.
Before you take Afinitor
3.
How to take Afinitor
4.
How to store Afinitor
6.
Further information
1.
WHAT AFINITOR IS AND WHAT IT IS USED FOR
Afinitor is an anticancer medicine containing the active substance everolimus. Everolimus reduces the
blood supply to the tumour and slows down the growth and spread of cancer cells.
Afinitor is used to treat advanced kidney cancer (advanced renal cell carcinoma), where other
treatments (so-called “VEGF-targeted therapy”) have not helped stop your disease.
2.
BEFORE YOU TAKE AFINITOR
Afinitor will only be prescribed for you by a doctor with experience in cancer treatment. Follow all the
doctor’s instructions carefully. They may differ from the general information contained in this leaflet.
If you have any questions about Afinitor or why it has been prescribed for you, ask your doctor.
Do not take Afinitor
−
if you are allergic
(hypersensitive) to everolimus, to related substances such as sirolimus or
temsirolimus, or to any of the other ingredients of Afinitor (listed in section 6 ‘What Afinitor
contains’).
If you think you may be allergic, ask your doctor for advice.
Take special care with Afinitor
Please
tell your doctor before taking Afinitor
:
−
if you have any problems with your liver or if you have ever had any disease which may have
affected your liver. If this is the case, your doctor may need to prescribe a different dose of
Afinitor.
−
if you have diabetes (high level of sugar in your blood). Afinitor may increase blood sugar
levels and worsen diabetes mellitus. This may result in the need for insulin and/or oral
antidiabetic agent therapy. Tell your doctor if you experience any excessive thirst or increased
frequency of urination.
−
if you need to receive a vaccine while taking Afinitor.
−
if you have high cholesterol. Afinitor may elevate cholesterol and/or other blood fats.
39
-
Keep this leaflet. You may need to read it again.
5.
Possible side effects
−
if you have had recent major surgery, or if you still have an unhealed wound following surgery.
Afinitor may increase the risk of problems with wound healing.
−
if you have an infection. It may be necessary to treat your infection before starting Afinitor.
−
if you have previously had hepatitis B, because this may be reactivated during treatment with
Afinitor (see section 4 Possible side effects).
Afinitor may also:
−
weaken your immune system. Therefore, you may be at risk of getting an infection while you
are taking Afinitor.
−
cause shortness of breath, cough and fever.
Tell your doctor
if you experience these symptoms.
Afinitor is not to be used in children or adolescents (age below 18 years).
You will have regular blood tests during treatment. These will check the amount of blood cells (white
blood cells, red blood cells and platelets) in your body to see if Afinitor is having an unwanted effect
on these cells. Blood tests will also be carried out to check your kidney function (level of creatinine)
and liver function (level of transaminases) and your blood sugar and cholesterol levels. This is because
these can also be affected by Afinitor.
Taking other medicines
Afinitor may affect the way some other medicines work. If you are taking other medicines at the same
time as Afinitor, your doctor may need to change the dose of Afinitor or the other medicines.
Please tell your doctor or pharmacist
if you are taking, have recently taken or before you start any
other medicines, including medicines obtained without a prescription. In particular, tell your doctor if
you are taking medicines containing any of the following active substances:
The following may increase the risk of side effects with Afinitor:
−
ketoconazole, itraconazole, voriconazole, or fluconazole and other antifungals used to treat
fungal infections.
−
clarithromycin, telithromycin or erythromycin, antibiotics used to treat bacterial infections.
−
ritonavir, efavirenz or nevirapine, used to treat HIV infection/AIDS.
−
verapamil or diltiazem, used to treat heart conditions or high blood pressure.
The following may reduce the effectiveness of Afinitor:
−
rifampicin, used to treat tuberculosis (TB).
−
St. John’s wort (
Hypericum perforatum
), a herbal product used to treat depression and other
conditions.
−
phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to stop seizures or fits.
These medicines should be avoided during your treatment with Afinitor. If you are taking any of them,
your doctor may switch you to a different medicine, or may change your dose of Afinitor.
Taking Afinitor with food and drink
You should take Afinitor at the same time every day, consistently either with or without food. Avoid
grapefruit and grapefruit juice while you are on Afinitor.
Pregnancy and breast-feeding
Afinitor could harm an unborn baby or a breast-fed baby.
Afinitor is not recommended during pregnancy. Tell your doctor if you are pregnant or think that you
may be pregnant. Your doctor will discuss with you whether you should take Afinitor during your
pregnancy.
40
Women who could potentially become pregnant should use effective contraception during treatment
with Afinitor. If, despite these measures, you think you may have become pregnant, ask your doctor
for advice
before
taking any more Afinitor.
You should not breast-feed during treatment with Afinitor. Tell your doctor if you are breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Male fertility
Afinitor may affect male fertility. Talk to your doctor if you may wish to father a child.
Driving and using machines
If you feel unusually tired (fatigue is a very common side effect), take special care when driving or
using machines.
Important information about some of the ingredients of Afinitor
Afinitor contains lactose (milk sugar). If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE AFINITOR
Always take Afinitor exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is 10 mg, taken once a day. Your doctor will tell you how many tablets of Afinitor to
take.
If you have liver problems, your doctor may start you on a lower dose of Afinitor (5 mg per day).
If you experience certain side effects (see section 4) while you are taking Afinitor, your doctor may
lower your dose or stop treatment, either for a short time or permanently.
Take Afinitor once a day, at about the same time every day, consistently either with or without food.
Swallow the tablet(s) whole with a glass of water. Do not chew or crush the tablets.
If you take more Afinitor than you should
−
If you have taken too much Afinitor, or if someone else accidentally takes your tablets, see a
doctor or go to a hospital immediately. Urgent treatment may be necessary.
−
Take the carton and this leaflet, so that the doctor knows what has been taken.
If you forget to take Afinitor
If you miss a dose, take your next dose as scheduled. Do not take a double dose to make up for the
forgotten tablets.
If you stop taking Afinitor
Do not stop taking Afinitor unless your doctor tells you to.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
41
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Afinitor can cause side effects, although not everybody gets them.
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.
Tell your doctor immediately
if you experience any
serious side effects:
−
Lung or breathing problems
(very common): new or worsening symptoms, such as cough or
shortness of breath.
−
Infections
(very common) including chest infections, serious infections that are commonly
known as blood poisoning and infections that are usually only seen in patients with organ
transplants such as fungal infections, with symptoms such as fever, chills or other signs of
infection.
−
Swelling mainly of the face and throat, causing difficulty in breathing (symptoms of an allergic
reaction).
You might need urgent treatment.
Other side effects of Afinitor include:
Very common side effects
−
Mouth ulcers
, pain or discomfort or open sores.
Tell your doctor
if you experience any of
these, since you might need treatment with a mouthwash or gel. Some mouthwashes and gels
can make ulcers worse, so always check with your doctor before trying anything.
−
Swelling of your arms, hands, feet, ankles or other parts of your body (signs of oedema)
−
Feeling sick (nausea), vomiting, diarrhoea, loss of appetite, disturbance of sense of taste
−
Feeling weak or tired
−
Rash, dry skin, itching
−
Nose bleeds
−
Decreased number of white cells in the blood, which may increase your risk of infection
−
Decreased haemoglobin
−
Decreased number of certain cells in the blood that help the blood to clot
−
High blood sugar
−
High cholesterol and other blood fats
Common side effects
−
Rash and pain on the palms of your hands or soles of your feet (hand-foot syndrome), skin
exfoliation, breaking of your nails and nail discolouration, redness of the skin, pimples and/or
acne
−
Dry mouth
−
Fever
−
Weight loss
−
Heartburn or indigestion (dyspepsia), difficulty in swallowing, chest pain, stomach ache
−
Headache, trouble sleeping (insomnia)
−
High blood pressure (hypertension)
−
Dehydration
−
Discharge from the eye with itching, redness and swelling
−
Coughing up blood
42
Uncommon side effects
−
Loss of sense of taste
−
Symptoms of heart failure such as breathlessness, difficulty breathing when lying down,
swelling of the feet or legs
−
New onset of diabetes mellitus
−
Problems with wound healing
Hepatitis B reactivation has been observed in some patients taking Afinitor. Tell your doctor if you
experience symptoms of hepatitis B during treatment with Afinitor. The first symptoms may include
fever, skin rash, joint pain and inflammation. Other symptoms may include fatigue, loss of appetite,
nausea, jaundice (yellowing of the skin), and pain in the upper right abdomen. Pale stools or dark
urine may also be signs of hepatitis.
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.
5.
HOW TO STORE AFINITOR
−
Keep out of the reach and sight of children.
−
Do not use Afinitor after the expiry date which is stated on the carton and blister foil. The
expiry date refers to the last day of that month.
−
Store in the original package in order to protect from light and moisture.
−
Do not use any pack that is damaged or shows signs of tampering.
6.
FURTHER INFORMATION
What Afinitor contains
−
The active substance is everolimus.
−
Each tablet of Afinitor 5 mg contains 5 mg everolimus.
−
Each tablet of Afinitor 10 mg contains 10 mg everolimus.
−
The other ingredients are butylated hydroxytoluene (E321), magnesium stearate, lactose
monohydrate, hypromellose, crospovidone type A and lactose anhydrous.
What Afinitor looks like and contents of the pack
Afinitor 5 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with “5” on
one side and “NVR” on the other.
Afinitor 10 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with
“UHE” on one side and “NVR” on the other.
Afinitor is available in packs containing 10, 30, 60 or 90 tablets. Not all pack sizes or strengths may be
marketed in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
43
Manufacturer
Novartis Pharma GmbH
Roonstrasse 25
D-90429 Nuremberg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
România
Novartis Pharma S.A.S.
él: +33 1 55 47 66 00
Novartis Pharma Servi
Tel: +40 21 31299 01
ces Inc.
T
Novartis Ireland Limite
el: +353 1 260 12 55
d
Novartis Pharma Servic
Tel: +386 1 300 75 50
es Inc.
T
Ísland
Vistor hf.
ími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
el: +421 2 5542 5439
44
Ireland
Slovenija
S
T
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
45
Source: European Medicines Agency
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