ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Nexavar 200 mg film-coated tablets
2.
2.1 General description
Each film-coated tablet contains 200 mg of sorafenib (as tosylate).
2.2 Qualitative and quantitative composition
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Red, round, biconvex film-coated tablets, debossed with Bayer cross on one side and "200" on the
other side.
4.
Hepatocellular carcinoma
Nexavar is indicated for the treatment of hepatocellular carcinoma (see section 5.1).
Renal cell carcinoma
Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed
prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.
Nexavar treatment should be supervised by a physician experienced in the use of anticancer therapies.
Posology
The recommended dose of Nexavar
in adults is 400 mg (two tablets of 200 mg) twice daily (equivalent
to a total daily dose of 800 mg). It is recommended that sorafenib should be administered without food
or with a low or moderate fat meal. If the patient intends to have a high-fat meal, sorafenib tablets
should be taken at least 1 hour before or 2 hours after the meal. The tablets should be swallowed with
a glass of water.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
Posology adjustments
Management of suspected adverse drug reactions may require temporary interruption or dose
reduction of Nexavar therapy. When dose reduction is necessary, the Nexavar dose should be reduced
to two tablets of 200 mg once daily (see section 4.4).
2
Paediatric population
The safety and efficacy of Nexavar in children and adolescents aged < 18 years have not yet been
established. No data are available.
Elderly population
No dose adjustment is required in the elderly (patients above 65 years of age).
Renal impairment
No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is
available in patients requiring dialysis (see section 5.2).
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
Hepatic impairment
No dose adjustment is required in patients with Child Pugh A and B (mild to moderate) hepatic
impairment. No data is available on patients with Child Pugh C (severe) hepatic impairment (see
section 4.4 and 5.2).
Method of administration
For oral use.
Hypersensitivity to the active substance or to any of the excipients.
Dermatological toxicities
Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common
adverse drug reactions with Nexavar. Rash and hand-foot skin reaction are usually CTC (Common
Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with
Nexavar. Management of dermatological toxicities may include topical therapies for symptomatic
relief, temporary treatment interruption and/or dose modification of Nexavar, or in severe or persistent
cases, permanent discontinuation of Nexavar (see section 4.8).
Hypertension
An increased incidence of arterial hypertension was observed in Nexavar-treated patients.
Hypertension was usually mild to moderate, occurred early in the course of treatment, and was
amenable to management with standard antihypertensive therapy. Blood pressure should be monitored
regularly and treated, if required, in accordance with standard medical practice. In cases of severe or
persistent hypertension, or hypertensive crisis despite institution of antihypertensive therapy,
permanent discontinuation of Nexavar should be considered (see section 4.8).
Haemorrhage
An increased risk of bleeding may occur following Nexavar administration. If any bleeding event
necessitates medical intervention it is recommended that permanent discontinuation of Nexavar should
be considered (see section 4.8).
3
Cardiac ischaemia and/or infarction
In a randomised, placebo-controlled, double-blind study (study 1, see section 5.1) the incidence of
treatment-emergent cardiac ischaemia/infarction events was higher in the Nexavar group (2.9 %)
compared with the placebo group (0.4 %). In study 3 (see section 5.1), the incidence of treatment-
emergent cardiac ischaemia/infarction events was 2.7 % in Nexavar patients compared with 1.3 % in
the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were
excluded from these studies. Temporary or permanent discontinuation of Nexavar should be
considered in patients who develop cardiac ischaemia and/or infarction (see section 4.8).
QT interval prolongation
Nexavar has been shown to prolong the QT/QTc interval (see section 5.1), which may lead to an
increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may
develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated
with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic
medicines or other medicinal products that lead to QT prolongation, and those with electrolyte
disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. When using Nexavar in
these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium,
potassium, calcium) should be considered.
Gastrointestinal perforation
Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients
taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumor.
Sorafenib therapy should be discontinued (see section 4.8).
Hepatic impairment
No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib is
mainly eliminated via the hepatic route exposure might be increased in patients with severe hepatic
impairment (see section 4.2 and 5.2).
Warfarin co-administration
Infrequent bleeding events or elevations in the International Normalised Ratio (INR) have been
reported in some patients taking warfarin while on Nexavar therapy. Patients taking concomitant
warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR or
clinical bleeding episodes (see sections 4.5 and 4.8).
Wound healing complications
No formal studies of the effect of sorafenib on wound healing have been conducted. Temporary
interruption of Nexavar therapy is recommended for precautionary reasons in patients undergoing
major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of
therapy following major surgical intervention. Therefore, the decision to resume Nexavar therapy
following a major surgical intervention should be based on clinical judgement of adequate wound
healing.
Elderly population
The experience with the use of Nexavar in elderly patients is limited. Cases of renal failure have been
reported. Monitoring of renal function should be considered.
Renal cell carcinoma
High Risk Patients, according to MSKCC (Memorial Sloan Kettering Cancer Center) prognostic
group, were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section
5.1); and benefit-risk in these patients has not been evaluated.
4
Drug-drug interactions
Caution is recommended when administering Nexavar with compounds that are
metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (see
section 4.5).
Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.5).
Co-administration of neomycin or other antibiotics that cause major ecological disturbances of the
gastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see section 4.5). The
risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment
course with antibiotics.
A randomized controlled trial comparing safety and efficacy of carboplatin and paclitaxel plus or
minus sorafenib in chemonaive patients with Stage IIIB-IV Non-Small Cell Lung Cancer (NSCLC)
was stopped early, when the independent Data Monitoring Committee concluded that the study would
not meet its primary endpoint of improved overall survival. Safety events were generally consistent
with those previously reported. However, higher mortality was observed in the subset of patients with
squamous cell carcinoma of the lung treated with sorafenib and carboplatin and paclitaxel versus those
treated with carboplatin and paclitaxel alone (HR 1.81, 95% CI 1.19-2.74). No definitive cause was
identified for this finding.
Inducers of metabolic enzymes
Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in
an average 37 % reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or
glucuronidation (e.g. Hypericum perforatum also known as St. John’s wort, phenytoin,
carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and
thus decrease sorafenib concentrations.
CYP3A4 inhibitors
Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male
volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that
clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.
CYP2B6, CYP2C8 and CYP2C9 substrates
Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9
in vitro
with similar potency. However, in
clinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily with
cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in a
clinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of
400 mg twice daily may not be an
in vivo
inhibitor of CYP2B6 or CYP2C8.
Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not result
in changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant
in vivo
inhibition of CYP2C9 by sorafenib may be expected to be low. However, patients taking warfarin or
phenprocoumon should have their INR checked regularly (see section 4.4).
CYP3A4, CYP2D6 and CYP2C19
substrates
Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are
substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure
of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome
P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of
these enzymes are unlikely.
UGT1A1 and UGT1A9 substrates
In vitro
, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this
finding is unknown (see below and section 4.4).
5
In vitro studies of CYP enzyme induction
CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with
sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.
P-gp-substrates
In vitro
, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased
plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant
treatment with sorafenib.
Combination with other anti-neoplastic agents
In clinical studies Nexavar has been administered with a variety of other anti-neoplastic agents at their
commonly used dosing regimens including gemcitabine, oxaliplatin, paclitaxel, carboplatin,
capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no clinically
relevant effect on the pharmacokinetics of gemcitabine, oxaliplatin or cyclophosphamide.
Paclitaxel/carboplatin
Administration of paclitaxel (225 mg/m
2
) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice
daily), administered with a 3-day break in sorafenib dosing (two days prior to and on the day of
paclitaxel/carboplatin administration), resulted in no significant effect on the pharmacokinetics of
paclitaxel.
Co-administration of paclitaxel (225 mg/m
2
, once every 3 weeks) and carboplatin (AUC=6) with
sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in
sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel
exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered
with sorafenib with a 3-day break in sorafenib dosing (two days prior to and on the day of
paclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib and
paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.
Capecitabine
Co-administration of capecitabine (750-1050 mg/m
2
twice daily, Days 1-14 every 21 days) and
sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no
significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52%
increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine
and 5-FU exposure when co-administered with sorafenib is unknown.
Doxorubicin/Irinotecan
Concomitant treatment with Nexavar resulted in a 21 % increase in the AUC of doxorubicin. When
administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1
pathway, there was a 67 - 120 % increase in the AUC of SN-38 and a 26 - 42 % increase in the AUC
of irinotecan. The clinical significance of these findings is unknown (see section 4.4).
Docetaxel
Docetaxel (75 or 100 mg/m
2
administered once every 21 days) when co-administered with sorafenib
(200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with
a 3-day break in dosing around administration of docetaxel) resulted in a 36-80 % increase in
docetaxel AUC and a 16-32 % increase in docetaxel C
max
. Caution is recommended when sorafenib is
co-administered with docetaxel (see section 4.4).
6
Combination with other agents
Neomycin
Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal
flora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and
Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day
regimen of neomycin the average exposure to sorafenib decreased by 54%. Effects of other antibiotics
have not been studied, but will likely depend on their ability to interfere with microorganisms with
glucuronidase activity.
Results from animal studies further indicate that sorafenib can impair male and female fertility (see
section 5.3).
There are no data on the use of sorafenib in pregnant women. Studies in animals have shown
reproductive toxicity including malformations (see section 5.3). In rats, sorafenib and its metabolites
were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the
foetus. Nexavar should not be used during pregnancy unless clearly necessary, after careful
consideration of the needs of the mother and the risk to the foetus.
Women of childbearing potential must use effective contraception during treatment.
It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its
metabolites were excreted in milk. Because sorafenib could harm infant growth and development (see
section 5.3), women must not breast-feed during sorafenib treatment.
No studies on the effects on the ability to drive and use machines have been performed. There is no
evidence that Nexavar affects the ability to drive or to operate machinery.
The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot syndrome
(corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA).
7
Table 1: Adverse reactions reported in at least 5
% of patients in any treatment group – study
11213 in renal cell carcinoma (see study 1 in section 5.1).
Nexavar N=451
Placebo N=451
System organ
class
Preferred term
all grades grade 3 grade 4 all grades grade 3 grade 4
Metabolism and
nutrition
disorders
anorexia
9%
<1%
0%
5%
<1%
0%
Nervous system
disorders
headache
6%
0%
0%
3%
0%
0%
Vascular
disorders
hypertension
12%
2%
<1%
1%
<1%
0%
flushing
6%
0%
0%
2%
0%
0%
Gastrointestinal
disorders
diarrhoea
38%
2%
0%
9%
<1%
0%
nausea
16%
<1%
0%
12%
<1%
0%
vomiting
10%
<1%
0%
6%
<1%
0%
constipation
6%
0%
0%
3%
0%
0%
Skin and
subcutaneous
tissue disorders
rash
28%
<1%
0%
9%
<1%
0%
alopecia
25%
<1%
0%
3%
0%
0%
hand foot
syndrome**
19%
4%
0%
3%
0%
0%
pruritus
17%
<1%
0%
4%
0%
0%
erythema
15%
0%
0%
4%
0%
0%
dry skin
11%
0%
0%
2%
0%
0%
skin exfoliation
7%
<1%
0%
2%
0%
0%
Musculoskeletal
and connective
tissue disorders
arthralgia
6%
<1%
0%
3%
0%
0%
pain in extremity
6%
<1%
0%
2%
0%
0%
General
disorders and
administration
site conditions
fatigue
15%
2%
0%
11%
<1%
0%
asthenia
9%
<1%
0%
4%
<1%
0%
8
Table 2: Adverse reactions reported in at least 5
% of patients in any treatment group – study
100554 in hepatocellular carcinoma (see study 3 in section 5.1).
Nexavar N= 297
Placebo N= 302
System organ
class
Preferred
term
all grades grade 3 grade 4 all grades grade 3 grade 4
Metabolism and
nutrition
disorders
anorexia
11%
<1%
0%
3%
<1%
0%
gastrointestinal
disorders
diarrhoea
39%
8%
0%
11%
2%
0%
nausea
11%
<1%
0%
8%
1%
0%
abdominal
pain
7%
2%
0%
3%
<1%
0%
vomiting
5%
1%
0%
3%
<1%
0%
Skin and
subcutaneous
tissue disorders
hand foot
syndrome**
18%
7%
0%
2%
0%
0%
alopecia
14%
0%
0%
2%
0%
0%
rash
11%
<1%
0%
8%
0%
0%
pruritus
8%
0%
0%
7%
<1%
0%
dry skin
8%
0%
0%
4%
0%
0%
General
disorders and
administration
site conditions
fatigue
17%
2%
<1%
13%
3%
<1%
asthenia
6%
1%
<1%
2%
<1%
0%
Investigations
weight
decreased
9%
2%
0%
<1%
0%
0%
Respiratory,
thoracic and
mediastinal
disorders
hoarseness
5%
0%
0%
<1%
0%
0%
Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below in
Table 3, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very
common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000,
<1/1,000), not known (cannot be estimated from the data available).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
9
Table 3: All adverse reactions reported in patients in multiple clinical trials or through post-
marketing use
System organ
class
Very common
≥ 1/10
Common
≥1/100, <1/10
Uncommon
≥1/1,000, <1/100
Rare
≥1/10,000,
<1/1,000
Not known
(cannot be
estimated from
the data
available)
Infections and
infestations
folliculitis
infection
Blood and
lymphatic
system
disorders
lymphopenia
leucopenia
neutropenia
anaemia
thrombocytopenia
Immune
system
disorders
hypersensitivity
reactions
(including skin
reactions and
urticaria)
angioedema
Endocrine
disorders
hypothyroidism
hyperthyroidism
hyponatraemia
dehydration
Metabolism
and nutrition
disorders
hypo-
phosphataemia
anorexia
Psychiatric
disorders
depression
Nervous
system
disorders
peripheral sensory
neuropathy
reversible
posterior
leukoencephalo-
pathy*
Ear and
labyrinth
disorders
tinnitus
Cardiac
disorders
congestive heart
failure*
myocardial
ischaemia and
infarction*
QT prolongation
Vascular
disorders
haemorrhage
(inc.
gastrointestinal
*, respiratory
tract* and
cerebral
haemorrhage*)
hypertension
hypertensive
crisis*
rhinorrhoea
interstitial lung
disease-like events
(pneumonitis,
radiation
pneumonitis, acute
respiratory
distress, etc.)
Respiratory,
thoracic and
mediastinal
disorders
hoarseness
10
System organ
class
Very common
≥ 1/10
Common
≥1/100, <1/10
Uncommon
≥1/1,000, <1/100
Rare
≥1/10,000,
<1/1,000
Not known
(cannot be
estimated from
the data
available)
Gastro-
intestinal
disorders
diarrhoea
nausea
vomiting
constipation
stomatitis
(including dry
mouth and
glossodynia)
dyspepsia
dysphagia
gastro oesophageal
reflux disease
pancreatitis
gastritis
gastrointestinal
perforations*
Hepatobiliary
disorders
increase in
bilirubin and
jaundice
cholecystitis
cholangitis
drug induced
hepatitis***
Skin and
subcutaneous
tissue
disorders
rash
alopecia
hand foot
syndrome**
erythema
pruritus
dry skin
dermatitis
exfoliative
acne
skin desquamation
eczema
erythema
multiforme
keratoacanthoma/
squamous cell
cancer of the skin
Stevens-Johnson
syndrome
radiation recall
dermatitis
Musculo-
skeletal and
connective
tissue
disorders
arthralgia
myalgia
Renal and
urinary
disorders
renal failure
Reproductive
system and
breast
disorders
erectile
dysfunction
gynaecomastia
General
disorders and
administration
site conditions
fatigue
pain (including
mouth,
abdominal,
bone, tumour
pain and
headache)
asthenia
fever
influenza like
illness
Investigations
increased
amylase
increased lipase
weight decreased
transient increase
in transaminases
transient increase
in blood alkaline
phosphatase,
INR abnormal,
prothrombin level
abnormal
* The adverse reactions may have a life-threatening or fatal outcome.
** Hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA.
*** Life-threatening and fatal cases have been observed.
11
Further information on selected adverse drug reactions
Congestive Heart Failure
: In company sponsored clinical trials congestive heart failure was reported
as an adverse event in 1.9% of patients treated with sorafenib (N= 2276). In study 11213 (RCC)
adverse events consistent with congestive heart failure were reported in 1.7% of patients treated with
sorafenib and 0.7% receiving placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib
and 1.1% receiving placebo were reported with these events.
Laboratory test abnormalities
Increased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevations
occurred in 11 % and 9 % of patients in the Nexavar group in study 1 (RCC) and study 3 (HCC),
respectively, compared to 7 % and 9 % of patients in the placebo group. CTCAE Grade 3 or 4 amylase
elevations were reported in 1 % and 2 % of patients in the Nexavar group in study 1 and study 3,
respectively, compared to 3 % of patients in each placebo group. Clinical pancreatitis was reported in
2 of 451 Nexavar treated patients (CTCAE Grade 4) in study 1, 1 of 297 Nexavar treated patients in
study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.
Hypophosphataemia was a very common laboratory finding, observed in 45 % and 35 % of Nexavar
treated patients compared to 12 % and 11 % of placebo patients in study 1 and study 3, respectively.
CTCAE Grade 3 hypophosphataemia (1 – 2 mg/dl) in study 1 occurred in 13 % of Nexavar treated
patients and 3 % of patients in the placebo group, in study 3 in 11 % of Nexavar treated patients and
2 % of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia
(< 1 mg/dl) reported in either Nexavar or placebo patients in study 1, and 1 case in the placebo group
in study 3. The aetiology of hypophosphataemia associated with Nexavar is not known.
CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥ 5 % of Nexavar treated patients included
lymphopenia and neutropenia.
There is no specific treatment for Nexavar overdose. The highest dose of sorafenib studied clinically is
800 mg twice daily. The adverse events observed at this dose were primarily diarrhoea and
dermatological events. In the event of suspected overdose Nexavar should be withheld and supportive
care instituted where necessary.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protein kinase inhibitors, ATC code: L01XE05
Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-
angiogenic properties
in vitro
and
in vivo
.
Mechanism of action and pharmacodynamic effects
Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation
in vitro
. Sorafenib inhibits
tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a
reduction of tumour angiogenesis. Sorafenib inhibits the activity of targets present in the tumour cell
(CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2,
VEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas
c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.
12
Clinical efficacy:
The clinical safety and efficacy of Nexavar have been studied in patients with hepatocellular
carcinoma (HCC) and in patients with advanced renal cell carcinoma (RCC).
Hepatocellular carcinoma
Study 3 (study 100554) was a Phase III, international, multi-centre, randomised, double blind,
placebo-controlled study in 602 patients with hepatocellular carcinoma. Demographics and baseline
disease characteristics were comparable between the Nexavar and the placebo group with regard to
ECOG status (status 0: 54 % vs. 54 %; status 1: 38 % vs. 39 %; status 2: 8 % vs. 7 %), TNM stage
(stage I: <1 % vs. <1 %; stage II: 10.4 % vs. 8.3 %; stage III: 37.8 % vs. 43.6 %; stage IV: 50.8 %
vs. 46.9 %), and BCLC stage (stage B: 18.1 % vs. 16.8 %; stage C: 81.6 % vs. 83.2 %; stage D: < 1 %
vs. 0 %).
The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy
boundary. This OS analysis showed a statistically significant advantage for Nexavar over placebo for
OS (HR: 0.69, p = 0.00058, see Table 4).
There are limited data from this study in patients with Child Pugh B liver impairment and only one
patient with Child Pugh C had been included.
Table 4: Efficacy Results from study 3 (study 100554) in hepatocellular carcinoma
Efficacy Parameter
Nexavar
(N=299)
Placebo
(N=303)
P-value
HR
(95% CI)
Overall Survival (OS)
[median, weeks (95%
CI)]
46.3
(40.9, 57.9)
34.4
(29.4, 39.4)
0.00058*
0.69
(0.55, 0.87)
Time to Progression
(TTP) [median, weeks
(95% CI)]**
24.0
(18.0, 30.0)
12.3
(11.7, 17.1)
0.000007
0.58
(0.45, 0.74)
CI=Confidence interval, HR=Hazard ratio (Nexavar over placebo)
*statistically significant as the p-value was below the prespecified O’Brien Fleming stopping
boundary of 0.0077
**independent radiological review
A second Phase III, international, multi-centre, randomised, double blind, placebo-controlled study
(Study 4, 11849) evaluated the clinical benefit of Nexavar in 226 patients with advanced
hepatocellular carcinoma. This study, conducted in China, Korea and Taiwan confirmed the findings
of Study 3 with respect to the favourable benefit-risk profile of Nexavar (HR (OS): 0.68, p = 0.01414).
In the prespecified stratification factors (ECOG status, presence or absence of macroscopic vascular
invasion and/or extrahepatic tumour spread) of both Study 3 and 4, the hazard ratio consistently
favoured Nexavar over placebo. Exploratory subgroup analyses suggested that patients with distant
metastases at baseline derived a less pronounced treatment effect.
Renal cell carcinoma
The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC) were
investigated in two clinical studies:
13
Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlled
study in 903 patients. Only patients with clear cell renal carcinoma and low and intermediate risk
MSKCC (Memorial Sloan Kettering Cancer Center) were included. The primary endpoints were
overall survival and progression-free survival (PFS).
Approximately half of the patients had an ECOG performance status of 0, and half of the patients were
in the low risk MSKCC prognostic group.
PFS was evaluated by blinded independent radiological review using RECIST criteria. The PFS
analysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patients
randomised to Nexavar compared to 84 days for placebo patients (HR = 0.44; 95 % CI: 0.35 - 0.55;
p < 0.000001). Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the
treatment effect size.
An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903
patients. The nominal alpha value for this analysis was 0.0094. The median survival was 19.3 months
for patients randomised to Nexavar compared to 15.9 months for placebo patients (HR = 0.77; 95 %
CI: 0.63 - 0.95; p = 0.015). At the time of this analysis, about 200 patients had crossed-over to
sorafenib from the placebo group.
Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies, including RCC.
Patients with stable disease on therapy with Nexavar were randomised to placebo or continued
Nexavar therapy. Progression-free survival in patients with RCC was significantly longer in the
Nexavar group (163 days) than in the placebo group (41 days) (p = 0.0001, HR = 0.29).
QT interval prolongation
In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pre-
treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximum
concentration of sorafenib, QTcB was prolonged by 4 ±19 msec and QTcF by 9 ±18 msec, as
compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the
post-treatment ECG monitoring (see section 4.4).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies, in all
subsets of the paediatric population, in kidney and renal pelvis carcinoma (excluding nephroblastoma,
nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and
rhabdoid tumour of the kidney) and liver and intrahepatic bile duct carcinoma (excluding
hepatoblastoma).
5.2 Pharmacokinetic properties
Absorption and distribution
After administration of Nexavar tablets the mean relative bioavailability is 38 - 49 % when compared
to an oral solution. The absolute bioavailability is not known. Following oral administration sorafenib
reaches peak plasma concentrations in approximately 3 hours. When given with a high-fat meal
sorafenib absorption was reduced by 30 % compared to administration in the fasted state.
Mean C
max
and AUC increased less than proportionally beyond doses of 400 mg administered twice
daily.
In vitro
binding of sorafenib to human plasma proteins is 99.5 %.
Multiple dosing of Nexavar for 7 days resulted in a 2.5- to 7-fold accumulation compared to single
dose administration. Steady state plasma sorafenib concentrations are achieved within 7 days, with a
peak to trough ratio of mean concentrations of less than 2.
14
Metabolism and elimination
The elimination half-life of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised
primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as
glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal
tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug. Co-
administration of neomycin has been shown to interfere with this process, decreasing the mean
bioavailability of sorafenib by 54%.
Sorafenib accounts for approximately 70 - 85 % of the circulating analytes in plasma at steady state.
Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The
main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows
in vitro
potency
similar to that of sorafenib. This metabolite comprises approximately 9 - 16 % of circulating analytes
at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96 % of the
dose was recovered within 14 days, with 77 % of the dose excreted in faeces, and 19 % of the dose
excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51 % of the
dose, was found in faeces but not in urine, indicating that biliary excretion of unchanged drug might
contribute to the elimination of sorafenib.
Pharmacokinetics in special populations
Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age
(up to 65 years) gender or body weight.
Paediatric population
No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.
Race
There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian
subjects.
Renal impairment
In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or
moderate renal impairment compared to the exposures in patients with normal renal function. In a
clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between
sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe
renal impairment. No data is available in patients requiring dialysis.
Hepatic impairment
In hepatocellular carcinoma patients with mild or moderate hepatic impairment, exposure values were
comparable and within the range of exposures observed in patients without hepatic impairment. There
are no data for patients with Child-Pugh C (severe) hepatic impairment. Sorafenib is mainly eliminated
via the liver, and exposure might be increased in this patient population.
5.3 Preclinical safety data
The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at
exposures below the anticipated clinical exposure (based on AUC comparisons).
After repeated dosing to young and growing dogs effects on bone and teeth were observed at
exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral
growth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of the
dentin composition. Similar effects were not induced in adult dogs.
15
The standard program of genotoxicity studies was conducted and positive results were obtained as an
increase in structural chromosomal aberrations in an
in vitro
mammalian cell assay (Chinese hamster
ovary) for clastogenicity in the presence of metabolic activation was seen. Sorafenib was not
genotoxic in the Ames test or in the
in vivo
mouse micronucleus assay. One intermediate in the
manufacturing process, which is also present in the final drug substance (< 0.15 %), was positive for
mutagenesis in an
in vitro
bacterial cell assay (Ames test). Furthermore, the sorafenib batch tested in
the standard genotoxicity battery included 0.34 % PAPE.
Carcinogenicity studies have not been conducted with sorafenib.
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility.
An adverse effect on male and female fertility can however be expected because repeat-dose studies in
animals have shown changes in male and female reproductive organs at exposures below the
anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and
retardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed central
necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular
degeneration in the testes and oligospermia.
Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at
exposures below the clinical exposure. Observed effects included decreases in maternal and foetal
body weights, an increased number of foetal resorptions and an increased number of external and
visceral malformations.
6.
6.1 List of excipients
Core:
Croscarmellose sodium
Microcrystalline cellulose
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Coating:
Hypromellose
Macrogol (3350)
Titanium dioxide (E 171)
Ferric oxide red (E 172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
112 (4 x 28) tablets in transparent (PP/Aluminium) blister packs.
16
6.6 Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/06/342/001
9.
19 July 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
17
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
18
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Bayer Schering Pharma AG
51368 Leverkusen
Germany
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.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 9.9 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 10.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by
the CHMP.
An updated Risk Management Plan, as per the CHMP Guideline on Risk Management Systems for
medicinal products for human use, should be submitted at the same time as the PSURs, within 60 days
of an important (Pharmacovigilance or Risk minimisation) milestone being reached or when the results
of a study becoming available or at the request of the Competent authority.
19
ANNEX III
LABELLING AND PACKAGE LEAFLET
20
A. LABELLING
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
{OUTER CARTON}
1.
Nexavar 200 mg film-coated tablets
Sorafenib
2.
STATEMENT OF ACTIVE SUBSTANCE
Each tablet contains 200 mg of sorafenib (as tosylate).
3.
LIST OF EXCIPIENTS
4.
112 film-coated tablets
5.
METHOD AND ROUTE 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
Do not store above 25 °C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
22
Bayer Schering Pharma AG
13342 Berlin
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/06/342/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Nexavar 200 mg
23
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Nexavar 200 mg tablets
Sorafenib
2.
Bayer (Logo)
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
MON
TUE
WED
THU
FRI
SAT
SUN
24
B. PACKAGE LEAFLET
25
PACKAGE LEAFLET: INFORMATION FOR THE USER
Nexavar 200 mg film-coated tablets
sorafenib
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. 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 Nexavar is and what it is used for
2.
Before you take Nexavar
3.
How to take Nexavar
4.
How to store Nexavar
6.
Further information
1.
WHAT NEXAVAR IS AND WHAT IT IS USED FOR
Nexavar is used to treat liver cancer (
hepatocellular carcinoma
).
Nexavar is also used to treat kidney cancer (
advanced renal cell carcinoma
) at an advanced stage
when standard therapy has not helped to stop your disease or is considered unsuitable.
Nexavar is a so-called
multikinase inhibitor.
It works by slowing down the rate of growth of cancer
cells and cutting off the blood supply that keeps cancer cells growing.
2.
BEFORE YOU TAKE NEXAVAR
Do not take Nexavar
-
If you are allergic
(hypersensitive) to sorafenib or any of the other ingredients of Nexavar. The
ingredients are listed at the end of this leaflet.
Take special care with Nexavar
-
If you experience skin problems.
Nexavar can cause rashes and skin reactions, especially on the
hands and feet. These can usually be treated by your doctor. If not, your doctor may interrupt
treatment or stop it altogether.
-
If you have high blood pressure.
Nexavar can raise blood pressure, and your doctor will usually
monitor your blood pressure and may give you a medicine to treat your high blood pressure.
-
If you get any bleeding problems, or are taking warfarin or phenprocoumon.
Treatment with
Nexavar may lead to a higher risk of bleeding. If you are taking warfarin or phenprocoumon,
medicines which thin the blood to prevent blood clots, there may be a greater risk of bleeding.
-
If you get chest pain or heart problems
. Your doctor may decide to interrupt treatment or stop it
altogether.
-
If you have a heart disorder
, such as an abnormal electrical signal called "prolongation of the
QT interval".
-
If you are going to have surgery, or if you had an operation recently
. Nexavar might affect the
way your wounds heal. You will usually be taken off Nexavar if you are having an operation.
Your doctor will decide when to start with Nexavar again.
26
5.
Possible side effects
-
If you are taking irinotecan or are given docetaxel,
which are also medicines for cancer.
Nexavar may increase the effects and, in particular, the side effects of these medicines.
-
If you are taking Neomycin or other antibiotics.
The effect of Nexavar may be decreased.
-
If you have severe liver impairment.
You may experience more severe side effects when taking
this medicine.
-
If you have poor kidney function
. Your doctor will monitor your fluid and electrolyte balance.
-
Fertility.
Nexavar may reduce fertility in both men and women. If you are concerned, talk to a
doctor.
-
Holes in the gut wall
(
gastrointestinal perforation
) may occur during treatment (see
Possible Side
Effects
, section 4). In this case your doctor will interrupt the treatment.
Tell your doctor if any of these affect you.
You may need treatment for them, or your doctor may
decide to change your dose of Nexavar, or stop treatment altogether. See also
Possible Side Effects
,
section 4.
Taking other medicines
Some medicines may affect Nexavar, or be affected by it. Tell your doctor or pharmacist if you are
taking anything in this list:
-
Rifampicin, Neomycin or other
antibiotics
-
St John’s wort, a herbal treatment for
depression
-
Phenytoin, carbamazepine or phenobarbital, treatments for
epilepsy
and other conditions
-
Dexamethasone, a
corticosteroid
used for various conditions
-
Warfarin or phenprocoumon, anticoagulants used to
prevent blood clots
-
Doxorubicin, capecitabine, docetaxel, paclitaxel and irinotecan, which are other
cancer
treatments
-
Digoxin, a treatment for mild to moderate
heart failure
Tell your doctor or pharmacist
if you are taking these or any other medicines (or have taken
anything recently) – even those not prescribed.
Pregnancy and breast-feeding
Avoid becoming pregnant while being treated with Nexavar.
If you could become pregnant use
adequate contraception during treatment. If you become pregnant while being treated with Nexavar,
immediately tell your doctor who will decide if the treatment should be continued.
You must not breast-feed your baby during Nexavar treatment
, as this medicine may interfere
with the growth and development of your baby.
Driving and using machines
There is no evidence that Nexavar will affect the ability to drive or to operate machinery.
3.
HOW TO TAKE NEXAVAR
The usual dose of Nexavar in adults is 2
x
200 mg tablets, twice daily.
This is equivalent to a daily dose of 800 mg or four tablets a day.
Swallow Nexavar tablets with a glass of water,
either without food or with a low-fat or moderate fat
meal. Do not take this medicine with high fat meals, as this may make Nexavar less effective. If you
intend to have a high fat meal take the tablets at least 1 hour before or 2 hours after the meal.
Always take Nexavar exactly as your doctor has told you to. Check with your doctor or pharmacist if
you are not sure.
It is important to take Nexavar at about the same times each day, so that there is a steady amount in the
bloodstream.
27
You will usually carry on taking Nexavar as long as you are getting clinical benefits, and not suffering
unacceptable side effects.
If you take more Nexavar than you should
Tell your doctor straight away
if you (or anyone else) have taken more than your prescribed dose.
Taking too much Nexavar makes side effects more likely or more severe, especially diarrhoea and skin
reactions. Your doctor may tell you to stop taking Nexavar.
If you forget to take Nexavar
If you have missed a dose, take it as soon as you remember. If it is nearly time for the next dose, forget
about the missed one and carry on as normal. Do not take a double dose to make up for forgotten
individual doses.
Use in children
The use of Nexavar in children below the age of 18 years has not been studied.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Nexavar can cause side effects although not everybody gets them. This medicine
may also affect the results of some blood tests.
Very common side effects
(affects more than 1 user in 10)
-
diarrhoea
-
feeling sick (
nausea
)
-
feeling weak or tired
-
pain (including mouth pain, abdominal pain, headache, bone pain, tumour pain)
-
hair loss
-
flushing
-
flushed or painful palms or soles (hand foot syndrome)
-
itching or rash
-
throwing up (
vomiting
)
-
bleeding (including bleeding in the brain, gut wall and respiratory tract;
haemorrhage
)
-
high blood pressure, or increases in blood pressure
28
Common side effects
( affects 1 to 10 users in 100)
-
flu-like illness
-
fever
-
indigestion
-
constipation
-
difficulty swallowing
-
inflamed or dry mouth, tongue pain
-
weight loss
-
loss of appetite
-
joint or muscle pain (
arthralgia
)
-
disturbed sensations in fingers and toes, including tingling or numbness
-
depression
-
erection problems (
impotence
)
-
hoarseness
-
acne
-
inflamed, dry or scaly skin that sheds
-
heart failure
-
tinnitus
-
kidney failure
Uncommon side effects
(affects 1 to 10 users in 1,000)
-
inflamed stomach lining (
gastritis
) and heartburn (
gastrooesophageal reflux disease
)
-
pain in the tummy (
abdomen
) caused by pancreatitis, inflammation of the gall bladder and/or bile
ducts
-
yellow skin or eyes (
jaundice
) caused by high levels of bile pigments (
hyperbilirubinaemia
)
-
allergic like reactions (including skin reactions and hives)
-
infections of hair follicles (
folliculitis
)
-
general infections
-
dehydration
-
enlarged breasts
-
persistent runny nose
-
breathing difficulty (
lung disease)
-
eczema
-
serious reactions of the skin and/or mucous membranes which may include painful blisters and
fever (
Stevens-Johnson syndrome
)
-
heart attack (
myocardial infarction
) or chest pain
-
underactive or overactive thyroid
-
multiple skin eruptions (
erythema multiforme
)
-
abnormally high blood pressure
-
holes in the gut wall (
gastrointestinal perforation
)
-
reversible swelling in the rear part of the brain that can be associated with headache, altered
consciousness, fits and visual symptoms including visual loss (
reversible posterior
leukoencephalopathy
)
-
benign localised skin growth
(keratoacanthoma)
/skin cancer
Rare side effects
(affects 1 to 10 users in 10,000)
-
abnormal heart rhythm
(QT prolongation)
Other side effects
(of which the frequency cannot be estimated from the available data)
- a sunburn-like rash that may occur on skin that has previously been exposed to radiotherapy and
can be severe (
radiation recall dermatitis)
29
- allergic reaction with swelling of the skin (e. g. face, tongue) that may cause difficulty in breathing
or swallowing (
angioedema
)
- inflammation of the liver, which may lead to nausea, vomiting, abdominal pain, and jaundice
(
drug induced 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 NEXAVAR
Keep out of the reach and sight of children.
Do not use the tablets after the expiry date
which is stated on the carton and on each blister after
EXP. The expiry date refers to the last day of that month.
Do not store above 25°C.
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 Nexavar contains
-
The
active
substance is sorafenib. 1 tablet contains 200 mg sorafenib (as tosylate).
-
The
other
ingredients are:
Core:
croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium laurilsulfate,
magnesium stearate.
Coating:
hypromellose, macrogol, titanium dioxide (E 171), ferric oxide red (E 172).
What Nexavar looks like and contents of the pack
Nexavar 200 mg tablets are red, round and film-coated, with the Bayer cross on one side and “200” on
the other side. They come in packs of 112: four transparent blister packs of 28 tablets each.
Marketing Authorisation Holder
Bayer Schering Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer Schering Pharma AG
51368 Leverkusen
Germany
30
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder. The list of local representatives is located at the end of this
leaflet/booklet.
België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
България
Байер България ЕООД
Тел. +359 02 81 401 01
Magyarország
Bayer Hungária Kft.
Tel.:+36-14 87-41 00
Česká republika
Bayer s.r.o.
Tel: +420 266 101 111
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Danmark
Bayer A/S
Tlf: +45-45 23 50 00
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31-(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf. +47 24 11 18 00
Eesti
Bayer OÜ
Tel: +372 655 85 65
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 46-0
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30 210 618 75 00
Polska
Bayer Sp. z o.o.
Tel.: +48-22-572 35 00
España
Química Farmacéutica Bayer S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A
Tel: +351-21-416 42 00
France
Bayer Santé
Tél: +33-(0)3 28 16 34 00
România
SC Bayer SRL
Tel.: +40 21 528 59 00
Ireland
Bayer Limited
Tel: +353 1 299 93 13
Slovenija
Bayer d. o. o.
Tel.: +386-1-58 14 400
Ísland
Icepharma hf.
Sími: +354 540 80 00
Slovenská republika
Bayer, spol. s r.o.
Tel: +421 2 59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-397 81
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358-20 785 21
Κύπρος
NOVAGEM Limited
Τηλ: +
357 22 74 77 47
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIA Bayer
Tel: +371 67 84 55 63
United Kingdom
Bayer plc
Tel: +44-(0)1 635-56 30 00
Lietuva
UAB Bayer
Tel. +370 5 23 36 868
This leaflet was last approved in {}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu.
31
Source: European Medicines Agency
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