LEVACT 2.5 MG/ML POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance: BENDAMUSTINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Levact 2.5 mg/ml powder for concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 25 mg bendamustine hydrochloride.
One vial contains 100 mg bendamustine hydrochloride.
1 ml of the concentrate contains 2.5 mg bendamustine hydrochloride when
reconstituted according to section 6.6.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion
White, microcrystalline powder

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in
patients for whom fludarabine combination chemotherapy is not appropriate.
Indolent non-Hodgkin’s lymphomas as monotherapy in patients who have
progressed during or within 6 months following treatment with rituximab or a
rituximab containing regimen.
Front line treatment of multiple myeloma (Durie-Salmon stage II with
progress or stage III) in combination with prednisone for patients older than 65

years who are not eligible for autologous stem cell transplantation and who
have clinical neuropathy at time of diagnosis precluding the use of thalidomide
or bortezomib containing treatment.

4.2

Posology and method of administration
For intravenous infusion over 30 - 60 minutes (see section 6.6).
Infusion must be administered under the supervision of a physician qualified
and experienced in the use of chemotherapeutic agents.
Poor bone marrow function is related to increased chemotherapy-induced
haematological toxicity. Treatment should not be started if leukocyte and/or
platelet values have dropped to < 3,000/µl or < 75,000/µl, respectively (see
section 4.3).
Monotherapy for chronic lymphocytic leukaemia
100 mg/m² body surface area bendamustine hydrochloride on days 1 and 2;
every 4 weeks.
Monotherapy for indolent non-Hodgkin’s lymphomas refractory to rituximab
120 mg/m² body surface area bendamustine hydrochloride on days 1 and 2;
every 3 weeks.
Multiple myeloma
120 - 150 mg/m² body surface area bendamustine hydrochloride on days 1 and
2, 60 mg/m² body surface area prednisone i.v. or per os on days 1 to 4; every 4
weeks.
Treatment should be terminated or delayed if leukocyte and/or platelet values
have dropped to < 3,000/µl or < 75,000/µl, respectively. Treatment can be
continued after leukocyte values have increased to > 4,000/µl and platelet
values to > 100,000/µl.
The leukocyte and platelet Nadir is reached after 14-20 days with regeneration
after 3-5 weeks. During therapy free intervals strict monitoring of the blood
count is recommended (see section 4.4).
In case of non-haematological toxicity dose reductions have to be based on the
worst CTC grades in the preceding cycle. A 50% dose reduction is
recommended in case of CTC grade 3 toxicity. An interruption of treatment is
recommended in case of CTC grade 4 toxicity.
If a patient requires a dose modification the individually calculated reduced
dose must be given on day 1 and 2 of the respective treatment cycle.
For preparation and administration instructions see section 6.6.

Hepatic impairment
On the basis of pharmacokinetic data, no dose adjustment is necessary in
patients with mild hepatic impairment (serum bilirubin < 1.2 mg/dl). A 30%
dose reduction is recommended in patients with moderate hepatic impairment
(serum bilirubin 1.2 - 3.0 mg/dl).
No data is available in patients with severe hepatic impairment (serum
bilirubin values of > 3.0 mg/dl) (see section 4.3).
Renal impairment
On the basis of pharmacokinetic data, no dose adjustment is necessary in
patients with a creatinine clearance of > 10 ml/min. Experience in patients
with severe renal impairment is limited.
Paediatric patients
There is no experience in children and adolescents with Levact.
Elderly patients
There is no evidence that dose adjustments are necessary in elderly patients
(see section 5.2).

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section
6.1)
During breast feeding
Severe hepatic impairment (serum bilirubin > 3.0 mg/dl)
Jaundice
Severe bone marrow suppression and severe blood count alterations (leukocyte
and/or platelet values dropped to < 3,000/µl or < 75,000/µl, respectively)
Major surgery less than 30 days before start of treatment
Infections, especially involving leukocytopenia
Yellow fever vaccination

4.4

Special warnings and precautions for use
Myelosuppression
Patients treated with bendamustine hydrochloride may experience
myelosuppression. In the event of treatment-related myelosuppression,
leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least
weekly. Prior to the initiation of the next cycle of therapy, the following
parameters are recommended: Leukocyte and/or platelet values > 4,000/µl or
> 100,000/µl, respectively.

Infections
Infection, including pneumonia and sepsis, has been reported. In rare cases,
infection has been associated with hospitalization, septic shock and death.
Patients with neutropenia and/or lymphopenia following treatment with
bendamustine hydrochloride are more susceptible to infections. Patients with
myelosuppression following bendamustine hydrochloride treatment should be
advised to contact a physician if they have symptoms or signs of infection,
including fever or respiratory symptoms.
Skin reactions
A number of skin reactions have been reported. These events have included
rash, toxic skin reactions and bullous exanthema. Some events occurred when
bendamustine hydrochloride was given in combination with other anticancer
agents, so the precise relationship is uncertain. Where skin reactions occur,
they may be progressive and increase in severity with further treatment. If skin
reactions are progressive, Levact should be withheld or discontinued. For
severe skin reactions where a relationship to bendamustine hydrochloride is
suspected, treatment should be discontinued.
Patients with cardiac disorders
During treatment with bendamustine hydrochloride the concentration of
potassium in the blood must be closely monitored and potassium supplement
must be given when K+ <3.5 mEq/l and ECG measurement must be
performed.
Nausea, vomiting
An antiemetic may be given for the symptomatic treatment of nausea and
vomiting.
Tumour lysis syndrome
Tumour lysis syndrome associated with Levact treatment has been reported in
patients in clinical trials. The onset tends to be within 48 hours of the first dose
of Levact and, without intervention, may lead to acute renal failure and death.
Preventive measures include adequate volume status and close monitoring of
blood chemistry, particularly potassium and uric acid levels. The use of
allopurinol during the first one to two weeks of Levact therapy can be
considered but not necessarily as standard. However, there have been a few
cases of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis reported
when bendamustine and allopurinol were administered concomitantly.
Anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred commonly in
clinical trials. Symptoms are generally mild and include fever, chills, pruritus
and rash. In rare instances severe anaphylactic and anaphylactoid reactions
have occurred. Patients must be asked about symptoms suggestive of infusion
reactions after their first cycle of therapy. Measures to prevent severe
reactions, including antihistamines, antipyretics and corticosteroids must be
considered in subsequent cycles in patients who have previously experienced
infusion reactions.

Patients who experienced Grade 3 or worse allergic-type reactions were
typically not re-challenged.
Contraception
Bendamustine hydrochloride is teratogenic and mutagenic.
Women should not become pregnant during treatment. Male patients should
not father a child during and up to 6 months after treatment. They should seek
advice about sperm conservation prior to treatment with bendamustine
hydrochloride because of possible irreversible infertility.
Extravasation
An extravasal injection should be stopped immediately. The needle should be
removed after a short aspiration. Thereafter the affected area of tissue should
be cooled. The arm should be elevated. Additional treatments like the use of
corticosteroids are not of clear benefit.

4.5

Interaction with other medicinal products and other forms of interaction
No in-vivo interaction studies have been performed.
When Levact is combined with myelosuppressive agents, the effect of Levact
and/or the co-administered medicinal products on the bone marrow may be
potentiated. Any treatment reducing the patient’s performance status or
impairing bone marrow function can increase the toxicity of Levact.
Combination of Levact with cyclosporine or tacrolimus may result in
excessive immunosuppression with risk of lymphoproliferation.
Cytostatics can reduce antibody formation following live-virus vaccination
and increase the risk of infection which may lead to fatal outcome. This risk is
increased in subjects who are already immunosuppressed by their underlying
disease.
Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme
(see section 5.2). Therefore, the potential for interaction with CYP1A2
inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine exists.

4.6

Pregnancy and lactation
Pregnancy
There are insufficient data from the use of Levact in pregnant women. In
nonclinical studies bendamustine hydrochloride was embryo-/fetolethal,
teratogenic and genotoxic (see section 5.3). During pregnancy Levact should

not be used unless clearly necessary. The mother should be informed about the
risk to the foetus. If treatment with Levact is absolutely necessary during
pregnancy or if pregnancy occurs during treatment, the patient should be
informed about the risks for the unborn child and be monitored carefully. The
possibility of genetic counselling should be considered.
Women of childbearing potential/contraception
Women of childbearing potential must use effective methods of contraception
both before and during Levact therapy.
Men being treated with Levact are advised not to father a child during and for
up to 6 months following cessation of treatment. Advice on conservation of
sperm should be sought prior to treatment because of the possibility of
irreversible infertility due to therapy with Levact.
Breast feeding
It is not known whether bendamustine passes into the breast milk, therefore,
Levact is contraindicated during breast feeding (see section 4.3). Breast
feeding must be discontinued during treatment with Levact.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. However, ataxia, peripheral neuropathy and somnolence have been
reported during treatment with Levact (see section 4.8). Patients should be
instructed that if they experience these symptoms they should avoid potentially
hazardous tasks such as driving and using machines.

4.8

Undesirable effects
The most common adverse reactions with bendamustine hydrochloride are
hematological adverse reactions (leukopenia, thrombopenia), dermatologic
toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal
symptoms (nausea, vomiting).
The table below reflects the data obtained with bendamustine hydrochloride in
clinical trials.

Uncommon
1/1,000 to
<1/100

Rare
1/10,000 to
<1/1, 000

Very rare
<1/10, 000

Sepsis





Infection NOS*

Neoplasms
benign, malignant
Blood and
lymphatic system
disorders

Common
1/100 to <1/10



Infections and
infestations

Very common
1/10

Pneumonia
primary
atypical



MedDRA system
organ class

Tumour lysis
syndrome
Leukopenia NOS*,
Thrombocytopenia

Haemorrhage,
Anaemia,
Neutropenia

Haemolysis

Immune system
disorders

Hypersensitivity
NOS*

Anaphylactic
reaction,
Anaphylactoid
reaction

Anaphylactic
shock

Nervous system
disorders

Insomnia

Somnolence,
Aphonia

Dysgeusia,
Paraesthesia,
Peripheral
sensory
neuropathy,
Anticholinergic
syndrome,
Neurological
disorders,
Ataxia,
Encephalitis

Cardiac disorders

Cardiac
dysfunction,
such as
palpitations,
angina pectoris,
Arrhythmia

Vascular
disorders

Hypotension,
Hypertension

Respiratory,
thoracic and
mediastinal
disorders

Pulmonary
dysfunction

Pulmonary
fibrosis

Diarrhoea,
Constipation,
Stomatitis

Haemorrhagic
oesophagitis,
Gastrointestinal
haemorrhage

Gastrointestinal
disorders

Nausea, Vomiting

Skin and
subcutaneous
tissue disorders

Alopecia,
Skin disorders
NOS*

Reproductive
system and breast
disorders

Amenorrhea

Pericardial
effusion

Tachycardia,
Myocardial
infarction,
Cardiac failure

Acute
circulatory
failure

Phlebitis

Erythema,
Dermatitis,
Pruritus,
Macular-papular
rash,
Hyperhidrosis
Infertility

Not known
(cannot be
estimated
from the
available
data)

General disorders
and
administration
site conditions

Mucosal
inflammation,
Fatigue,
Pyrexia

Pain, Chills,
Dehydration,
Anorexia

Investigations

Haemoglobin
decrease,
Creatinine increase,
Urea increase

Uncommon
1/1,000 to
<1/100

AST increase,
ALT increase,
Alkaline
phosphatase
increase,
Bilirubin increase,
Hypokalemia



Common
1/100 to <1/10

Rare
1/10,000 to
<1/1, 000



Very common
1/10





MedDRA system
organ class

Very rare
<1/10, 000

Multi organ
failure

NOS = Not otherwise specified
A small number of cases of Stevens-Johnson Syndrome and Toxic Epidermal
Necrolysis have been reported in patients using bendamustine in combination
with allopurinol or in combination with allopurinol and rituximab.
The CD4/CD8 ratio may be reduced. A reduction of the lymphocyte count was
seen. In immuno-suppressed patients, the risk of infection (e.g. with herpes
zoster) may be increased.
There have been isolated reports of necrosis after accidental extra-vascular
administration and toxic epidermal necrolysis, tumour lysis syndrome and
anaphylaxis.
There are reports of secondary tumours, including myelodysplastic syndrome,
myeloproliferative disorders, acute myeloid leukaemia and bronchial
carcinoma. The association with Levact therapy has not been determined.

4.9

Overdose
After application of a 30 min infusion of Levact once every 3 weeks the
maximum tolerated dose (MTD) was 280 mg/m². Cardiac events of CTC grade
2 which were compatible with ischaemic ECG changes occurred which were
regarded as dose limiting.
In a subsequent study with a 30 min infusion of Levact at day 1 and 2 every 3
weeks the MTD was found to be 180 mg/m2. The dose limiting toxicity was
grade 4 thrombocytopenia. Cardiac toxicity was not dose limiting with this
schedule.

Not known
(cannot be
estimated
from the
available
data)

Counter measures
There is no specific antidote. Bone marrow transplantation and transfusions
(platelets, concentrated erythrocytes) may be made or haematological growth
factors may be given as effective countermeasures to control haematological
side effects.
Bendamustine hydrochloride and its metabolites are dialyzable to a small
extent.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents,
ATC code: L01AA09
Bendamustine hydrochloride is an alkylating antitumour agent with unique
activity. The antineoplastic and cytocidal effect of bendamustine
hydrochloride is based essentially on a cross-linking of DNA single and
double strands by alkylation. As a result, DNA matrix functions and DNA
synthesis and repair are impaired. The antitumour effect of bendamustine
hydrochloride
has
been
demonstrated
by
several
in vitro studies in different human tumour cell lines (breast cancer, non-small
cell and small cell lung cancer, ovarian carcinoma and different leukaemia)
and in vivo in different experimental tumour models with tumours of mouse,
rat and human origin (melanoma, breast cancer, sarcoma, lymphoma,
leukaemia and small cell lung cancer).
Bendamustine hydrochloride showed an activity profile in human tumour cell
lines different to that of other alkylating agents. The active substance revealed
no or very low cross-resistance in human tumour cell lines with different
resistance mechanisms at least in part due to a comparatively persistent DNA
interaction. Additionally, it was shown in clinical studies that there is no
complete cross-resistance of bendamustine with anthracyclines, alkylating
agents or rituximab. However, the number of assessed patients is small.
Chronic lymphocytic leukaemia
The indication for use in chronic lymphocytic leukaemia is supported by a
single open label study comparing bendamustine with chlorambucil. In the
prospective, multi-centre, randomised study, 319 previously untreated patients
with chronic lymphocytic leukaemia stage Binet B or C requiring therapy were
included. The first line therapy with bendamustine hydrochloride 100 mg/m²
i.v. on days 1 and 2 (BEN) was compared to treatment with chlorambucil
0.8 mg/kg days 1 and 15 (CLB) for 6 cycles in both arms. Patients received
allopurinol in order to prevent tumour lysis syndrome.
Patients with BEN had a significantly longer median progression free survival
than patients with CLB treatment (21.5 versus 8.3 months, p < 0.0001 in the

latest follow-up). Overall survival was not statistically significantly different
(median not reached). The median duration of remission was 19 months with
BEN and 6 months with CLB treatment (p < 0.0001). The safety evaluation in
both treatment arms did not reveal any unexpected undesirable effects in
nature and frequency. The dose of BEN was reduced in 34% of the patients.
Treatment with BEN was discontinued in 3.9% of patients due to allergic
reactions.
Indolent non-Hodgkin’s lymphomas
The indication for indolent non-Hodgkin’s lymphomas relied on two
uncontrolled phase II trials.
In the pivotal prospective, multi-centre, open study 100 patients with indolent
B-cell non-Hodgkin´s lymphomas refractory to rituximab mono- or
combination therapy were treated with BEN single agent. Patients had
received a median of 3 previous chemotherapy or biological therapy courses.
The median number of previous rituximab-containing courses was 2. The
patients had had no response or there had been progression within 6 months
after rituximab treatment. The dose of BEN was 120 mg/m² i.v. on days 1 and
2 planned for at least 6 cycles. Duration of treatment depended on response (6
cycles planned). The overall response rate was 75% including 17% complete
(CR and CRu) and 58% partial response as assessed by independent review
committee. The median duration of remission was 40 weeks. BEN was
generally well tolerated when given in this dose and schedule.
The indication is further supported by another prospective, multi-centre, open
study including 77 patients. The patient population was more heterogeneous
including: indolent or transformed B-cell non-Hodgkin’s lymphomas
refractory to rituximab mono- or combination therapy. The patients had no
response or there had been progression within 6 months or had had an
untoward reaction to prior rituximab treatment. Patients had received a median
of 3 previous chemotherapy or biological therapy courses. The median number
of previous rituximab-containing courses had been 2. The overall response rate
was 76% with a median duration of response of 5 months (29 [95% CI 22.1,
43.1] weeks).
Multiple myeloma
In a prospective, multi-centre, randomised, open study 131 patients with
advanced multiple myeloma (Durie-Salmon stage II with progression or stage
III) were included. The first line therapy with bendamustine hydrochloride in
combination with prednisone (BP) was compared to treatment with melphalan
and prednisone (MP). Neither transplant-eligibility nor the presence of specific
co-morbidities played a role for inclusion into the trial. The dose was
bendamustine hydrochloride 150 mg/m² i.v. on days 1 and 2 or melphalan 15
mg/m² i.v. on day 1 each in combination with prednisone. Duration of
treatment depended on response and averaged 6.8 cycles in the BP and 8.7
cycles in the MP group.
Patients with BP treatment had a longer median progression free survival than
patients with MP (15 [95% CI 12-21] versus 12 [95% CI 10-14] months)
(p=0.0566). The median time to treatment failure was 14 months with BP and
9 months with MP treatment. The duration of remission was 18 months with

BP and 12 months with MP treatment. The difference in overall survival was
not significantly different (35 months BP versus 33 months MP). Tolerability
in both treatment arms was in line with the known safety profile of the
respective medicinal products with significantly more dose reductions in the
BP arm.

5.2

Pharmacokinetic properties
Distribution
The elimination half-life t1/2ß after 30 min i.v. infusion of 120 mg/m2 area to 12
subjects was 28.2 minutes.
Following 30 min i.v. infusion the central volume of distribution was 19.3 l.
Under steady-state conditions following i.v. bolus injection the volume of
distribution was 15.8-20.5 l.
More than 95% of the substance is bound to plasma proteins (primarily
albumin).
Metabolism
A major route of clearance of bendamustine is the hydrolysis to monohydroxyand dihydroxy-bendamustine. Formation of N-desmethyl-bendamustine and
gamma-hydroxy-bendamustine by hepatic metabolism involves cytochrome
P450 (CYP) 1A2 isoenzyme. Another major route of bendamustine
metabolism involves conjugation with glutathione.
In-vitro bendamustine does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6,
CYP 2E1 or CYP 3A4.
Elimination
The mean total clearance after 30 min i.v. infusion of 120 mg/m2 body surface
area to 12 subjects was 639.4 ml/minute. About 20% of the administered dose
was recovered in urine within 24 hours. Amounts excreted in urine were in the
order monohydroxy-bendamustine > bendamustine > dihydroxy-bendamustine
> oxidised metabolite > N-desmethyl bendamustine. In the bile, primarily
polar metabolites are eliminated.
Hepatic impairment
In patients with 30 - 70% tumour infestation of the liver and mild hepatic
impairment (serum bilirubin < 1.2 mg/dl) the pharmacokinetic behaviour was
not changed. There was no significant difference to patients with normal liver
and kidney function with respect to Cmax, tmax, AUC, t1/2ß , volume of
distribution and clearance. AUC and total body clearance of bendamustine
correlate inversely with serum bilirubin.
Renal impairment
In patients with creatinine clearance > 10 ml/min including dialysis dependent
patients, no significant difference to patients with normal liver and kidney

function was observed with respect to Cmax, tmax, AUC, t1/2ß, volume of
distribution and clearance.
Elderly subjects
Subjects up to 84 years of age were included in pharmacokinetic studies.
Higher age does not influence the pharmacokinetics of bendamustine.

5.3

Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at
exposure levels similar to clinical exposure levels and with possible relevance
to clinical use were as follows:
Histological investigations in dogs showed macroscopic visible hyperaemia of
the mucosa and haemorrhagia in the gastrointestinal tract. Microscopic
investigations showed extensive changes of the lymphatic tissue indicating an
immunosuppression and tubular changes of kidneys and testis, as well as
atrophic, necrotic changes of the prostate epithelium.
Animal studies showed that bendamustine is embryotoxic and teratogenic.
Bendamustine induces aberrations of the chromosomes and is mutagenic in
vivo as well as in vitro. In long-term studies in female mice bendamustine is
carcinogenic.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products
except those mentioned in section 6.6.

6.3

Shelf life
3 years.
The powder should be reconstituted immediately after opening of the vial.
The reconstituted concentrate should be diluted immediately with 0.9%
sodium chloride solution.
Solution for infusion
After reconstitution and dilution, chemical and physical stability has been
demonstrated for 3.5 hours at 25 ºC/ 60% RH and 2 days at 2 ºC to 8 ºC in
polyethylene bags.
From a microbiological point of view, the solution should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user.

6.4

Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted or diluted medicinal product, see
section 6.3.

6.5

Nature and contents of container

Type I brown glass vials of 25/26 ml or 60 ml with rubber stopper and an aluminium
flip-off cap.
25/26 ml-vials contain 25 mg bendamustine hydrochloride and are supplied in packs
of 5, 10 and 20 vials.
60 ml-vials contain 100 mg bendamustine hydrochloride and are supplied in packs of
5 vials.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

When handling Levact, inhalation, skin contact or contact with mucous
membranes should be avoided (wear gloves and protective clothes!).
Contaminated body parts should be carefully rinsed with water and soap, the
eyes should be rinsed with physiological saline solution. If possible it is
recommended to work on special safety workbenches (laminar flow) with
liquid-impermeable, absorbent disposable foil. Pregnant personnel should be
excluded from handling cytostatics.
The powder for concentrate for solution for infusion has to be reconstituted
with water for injection, diluted with sodium chloride 9 mg/ml (0.9%) solution
for injection and then administered by intravenous infusion. Aseptic technique
is to be used.
1. Reconstitution
Reconstitute each vial of Levact containing 25 mg bendamustine
hydrochloride in 10 ml water for injection by shaking;
Reconstitute each vial of Levact containing 100 mg bendamustine
hydrochloride in 40 ml water for injection by shaking.
The reconstituted concentrate contains 2.5 mg bendamustine hydrochloride per
ml and appears as a clear colourless solution.
2. Dilution
As soon as a clear solution is obtained (usually after 5-10 minutes) dilute the
total recommended dose of Levact immediately with 0.9% NaCl solution to
produce a final volume of about 500 ml.
Levact must be diluted with 0.9% NaCl solution and not with any other
injectable solution.
3. Administration
The solution is administered by intravenous infusion over 30-60 min.
The vials are for single use only.
Any unused product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Astellas Pharma GmbH
Postfach 50 01 66
80971 München
Germany
Phone: +49 (0)89 45 44 01
Fax: +49 (0)89 45 44 13 29

8

MARKETING AUTHORISATION NUMBER(S)
PL 14427/0026

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/08/2010

10

DATE OF REVISION OF THE TEXT
16/07/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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