ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
NeuroBloc 5000 U/ml solution for injection.
2.
Each ml contains 5000 U Botulinum Toxin Type B.
Each 0.5 ml vial contains 2500 U Botulinum Toxin Type B.
Each 1.0 ml vial contains 5000 U Botulinum Toxin Type B.
Each 2.0 ml vial contains 10,000 U Botulinum Toxin Type B.
Produced in
Clostridium botulinum
Serotype B (Bean Strain) cells.
For a full list of excipients, see section 6.1.
3.
Solution for injection.
Clear and colourless to light yellow solution.
4.
NeuroBloc is indicated for the treatment of cervical dystonia (torticollis)..
See section 5.1 for data on efficacy in patients responsive / resistant to Botulinum Toxin Type A.
NeuroBloc should only be administered by a physician who is familiar with and experience in the
treatment of cervical dystonia and in the use of botulinum toxins.
Restricted to hospital use only.
Posology
The initial dose is 10,000 U and should be divided between the two to four most affected muscles.Data
from clinical studies suggest that efficacy is dose dependent, but these trials, because they were not
powered for a comparison, do not show a significant difference between 5000 U and 10,000 U. Therefore
an initial dose of 5000 U may also be considered, but a dose of 10,000 U may increase the likelihood of
clinical benefit.
Injections should be repeated as required to maintain good function and minimise pain. In long term
clinical studies, the average dosing frequency was approximately every 12 weeks, however this may vary
between subjects and a proportion of patients maintained a significant improvement relative to baseline
for 16 weeks or longer. The dosing frequency should therefore be adapted based on the clinical assessment
/response of an individual patient.
For patients with reduced muscle mass the dose should be adjusted according to individual patient need.
2
The potency of this medicinal product is expressed in NeuroBloc 5000 U/ml. These units are not
interchangeable with the units used to express the potency of other botulinum toxin preparations (see
section 4.4).
Elderly population
No dose adjustment is required in the elderly population ≥ 65 years of age.
Renal and hepatic impairment
Studies have not been carried out in patients with hepatic or renal impairment. However, the
pharmacological characteristics do not indicate any need to adjust the dose.
Paediatric population
The safety and efficacy of NeuroBloc in children aged 0-18 years have not yet been established. No data
are available. NeuroBloc is not recommended in children aged 0-18 years until further data become
available.
Method of administration
NeuroBloc must only be administered by intramuscular injection.
The initial dose of 10,000 U should be divided between the two to four most affected muscles.
To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium
chloride 9 mg/ml (0.9%) solution for injection and the solution used immediately. For instructions on
dilution of the product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Individuals with other known neuromuscular diseases (e.g. amyotrophic lateral sclerosis or peripheral
neuropathy) or known neuromuscular junctional disorders (e.g. myasthenia gravis or Lambert-Eaton
syndrome) must not be given NeuroBloc.
NeuroBloc is recommended for intramuscular administration only. Particular caution should be paid to
ensure that it is not injected into a blood vessel.
Seroconversion
As with many biological/biotechnology proteins used as therapeutic agents, repeated administration of
NeuroBloc may be associated with development of antibodies to Botulinum Toxin Type B in some
patients. Immunogenicity data from three long term clinical studies indicate that approximately one third
of patients develop antibodies, as determined by the mouse neutralisation / mouse protection assay
dependent on duration of exposure (see section 5.1).
An investigation into the consequence of seroconversion showed that the presence of antibodies was not
synonymous with a loss of clinical response, and did not have an impact on the overall safety profile.
However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation /
mouse protection assay is uncertain.
Caution should be used in patients with bleeding disorders or receiving anticoagulant therapy.
3
Spread of toxin effect
Neuromuscular effects related to spread of toxin, distant from the site of administration have been
reported (see section 4.8).
Pre-Existing neuromuscular disorders
Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with
neuromuscular disorders may be at increased risk of clinically significant effects including severe
dysphagia and respiratory compromise from typical doses of NeuroBloc (see section 4.3).
Dysphagia and breathing difficulties
There have been spontaneous reports of dysphagia, aspiration pneumonia and/or potentially fatal
respiratory disease, after treatment with botulinum toxin type A/B.
Patients with underlying neuromuscular disorders including swallowing disorders are at increased risk of
these adverse reactions. In patients with neuromuscular disorders or history of dysphagia and aspiration,
botulinum toxins should be used under close medical supervision and only if the benefit clearly outweighs
the risk.
Following NeuroBloc treatment, all patients and caregivers should be advised to seek medical attention for
respiratory difficulties, choking or any new or worsening dysphagia.
Dysphagia has been reported following injection to sites other than the cervical musculature.
Lack of interchangeability between botulinum toxin products
The initial starting dose of 10,000 U (or 5000 U) is relevant only to NeuroBloc (Botulinum Toxin
Type B). These dose units are specific to NeuroBloc only and are not relevant to preparations of
Botulinum Toxin Type A. The unit dose recommendations for Botulinum Toxin Type A are significantly
lower than those for NeuroBloc and administration of Botulinum Toxin Type A at the unit dose
recommended for NeuroBloc may result in systemic toxicity and life-threatening clinical sequelae.
The effect of administering different botulinum neurotoxin serotypes concurrently is unknown. However,
in clinical studies, NeuroBloc was administered 16 weeks after the injection of Botulinum Toxin Type A.
Co-administration of NeuroBloc and aminoglycosides or agents interfering with neuromuscular
transmission (e.g. curare-like compounds) should be considered with caution.
Pregnancy
Animal reproduction studies are insufficient with respect to effects on pregnancy and embryonal/foetal
development. The potential risk for humans is unknown. NeuroBloc should not be used during pregnancy
unless the clinical condition of the woman requires treatment with Botulinum Toxin Type B.
Breast-feeding
It is unknown whether Botulinum Toxin Type B is excreted in human breast milk. The excretion of
Botulinum Toxin Type B in milk has not been studied in animals. A decision must be made on whether to
continue/discontinue breast-feeding or to continue/discontinue therapy with NeuroBloc taking into
account the benefit of breast-feeding to the child and the benefit of NeuroBloc therapy to the woman.
4
Fertility
No fertility studies have been performed and it is not known whether NeuroBloc can affect reproduction
capacity.
No studies on the effects on the ability to drive and use machines have been performed. Neurobloc may
impair the ability to drive or operate machinery in case of adverse reactions such as muscle weakness and
eye disorders (blurred vision, eyelid ptosis).
The most commonly reported adverse reactions associated with NeuroBloc treatment were dry mouth,
dysphagia, dyspepsia, and injection site pain.
Adverse reactions related to spread of toxin distant from the site of administration have been reported:
exaggerated muscle weakness, dysphagia, dyspnoea, aspiration pneumonia with fatal outcome in some
cases (see section 4.4).
Adverse reactions seen in all clinical studies are listed below according to MedDRA system organ class
and in decreasing frequency which is defined as follows: Very Common (
>
1/10); Common (
>
1/100
to <1/10); Uncommon (
>
1/1000 to <1/100).
Patients with Prior Botulinum Toxin Type A Exposure
System Organ Class
Very Common
Common
Nervous system disorders
dry mouth
torticollis (worsening from
baseline), taste perversion
Respiratory thoracic and
mediastinal disorders
voice alteration
Gastrointestinal disorders
dysphagia
dyspepsia
Musculoskeletal connective
tissue and bone disorders
myasthenia
General disorders and
administration site conditions
injection site pain
neck pain
Patients Naïve to Botulinum Toxins
System Organ Class
Very Common
Common
Nervous system disorders
dry mouth, headache
Torticollis
Eye disorders
blurred vision
Respiratory thoracic and
mediastinal disorders
Dysphonia
Gastrointestinal disorders
dysphagia
Dyspepsia
General disorders and
administration site conditions
injection site pain
In common with Botulinum Toxin Type A, electrophysiological jitter, which is not associated with
clinical weakness or other electrophysiological abnormalities, may be experienced in some distant
muscles.
5
Post marketing experience
Side effects related to spread of toxin distant from the site of administration have been reported
(exaggerated muscle weakness, dysphagia, dyspnoea, aspiration pneumonia with fatal outcome in some
cases) (see section 4.4).
The following effects have also been reported during post marketing use: abnormal accommodation,
ptosis, vomiting, constipation, flu-like symptoms, asthenia, angioedema, rash, urticaria and pruritus.
Cases of overdose (some with signs of systemic toxicity) have been reported. In the event of an overdose,
general medical supportive measures should be instituted. Doses of up to 15,000 U have infrequently
resulted in clinically significant systemic toxicity in adults. However, in children (non-approved use)
clinically significant systemic toxicity has occurred at doses approved for the treatment of adult patients.
If botulism is clinically suspected, hospitalisation for the monitoring of respiratory function (incipient
respiratory failure) may be required.
In the event of an overdose or injection into a muscle that normally compensates for the cervical dystonia,
it is conceivable that the dystonia may worsen. As with other botulinum toxins spontaneous recovery will
occur over a period of time.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: muscle relaxant, peripherally acting agents, ATC code: M03AX 01
NeuroBloc is a neuromuscular blocking agent. The mechanism of action of NeuroBloc in blocking
neuromuscular conduction occurs by a three-step process:
1.
Extracellular binding of the toxin to specific acceptors on motor nerve terminals
2.
Inhibition of acetylcholine release from nerve terminals at the neuromuscular junction
When injected directly into a muscle, NeuroBloc causes a localised paralysis that gradually reverses over
time. The mechanism by which muscle paralysis is reversed over time remains unknown, but may be
associated with the intraneuronal turnover of the affected protein and/or sprouting of the nerve ending.
A series of clinical studies have been conducted to evaluate the efficacy and safety of NeuroBloc in the
treatment of cervical dystonia. These studies have demonstrated the activity of NeuroBloc in both
treatment-naïve patients, and patients who have previously received treatment with Botulinum Toxin Type
A, including those that were considered clinically resistant to Botulinum Toxin Type A.
Two Phase III randomised, multicentre, double-blind, placebo-controlled studies were conducted in
patients with cervical dystonia. Both studies enrolled adult patients (≥ 18 years) who had a history of
receiving Botulinum Toxin Type A. The first study enrolled patients who were clinically resistant to type
A toxin (A-non responders), confirmed by a Frontalis Type A test. The second study enrolled patients who
continued to respond to type A toxin (A-responders). In the first study, type A resistant patients (A-non
responders)
were randomised to receive placebo or 10,000 U of NeuroBloc and in the second, type A
toxin responsive patients (A-responders) were randomised to receive placebo, 5000 U or 10,000 U of
toxin. The medicinal product was injected on a single occasion into 2 to 4 of the following muscles:
splenius capitus, sternocleidomastoid, levator scapulae, trapezius, semispinalis capitus and scalene. The
6
3.
Internalisation and release of the toxin into the cytosol of the nerve terminals
total dose was divided between the selected muscles and 1 to 5 injections per muscle were administered.
There were 77 subjects enrolled into the first study and 109 into the second. Patient evaluations continued
for 16 weeks post injection.
The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis
Rating Scale (TWSTRS)-Total score (range of possible scores is 0-87) at Week 4. The secondary
endpoints included Visual Analogue Scales (VAS) to quantify the Patient Global Assessment of change
and the Physician Global Assessment of change, both from baseline to Week 4. On these scales, scores of
50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and
secondary efficacy variables are summarised in Table 1. Analysis of the TWSTRS sub scales revealed
significant effects on the severity of cervical dystonia and its associated pain and disability.
Table 1:
Efficacy Results from Phase III NeuroBloc Studies
STUDY 1
(A-Resistant Patients)
STUDY 2
(A-Responsive Patients)
Assessments
Placebo
10,000 U
Placebo
5000 U
10,000 U
n = 38
n = 39
n = 36
n = 36
n = 37
TWSTRS-Total
Mean At Baseline
51.2
52.8
43.6
46.4
46.9
Mean at Week 4
49.2
41.8
39.3
37.1
35.2
Change from Baseline
-2.0
-11.1
-4.3
-9.3
-11.7
P-Value*
0.0001
0.0115
0.0004
Patient Global
Mean at Week 4
39.5
60.2
43.6
60.6
64.6
P-Value*
0.0001
0.0010
0.0001
Physician Global
Mean at Week 4
47.9
60.6
52.0
65.3
64.2
P-Value*
0.0001
0.0011
0.0038
* Analysis of covariance, two-tailed tests, α = 0.05
A further
randomised, multicentre, double-blind
study was conducted to compare the efficacy of
NeuroBloc (10,000 U) to Botulinum Toxin Type A (150 U) in patients with cervical dystonia who have
never previously received a botulinum toxin product. The primary efficacy assessment was the TWSTRS
Total score, and secondary efficacy assessments included VAS assessment of change evaluated by patient
and investigator, conducted at 4, 8 and 12 weeks after treatment. The study met the pre-defined criteria
for non-inferiority of NeuroBloc compared to Botulinum Toxin Type A, both in terms of mean TWSTRS
total score at week 4 after first and second treatment sessions, and in terms of duration of effect.
The non-inferiority of NeuroBloc compared to Botulinum Toxin Type A was further supported by a
responder analysis where similar percentages of subjects showed improvement in the TWSTRS score at
Week 4 of Session 1 (86% NeuroBloc and 85% Botox), and a similar proportion of subjects experienced
at least a 20% decrease from baseline in the TWSTRS score at Week 4 of Session 1 (51% NeuroBloc,
47% Botox).
Further clinical studies and open label follow-up have shown that subjects can continue to respond to
NeuroBloc for prolonged periods of time, with some subjects receiving more than 14 treatment sessions
over a period of more than 3.5 years. In addition to improved function as demonstrated by a reduction in
TWSTRS-total score, treatment with NeuroBloc was associated with a significant reduction in TWSTRS-
Pain and pain VAS scores at each treatment session at weeks 4, 8 and 12 relative to baseline. In these
studies, the average dosing frequency was approximately every 12 weeks.
7
The immunogenicity of NeuroBloc has been evaluated in two clinical studies and an open-label extension
study. The presence of antibodies in these studies was assessed using the mouse protection assay (also
known as the Mouse Neutralization Assay, MNA).
Immunogenicity data from three long-term clinical studies indicate that approximately one third of
patients develop antibodies, as determined by the mouse neutralisation / mouse protection assay dependent
on duration of exposure. Specifically, these studies showed approximately 19-25% seroconverted within
18 months of initiation of treatment, increasing to approximately 33-44% with up to 45 months of
treatment. An investigation into the consequence of seroconversion showed that the presence of antibodies
was not synonymous with a loss of clinical response, and did not have an impact on the overall safety
profile. However, the clinical relevance of the presence of antibodies as determined by the mouse
neutralisation / mouse protection assay is uncertain.
The extent and time course of seroconversion were similar in patients with prior toxin A exposure and
those who were toxin A naïve, and between toxin A resistant and toxin A responsive patients.
5.2 Pharmacokinetic properties
NeuroBloc injected intramuscularly produces localised muscle weakness by chemical denervation.
Following local intramuscular injection of NeuroBloc serious adverse events that may have been due to
systemic effects of Botulinum Toxin Type B, were observed in 12% of adverse reaction cases reported
during the post-marketing experience (including the following adverse reactions: dry mouth, dysphagia
and blurred vision). However, no pharmacokinetic or Absorption, Distribution, Metabolism and Excretion
(ADME) studies have been performed.
5.3 Preclinical safety data
Single dose pharmacology studies in cynomolgus monkeys have shown no effects other than the
anticipated dose-dependent paralysis of injected muscles, together with some diffusion of toxin at high
doses producing similar effects in neighbouring non-injected muscles.
Single dose intramuscular toxicology studies have been performed in cynomolgus monkeys. The systemic
No Observed Effect Level (NOEL) was shown to be approximately 960 U/kg. The dose resulting in death
was 2400 U/kg.
Because of the nature of the product, no animal studies have been carried out to establish the carcinogenic
effects of NeuroBloc. Standard tests to investigate the mutagenicity of NeuroBloc have not been
performed.
Development studies in rats and rabbits have shown no evidence of foetal malformations or changes to
fertility. In the development studies, the No Observed Adverse Effect Dose Level (NOAEL) in rats was
1000 U/kg/day for maternal effects and 3000 U/kg/day for foetal effects. In rabbits, the NOAEL was
0.1 U/kg/day for maternal effects and 0.3 U/kg/day for foetal effects. In the fertility studies the NOAEL
was 300 U/kg/day for general toxicity in both males and females and 1000 U/kg/day for fertility and
reproductive performance.
6.
6.1 List of excipients
Disodium succinate
8
Sodium chloride
Human serum albumin
Hydrochloric acid (for pH adjustment)
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years, as packaged for sale.
Use immediately if diluted (see section 4.2 and section 6.6).
From a microbiological point of view, unless the method of opening/dilution precludes the risk of
microbial contamination the product should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator at 2
o
C-8
o
C.
Do not freeze.
Keep the container in the outer carton in order to protect from light.
Within its shelf-life
,
the product may be removed from the refrigerator for a single period of up to 3
months at a temperature not above 25°C, without being refrigerated again. At the end of this period, the
product should not be put back in the refrigerator
and should be disposed of.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
0.5 ml, 1 ml or 2 ml solution in a 3.5 ml Type I glass vial, with siliconised butyl rubber stoppers
oversealed by aluminium crimped caps.
Pack size of 1.
6.6 Special precautions for disposal and other handling
NeuroBloc is provided in vials for single use only.
The medicinal product is ready to use and no reconstitution is required. Do not shake.
To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium
chloride 9 mg/ml (0.9%) solution for injection (see section 4.2). Such dilutions with sodium chloride
should be done in a syringe, pulling out the desired amount of Neurobloc into the syringe first, and then
adding sodium chloride to the syringe. In non clinical experiments, NeuroBloc solution has been diluted
up to 6-fold without any resulting change in potency. Once diluted, the medicinal product must be used
immediately as the formulation does not contain a preservative.
9
Any unused solution, all vials of expired NeuroBloc and equipment used in the administration of the
medicinal product should be carefully discarded as Medical Bioharzardous Waste in accordance with local
requirements. Vials should be visually inspected prior to use. If the NeuroBloc solution is not clear and
colourless/light yellow or if the vial appears damaged, the product should not be used, but discarded as
Medical Biohazardous Waste in accordance with local requirements.
Decontaminate any spill with 10% caustic solution, or sodium hypochlorite (household chlorine bleach –
2 ml (0.5%): 1 litre water) solution. Wear waterproof gloves and soak up the liquid with an appropriate
absorbent. Place the absorbed toxin in an autoclave bag, seal it and process as Medical Biohazardous
Waste in accordance with local requirements.
7.
Eisai Limited
European Knowledge Centre
Mosquito Way
Hatfield
Hertfordshire
AL10 9SN
United Kingdom
EU/1/00/166/001 – 2500 U
EU/1/00/166/002 – 5000 U
EU/1/00/166/003 – 10,000 U
Date of first authorisation: 22 January 2001
Date of first renewal: 22 January 2006
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
/
10
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE
AND MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
11
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Solstice Neurosciences Inc
701 Gateway Blvd, South San Francisco
California 94080
USA
Name and address of the manufacturer responsible for batch release
Eisai Manufacturing Limited
European Knowledge Centre
Mosquito Way
Hatfield
Hertfordshire
AL10 9SN
United Kingdom
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
The Marketing Authorisation Holder (MAH) shall ensure that educational activities aimed at risk
minimisation and to support safe and effective use of Neurobloc are implemented within the EU.
The MAH commits to develop educational materials to physicians covering the following:
1. Appropriate injection technique
2. Appropriate dose selection and dosing interval
3. Awareness that toxin dosages are
NOT
interchangeable between
botulinum toxin containing
products
4. Continued observation for patients with risk factors for toxin spread
from the site of injection to
other parts of the body
and identification of these patients so caution can be exercised.
5. Plan for thorough discussion between physician and patient regarding risk/benefit
6. Awareness of educational material for patients
The MAH commits to develop educational material which will be distributed to patients
through
physicians
to increase awareness of the following:
1. Early recognition of symptoms that could indicate spread of toxin e.g. swallowing, speech or respiratory
difficulties
12
2. Need to seek immediate medical attention especially in event of swallowing, speech and respiratory
difficulties.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON OUTER PACKAGING
Outer carton 0.5 ml vial
NeuroBloc 5000 U/ml solution for injection
Botulinum Toxin Type B
2.
STATEMENT OF ACTIVE SUBSTANCES
Each ml contains 5000 U Botulinum Toxin Type B
One vial of 0.5 ml contains 2500 U of Botulinum Toxin Type B
3.
LIST OF EXCIPIENTS
Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for
injections
Solution for injection
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Do not shake.
Read the package leaflet before use.
Intramuscular use.
For single use only.
6.
SPECIAL WARNINGS 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
The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not
interchangeable with the units used to express the potency of other Botulinum toxin preparations.
8.
EXPIRY DATE
EXP
After dilution, use immediately
16
9.
SPECIAL STORAGE PRECAUTIONS
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the container in the outer carton in order to protect from light.
Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3
months at a temperature not above 25
o
C without being refrigerated again. At the end of this period, the
product should not be put back in the refrigerator and should be disposed of.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read package leaflet for special precautions for handling, in-use storage and disposal.
Marketing Authorisation Holder:
Eisai Limited
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
EU/1/00/166/001
13.
BATCH NUMBER
LOT
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label 0.5 ml vial
NeuroBloc 5000 U/ml solution for injection
IM
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
CONTENTS BY WEIGHT, VOLUME OR BY UNIT
2500 U
18
PARTICULARS TO APPEAR ON OUTER PACKAGING
Outer carton 1.0 ml vial
NeuroBloc 5000 U/ml Solution for injection
Botulinum Toxin Type B
2.
STATEMENT OF ACTIVE SUBSTANCES
Each ml contains 5000 U Botulinum Toxin Type B
One vial of 1 ml contains 5000 U of Botulinum Toxin Type B
3.
LIST OF EXCIPIENTS
Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for
injections
Solution for injection
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Do not shake.
Read the package leaflet before use.
Intramuscular use.
For single use only.
6.
SPECIAL WARNINGS 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
The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not
interchangeable with the units used to express the potency of other Botulinum toxin preparations.
8.
EXPIRY DATE
EXP
After dilution, use immediately
19
9.
SPECIAL STORAGE PRECAUTIONS
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the container in the outer carton in order to protect from light.
Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3
months at a temperature not above 25
o
C without being refrigerated again. At the end of this period, the
product should not be put back in the refrigerator and should be disposed of.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read package leaflet for special precautions for handling, in-use storage and disposal.
Marketing Authorisation Holder:
Eisai Limited
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
EU/1/00/166/002
13.
BATCH NUMBER
LOT
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
20
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING
UNITS
Vial label 1.0 ml vial
NeuroBloc 5000 U/ml solution for injection
IM
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
CONTENTS BY WEIGHT, VOLUME OR BY UNIT
5000 U
21
PARTICULARS TO APPEAR ON OUTER PACKAGING
Outer carton 2.0 ml vial
NeuroBloc 5000 U/ml Solution for injection
Botulinum Toxin Type B
2.
STATEMENT OF ACTIVE SUBSTANCES
Each ml contains 5000 U of Botulinum Toxin Type B
One vial of 2 ml contains 10,000 U of Botulinum Toxin Type B
3.
LIST OF EXCIPIENTS
Disodium succinate, sodium chloride, human serum albumin solution, hydrochloric acid and water for
injections
Solution for injection
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Do not shake.
Read the package leaflet before use.
Intramuscular use.
For single use only.
6.
SPECIAL WARNINGS 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
The potency of Neurobloc is 5000 U/ml. The units expressed are Type B Units, which are not
interchangeable with the units used to express the potency of other Botulinum toxin preparations.
8.
EXPIRY DATE
EXP
After dilution, use immediately
22
9.
SPECIAL STORAGE PRECAUTIONS
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the container in the outer carton in order to protect from light.
Within its shelf-life, the product may be removed from the refrigerator for one single period of up to 3
months at a temperature not above 25
o
C without being refrigerated again. At the end of this period, the
product should not be put back in the refrigerator and should be disposed of.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read package leaflet for special precautions for handling, in-use storage and disposal.
Marketing Authorisation Holder:
Eisai Limited
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
EU/1/00/166/003
13.
BATCH NUMBER
LOT
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
23
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label 2.0 ml vial
NeuroBloc 5000 U/ml solution for injection
IM
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
CONTENTS BY WEIGHT, VOLUME OR BY UNIT
10,000 U
24
B. PACKAGE LEAFLET
25
PACKAGE LEAFLET: INFORMATION FOR THE USER
NeuroBloc 5000 U/ml Solution for Injection
Botulinum Toxin Type B
Read all of this leaflet carefully before you are given this medicine.
-
If you have further questions, please ask your doctor or your pharmacist.
-
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 NeuroBloc is and what it is used for
3.
How you will be given NeuroBloc
4.
Possible side effects
5.
How to store NeuroBloc
6.
Further Information
1.
WHAT NEUROBLOC IS AND WHAT IT IS USED FOR
NeuroBloc injection works by reducing or stopping muscle contractions. It contains the active ingredient
‘Botulinum Toxin Type B’.
NeuroBloc is used to treat an illness called cervical dystonia (torticollis). This is where you have
contractions of your neck or shoulder muscles that you cannot control.
2.
BEFORE YOU ARE GIVEN NEUROBLOC
You must not be given NeuroBloc:
•
if you are allergic (hypersensitive) to Botulinum Toxin Type B or any of the other ingredients of
NeuroBloc (listed in section 6 “Further information”)
•
if you have other problems with your nerves or muscles, such as amyotrophic lateral sclerosis
(Lou Gehrig's disease), peripheral neuropathy, myasthenia gravis or Lambert-Eaton syndrome
(muscle weakness or numbness or pain)
You must not be given NeuroBloc if any of the above applies to you. If you are not sure talk to your
doctor or pharmacist.
Take special care with
NeuroBloc
Check with your doctor or pharmacist before you are given NeuroBloc:
•
if you have a bleeding problem such as haemophilia
•
if you have lung problems
•
if you have difficulty swallowing. This is because swallowing problems could make you breathe
food or liquids into your lungs, which could then cause very serious pneumonia
Use in children
NeuroBloc is not to be used in children aged 0-18 years.
26
-
Keep this leaflet. You may need to read it again.
2.
Before you are given NeuroBloc
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. This is because NeuroBloc can affect the way some
medicines work and other medicines can also affect the way NeuroBloc works.
In particular, tell your doctor or pharmacist if you are taking any of the following medicines:
•
aminoglycoside antibiotics for an infection
•
medicines to stop blood clotting, such as warfarin
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before you are
given NeuroBloc.
Before having an operation
If you are going to have an operation, please tell your doctor that you have been given NeuroBloc. This is
because NeuroBloc can affect the medicines you may be given before a general anaesthetic.
Pregnancy and breast feeding
•
you will not normally be given NeuroBloc if you are pregnant or breast-feeding. This is because it
is not known how NeuroBloc affects patients who are pregnant and it is not known if NeuroBloc
passes into a nursing mother’s breast milk
•
ask your doctor or pharmacist for advice before taking any medicine, if you are pregnant or
breast-feeding
Driving and using machines
You may have muscle weakness or eye problems such as blurred vision or eyelid drooping after being
given NeuroBloc. If this happens, do not drive or use any tools or machines.
Important information about some of the ingredients of NeuroBloc
NeuroBloc contains less than 1 mmol sodium (23 mg) per 10,000 units of NeuroBloc. This means it is
essentially “sodium free”.
3.
HOW YOU WILL BE GIVEN NEUROBLOC
NeuroBloc will be given to you by a doctor
with specialist experience in the treatment of cervical dystonia
and in the use of botulinum toxins.
How much will be given
•
your doctor will decide how much NeuroBloc to give you
•
the usual dose is 10,000 units, however, it can be higher or lower
•
if you have had NeuroBloc injections before, your doctor will take into account how well it
worked the other times
How NeuroBloc is given
•
NeuroBloc will be injected into your neck or shoulder muscles, depending on which ones are
causing the problem
•
your doctor may inject part of the dose into different places in your muscles
Having more injections of NeuroBloc
•
the effects of NeuroBloc will usually last about 12 to 16 weeks
•
your doctor will decide if you need another injection and how much to give you
If you think that the effect of NeuroBloc is too strong or too weak, talk to your doctor.
27
If you are given too much NeuroBloc
•
if you have been given more NeuroBloc than you need, some of your muscles that were not
injected may feel weak
or you may develop symptoms away from the injected muscles, like
difficulty in swallowing or breathing. This may occur when higher doses of up to 15,000 units are
given
•
if you have difficulty breathing
or you are worried by any symptoms you develop away from the
place of the injection,
talk to your doctor immediately. If he/she is unavailable seek emergency
assistance. You may need urgent medical treatment
A serious condition called “botulism” which causes paralysis of muscles and respiratory failure could
occur if too much of the active ingredient (botulinum toxin) is injected into the body. If your doctor
suspects that botulism may have occurred, you will be admitted to hospital and your breathing (respiratory
function) will be monitored. Recovery usually takes place over a period of time.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, NeuroBloc can cause side effects, although not everybody gets them. They may
happen days to weeks after you have had the injection. You may feel pain at the place where you had the
injection, but this should wear off after a few minutes.
You may get a dry mouth and it might become difficult to swallow. In rare cases difficulty in swallowing
may be severe and choking is possible.
If your swallowing difficulty gets worse or you have choking or
breathing problems, see a doctor immediately. You may need urgent medical treatment.
Aspiration pneumonia caused by food particles or vomit entering into the lungs, and respiratory disease,
have been reported after treatment with botulinum toxins (Type A and Type B). These side effects have
sometimes resulted in death and are possibly related to the spread of botulinum toxin to body parts away
from the place where the injection is given.
Other side effects include:
Very common
(affects more than 1 user in 10)
•
dry mouth
•
difficulty swallowing
•
headache
Common
(affects 1 to 10 users in 100)
•blurred vision or drooping of your upper eyelid
•indigestion or being sick (vomiting)
•constipation
•neck pain
•feeling weak, pain or stiff muscles around your body
•loss of strength or energy
•changes in the taste of your food and drink
•changes in the sound of your voice
•flu-like symptoms
Skin allergies such as rash with or without paleness, redness, patches, severe itching; and skin eruptions
such as welts or hives have also been reported after receiving NeuroBloc. The frequency of these side
effects is not known.
It is possible that cervical dystonia could become worse after you have had your injection.
28
If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE NEUROBLOC
•
keep out of the reach and sight of children
•
do not use after the expiry date which is stated on the carton and on the vial after EXP.
•
store in a refrigerator (2°C-8°C). Do not freeze
•
keep the vial in the outer carton in order to protect from light
•
Within its shelf-life, NeuroBloc may be removed from the refrigerator for a single period of up to
3 months at a temperature not above 25
o
C. At the end of this period, the product should not be put
back in the refrigerator and should be disposed of.
•
The date at which the medicine was taken out from the refrigerator will be put on the outer carton.
•
if the medicine is diluted, the doctor will use it immediately
•
before using the medicine the doctor will check that the solution is clear and colourless/light
yellow. If there are any visible signs of deterioration, the medicine should not be used, but
discarded.
•
any unused solution should be discarded
•
due to the special nature of NeuroBloc, the doctor will ensure that all used vials, needles and
syringes must be processed as Medical Biohazardous Waste in accordance with local requirements
6.
FURTHER INFORMATION
What NeuroBloc contains
The active substance is Botulinum Toxin Type B. One millilitre (ml) contains 5000 U.
One vial of 0.5 ml contains 2500 U of Botulinum Toxin Type B.
One vial of 1 ml contains 5000 U of Botulinum Toxin Type B.
One vial of 2 ml contains 10,000 U of Botulinum Toxin Type B.
The other ingredients are disodium succinate, sodium chloride, human serum albumin solution,
hydrochloric acid (for pH adjustment) and water for injections
What NeuroBloc looks like and contents of the pack
NeuroBloc is presented as a solution for injection in a vial that contains 0.5 ml (2500 Units), 1.0 ml
(5000 Units) or 2.0 ml (10,000 Units). The solution is clear and colourless to pale yellow.
Pack size of 1.
Marketing Authorisation holder
:
Eisai Limited
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
Manufacturer
Eisai Manufacturing Limited
Mosquito Way
Hatfield
Herts
29
AL10 9SN
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Eisai Ltd.
Tél/Tel: + 44 (0) 208 600 1400
(Royaume-Uni/Verenigd Koninkrijk/Vereinigtes
Königreich)
Luxembourg/Luxemburg
Eisai Ltd.
Tél/Tel: + 44 (0) 600 1400
(Royaume-Uni/Verenigd Koninkrijk)
България
Eisai Ltd.
Teл.: + 44 (0) 208 600 1400
Великобритания (Обединеното кралство)
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
Malta
Associated Drug Company Ltd
Tel: +356 2277 8000
Danmark
Eisai AB
Tlf: +46 (0) 8 501 01 600
(Sverige)
Nederland
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Verenigd Koninkrijk)
Deutschland
Eisai GmbH
Tel: + 49 (0) 696 65 85-0
Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Eesti
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Ühendkuningriik)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
Eisai Ltd.
Tel.: + 44 (0) 208 600 1400
(Wielka Brytania)
España
Eisai Farmacéutica, S.A.
Tel: +34 91 455 94 55
Portugal
Eisai Farmacêutica,
Unipessoal Lda
Tel: +351 214 875 540
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Marea Britanie)
30
Ireland
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(United Kingdom)
Slovenija
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Velika Britanija)
Ísland
Vistor hf.
Hörgatún 2
Sími/Tel: + 354 535 7000
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 5181401
Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi/Sverige)
Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600
Latvija
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Lielbritānija)
United Kingdom
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
Lietuva
Eisai Ltd.
Tel. + 44 (0) 208 600 1400
(Jungtinė Karalystė)
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
31
-------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only
INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL
NeuroBloc is provided in vials for single use only.
The medicinal product is ready to use and no reconstitution is required. Do not shake.
To allow division of the total dose between several injections, NeuroBloc may be diluted with sodium
chloride 9 mg/ml (0.9%) solution for injection (see section 4.2). Such dilutions with sodium chloride
should be done in a syringe, pulling out the desired amount of Neurobloc into the syringe first, and then
adding sodium chloride to the syringe. In non clinical experiments, NeuroBloc solution has been diluted
up to 6-fold without any resulting change in potency. Once diluted, the medicinal product must be used
immediately as the formulation does not contain a preservative.
Any unused solution, all vials of expired NeuroBloc and equipment used in the administration of the
medicinal product should be carefully discarded as Medical Bioharzardous Waste in accordance with local
requirements. Vials should be visually inspected prior to use. If the NeuroBloc solution is not clear and
colourless/light yellow or if the vial appears damaged, the product should not be used, but discarded as
Medical Biohazardous Waste in accordance with local requirements.
Decontaminate any spill with 10% caustic solution, or sodium hypochlorite (household chlorine bleach –
2 ml (0.5%): 1 litre water) solution. Wear waterproof gloves and soak up the liquid with an appropriate
absorbent. Place the absorbed toxin in an autoclave bag, seal it and process as Medical Biohazardous
Waste in accordance with local requirements.
Do not use after the expiration date stamped on the vial.
32
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/neurobloc.html
Copyright © 1995-2021 ITA all rights reserved.