NEUROBLOC 5000U / ml solution for injection medication leaflet

NeuroBloc 5000 U/ml solution for injection.

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 the full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless to light yellow solution.

NeuroBloc is indicated for the treatment of cervical dystonia (torticollis) in adults.

NeuroBloc should only be administered by a physician who is familiar with and experience in thetreatment of cervical dystonia and in the use of botulinum toxins.

Restricted to hospital use only.

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 werenot 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 thelikelihood of clinical benefit.

Injections should be repeated as required to maintain good function and minimise pain. In long termclinical studies, the average dosing frequency was approximately every 12 weeks, however this mayvary between subjects, and a proportion of patients maintained a significant improvement relative tobaseline for 16 weeks or longer. The dosing frequency should therefore be adapted based on theclinical assessment/response of an individual patient.

For patients with reduced muscle mass the dose should be adjusted according to individual patientneed.

The potency of this medicinal product is expressed in NeuroBloc 5000 U/ml. These units are notinterchangeable with the units used to express the potency of other botulinum toxin preparations (seesection 4.4).

No dose adjustment is required in older people ≥ 65 years of age.

Studies have not been carried out in patients with hepatic or renal impairment. However, thepharmacological characteristics do not indicate any need to adjust the dose.

The safety and efficacy of NeuroBloc in children aged less than 18 years have not yet beenestablished. No data are available.

NeuroBloc must only be administered by intramuscular injection. Particular caution should be paid toensure that it is not injected into a blood vessel.

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 sodiumchloride 9 mg/ml (0.9%) solution for injection and the solution used immediately. For instructions ondilution of the product before administration, see section 6.6.

Individuals with known neuromuscular diseases (e.g. amyotrophic lateral sclerosis or peripheralneuropathy) or known neuromuscular junctional disorders (e.g. myasthenia gravis or Lambert-Eatonsyndrome) must not be given NeuroBloc.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

NeuroBloc is recommended for intramuscular administration only.

The safety of NeuroBloc outside the approved indication has not been established. This warningincludes use in children and in any other indication besides cervical dystonia. The risks, which caninclude death, may outweigh the potential benefits.

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 somepatients. Immunogenicity data from three long term clinical studies indicate that approximately onethird of patients develop antibodies, as determined by the mouse neutralisation/mouse protection assaydependent on duration of exposure (see section 5.1).

An investigation into the consequence of seroconversion showed that the presence of antibodies wasnot synonymous with a loss of clinical response, and did not have an impact on the overall safetyprofile. However, the clinical relevance of the presence of antibodies as determined by the mouseneutralisation/mouse protection assay is uncertain.

Caution should be used in patients with bleeding disorders or receiving anticoagulant therapy.

Spread of toxin effect

Neuromuscular effects related to spread of toxin, distant from the site of administration have beenreported (see section 4.8). These include dysphagia and breathing difficulties.

Pre-Existing neuromuscular disorders

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients withneuromuscular disorders may be at increased risk of clinically significant effects including severedysphagia and respiratory compromise from typical doses of NeuroBloc (see section 4.3).

There have been spontaneous reports of dysphagia, aspiration pneumonia and/or potentially fatalrespiratory disease, after treatment with Botulinum Toxin Type A/B.

Children (non approved use) and patients with underlying neuromuscular disorders includingswallowing disorders are at increased risk of these adverse reactions. In patients with neuromusculardisorders or history of dysphagia and aspiration, botulinum toxins should only be used in anexperimental setting under strict medical supervision.

Following NeuroBloc treatment, all patients and caregivers should be advised to seek medicalattention 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 aresignificantly lower than those for NeuroBloc and administration of Botulinum Toxin Type A at theunit dose recommended for NeuroBloc may result in systemic toxicity and life-threatening clinicalsequelae.

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 neuromusculartransmission (e.g. curare-like compounds) should be considered with caution.

Animal reproduction studies are insufficient with respect to effects on pregnancy and embryonal/foetaldevelopment. The potential risk for humans is unknown. NeuroBloc should not be used duringpregnancy unless the clinical condition of the woman requires treatment with Botulinum Toxin

Type B (see section 5.3).

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 onwhether to continue/discontinue breast-feeding or to continue/discontinue therapy with NeuroBloctaking into account the benefit of breast-feeding to the child and the benefit of NeuroBloc therapy tothe woman.

No fertility studies have been performed and it is not known whether NeuroBloc can affectreproduction capacity.

No studies on the effects on the ability to drive and use machines have been performed. Neuroblocmay impair the ability to drive or operate machinery in case of adverse reactions such as muscleweakness 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 somecases (see section 4.4).

Adverse reactions seen in all clinical studies are listed below according to MedDRA system organclass 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).

System Organ Class Very Common Common

Nervous system disorders dry mouth, headache torticollis (worsening frombaseline), taste perversion

Eye disorders blurred vision

Respiratory thoracic and dysphoniamediastinal disorders

Gastrointestinal disorders dysphagia dyspepsia

Musculoskeletal connective myastheniatissue and bone disorders

General disorders and injection site pain neck painadministration site conditions influenza like illness

In common with Botulinum Toxin Type A, electrophysiological jitter, which is not associated withclinical weakness or other electrophysiological abnormalities, may be experienced in some distantmuscles.

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 insome cases) (see section 4.4).

The following effects have also been reported during post marketing use: abnormal accommodation,dry eye, ptosis, vomiting, constipation, flu-like symptoms, asthenia, angioedema, rash, urticaria andpruritus.

The available reports indicate that the product has been used in the paediatric population. Case reportsare more likely to be serious in children (40%) compared to those in adults and older people (12%),possibly as a result of using an inappropriately high dosage for the child (see section 4.9).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of overdose (some with signs of systemic toxicity) have been reported. In the event of anoverdose, general medical supportive measures should be instituted. Doses of up to 15,000 U haveinfrequently resulted in clinically significant systemic toxicity in adults. If botulism is clinicallysuspected, hospitalisation for the monitoring of respiratory function (incipient respiratory failure) maybe required.

In the event of an overdose or injection into a muscle that normally compensates for the cervicaldystonia, it is conceivable that the dystonia may worsen. As with other botulinum toxins spontaneousrecovery will occur over a period of time.

Paediatric use (non approved): in children, clinically significant systemic toxicity has occurred atdoses approved for the treatment of adult patients. The risk of spreading of effect is greater than inadults, and more frequently severe. This can be due to the high dosages usually used in thispopulation.

Pharmacotherapeutic group: muscle relaxant, peripherally acting agents, ATC code: M03AX 01.

NeuroBloc is a neuromuscular blocking agent. The mechanism of action of NeuroBloc in blockingneuromuscular conduction occurs by a three-step process:

1. Extracellular binding of the toxin to specific acceptors on motor nerve terminals2. Internalisation and release of the toxin into the cytosol of the nerve terminals3. Inhibition of acetylcholine release from nerve terminals at the neuromuscular junction

When injected directly into a muscle, NeuroBloc causes a localised paralysis that gradually reversesover time. The mechanism by which muscle paralysis is reversed over time remains unknown, butmay be associated with the intraneuronal turnover of the affected protein and/or sprouting of the nerveending.

A series of clinical studies have been conducted to evaluate the efficacy and safety of NeuroBloc inthe treatment of cervical dystonia. These studies have demonstrated the activity of NeuroBloc in bothtreatment-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 inpatients with cervical dystonia. Both studies enrolled adult patients (≥ 18 years) who had a history ofreceiving Botulinum Toxin Type A. The first study enrolled patients who were clinically resistant totype A toxin (A-non responders), confirmed by a Frontalis Type A test. The second study enrolledpatients who continued to respond to type A toxin (A-responders). In the first study, type A resistantpatients (A-non responders) were randomised to receive placebo or 10,000 U of NeuroBloc and in thesecond, type A toxin responsive patients (A-responders) were randomised to receive placebo, 5000 Uor 10,000 U of toxin. The medicinal product was injected on a single occasion into 2 to 4 of thefollowing muscles: splenius capitus, sternocleidomastoid, levator scapulae, trapezius, semispinaliscapitus and scalene. The total dose was divided between the selected muscles and 1 to 5 injections permuscle were administered. There were 77 subjects enrolled into the first study and 109 subjects intothe 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. Thesecondary 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 ofcomparisons of the primary and secondary efficacy variables are summarised in Table 1. Analysis ofthe TWSTRS sub scales revealed significant effects on the severity of cervical dystonia and itsassociated pain and disability.

Table 1 Efficacy Results from Phase III NeuroBloc Studies

STUDY 1 STUDY 2(A-Resistant Patients) (A-Responsive Patients)

Assessments Placebo 10,000 U Placebo 5000 U 10,000 Un = 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 whohave never previously received a botulinum toxin product. The primary efficacy assessment was the

TWSTRS Total score, and secondary efficacy assessments included VAS assessment of changeevaluated by patient and investigator, conducted at 4, 8 and 12 weeks after treatment. The study metthe pre-defined criteria for non-inferiority of NeuroBloc compared to Botulinum Toxin Type A, bothin terms of mean TWSTRS total score at week 4 after first and second treatment sessions, and in termsof duration of effect.

The non-inferiority of NeuroBloc compared to Botulinum Toxin Type A was further supported by aresponder analysis where similar percentages of subjects showed improvement in the TWSTRS scoreat Week 4 of Session 1 (86% NeuroBloc and 85% Botox), and a similar proportion of subjectsexperienced 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 treatmentsessions over a period of more than 3.5 years. In addition to improved function as demonstrated by areduction in TWSTRS-total score, treatment with NeuroBloc was associated with a significantreduction in TWSTRS-Pain and pain VAS scores at each treatment session at weeks 4, 8 and 12relative to baseline. In these studies, the average dosing frequency was approximately every 12 weeks.

The immunogenicity of NeuroBloc has been evaluated in two clinical studies and an open-labelextension study. The presence of antibodies in these studies was assessed using the mouse protectionassay (also known as the Mouse Neutralization Assay, MNA).

Immunogenicity data from three long-term clinical studies indicate that approximately one third ofpatients develop antibodies, as determined by the mouse neutralisation/ mouse protection assaydependent on duration of exposure. Specifically, these studies showed approximately 19-25%seroconverted within 18 months of initiation of treatment, increasing to approximately 33-44% withup to 45 months of treatment. An investigation into the consequence of seroconversion showed thatthe presence of antibodies was not synonymous with a loss of clinical response, and did not have animpact on the overall safety profile. However, the clinical relevance of the presence of antibodies asdetermined 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 andthose who were toxin A naïve, and between toxin A resistant and toxin A responsive patients.

NeuroBloc injected intramuscularly produces localised muscle weakness by chemical denervation.

Following local intramuscular injection of NeuroBloc serious adverse events that may have been dueto systemic effects of Botulinum Toxin Type B, were observed in 12% of adverse reaction casesreported during the post-marketing experience (including the following adverse reactions: dry mouth,dysphagia and blurred vision). However, no pharmacokinetic or Absorption, Distribution, Metabolismand Excretion (ADME) studies have been performed.

Single dose pharmacology studies in cynomolgus monkeys have shown no effects other than theanticipated dose-dependent paralysis of injected muscles, together with some diffusion of toxin at highdoses producing similar effects in neighbouring non-injected muscles.

Single dose intramuscular toxicology studies have been performed in cynomolgus monkeys. Thesystemic No Observed Effect Level (NOEL) was shown to be approximately 960 U/kg. The doseresulting in death was 2400 U/kg.

Because of the nature of the product, no animal studies have been carried out to establish thecarcinogenic effects of NeuroBloc. Standard tests to investigate the mutagenicity of NeuroBloc havenot been performed.

Development studies in rats and rabbits have shown no evidence of foetal malformations or changes tofertility. In the development studies, the No Observed Adverse Effect Dose Level (NOAEL) in ratswas 1000 U/kg/day for maternal effects and 3000 U/kg/day for foetal effects. In rabbits, the NOAELwas 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 forfertility and reproductive performance.

Disodium succinate

Sodium chloride

Human serum albumin

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

5 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 ofmicrobial contamination the product should be used immediately.

Store in a refrigerator at 2oC-8oC.

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 to3 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 after dilution of the medicinal product, see section 6.3.

0.5 ml, 1 ml or 2 ml solution in a 3.5 ml Type I glass vial, with siliconised butyl rubber stoppersoversealed by aluminium crimped caps.

Pack size of 1.

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 sodiumchloride 9 mg/ml (0.9%) solution for injection (see section 4.2). Such dilutions with sodium chlorideshould be done in a syringe, pulling out the desired amount of Neurobloc into the syringe first, andthen adding sodium chloride to the syringe. In non clinical experiments, NeuroBloc solution has beendiluted up to 6-fold without any resulting change in potency. Once diluted, the medicinal product mustbe 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 themedicinal product should be carefully discarded as Medical Bioharzardous Waste in accordance withlocal requirements. Vials should be visually inspected prior to use. If the NeuroBloc solution is notclear and colourless/light yellow or if the vial appears damaged, the product should not be used, butdiscarded as Medical Biohazardous Waste in accordance with local requirements.

Decontaminate any spill with 10% caustic solution, or sodium hypochlorite (household chlorinebleach -2 ml (0.5%): 1 litre water) solution. Wear waterproof gloves and soak up the liquid with anappropriate absorbent. Place the absorbed toxin in an autoclave bag, seal it and process as Medical

Biohazardous Waste in accordance with local requirements.

Sloan Pharma S.à.r.l.33, Rue du Puits Romain8070 Bertrange

Luxembourg

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 latest renewal: 29 November 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.