BOTULINUM TOXIN TYPE A 300 UNITS POWDER FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Botulinum Toxin Type A

300 units

Powder for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Clostridium botulinum type A toxin-haemagglutinin complex 300 units.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Botulinum Toxin Type A is indicated for symptomatic treatment of focal spasticity of:

– Upper limbs in adults

– Lower limbs in adults affecting the ankle joint due to stroke or traumatic brain injury (TBI)

– Dynamic equinus foot deformity in ambulant paediatric cerebral palsy patients, two years of age or older

– Upper limbs in paediatric cerebral palsy patients, two years of age or older.

Botulinum Toxin Type A is indicated in adults for symptomatic treatment of:

– Spasmodic torticollis

– Blepharospasm

– Hemifacial spasm

– Severe primary hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics.

Botulinum Toxin Type A is indicated for the temporary improvement in the appearance of moderate to severe:

– Glabellar lines (vertical lines between the eyebrows) seen at maximum frown and/or

– Lateral canthal lines (crow’s feet lines) seen at maximum smile

in adult patients under 65 years, when the severity of these lines has an important psychological impact on the patient.

4.2 Posology and method of administration

Botulinum Toxin Type A should only be administered by an appropriately qualified healthcare practitioner with expertise in the treatment of the relevant indication and the use of the required equipment, in accordance with national guidelines.

For instructions on reconstitution of the powder for solution for injection, handling and disposal of vials please refer to section 6.6.

Focal spasticity in adults

Upper limb:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with Botulinum Toxin Type A. In clinical trials, doses of 500 units and 1000 units were divided among selected muscles at a given treatment session as shown below.

No more than 1 ml should generally be administered at any single injection site. The total dose should not exceed 1000 units at a given treatment session.

Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Clinical improvement may be expected one week after injection and may last up to 20 weeks. Injections may be repeated every 12 – 16 weeks or as required to maintain response, but not more frequently than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Botulinum Toxin Type A and muscles to be injected.

Lower limb spasticity affecting the ankle joint:

Posology

In clinical trials, doses of 1000U and 1500U were divided among selected muscles. The exact dosage in initial and sequential treatment sessions should be tailored to the individual based on the size and number of muscles involved, the severity of the spasticity, also taking into account the presence of local muscle weakness and the patient’s response to previous treatment. However, the total dose should not exceed 1500U.

No more than 1 ml should generally be administered at any single injection site.

The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Botulinum Toxin Type A and muscles to be injected.

Although actual location of the injection sites can be determined by palpation, the use of injection guiding techniques, e.g. electromyography, electrical stimulation or ultrasound are recommended to help accurately target the injection sites.

Repeat Botulinum Toxin Type A treatment should be administered every 12 to 16 weeks, or longer as necessary, based on return of clinical symptoms but no sooner than 12 weeks after the previous injection.

Upper and Lower limbs:

If treatment is required in the upper and lower limbs during the same treatment session, the dose of Botulinum Toxin Type A to be injected in each limb should be tailored to the individual’s need according to the relevant posology and without exceeding a total dose of 1500U.

Elderly patients (> 65 years): Clinical experience has not identified differences in response between the elderly and younger adult patients. In general, elderly patients should be observed to evaluate their tolerability of Botulinum Toxin Type A, due to the greater frequency of concomitant disease and other drug therapy.

Method of administration

When treating focal spasticity affecting the upper and lower limbs in adults, Botulinum Toxin Type A is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing either 100 units per ml, 200 units per ml or 500 units per ml of Botulinum Toxin Type A (see section 6.6).

Botulinum Toxin Type A is administered by intramuscular injection into the muscles as described above.

Focal spasticity in paediatric cerebral palsy patients, two years of age or older

Botulinum Toxin Type A maximum total doses per treatment session and minimum times before retreatment

whichever is lower

Please see below for full posology and method of administration by treatment indication.

Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient’s response to previous treatment, and/or adverse event history with botulinum toxins. For treatment initiation, consideration should be given to start with a lower dose.

The maximum total dose of Botulinum Toxin Type A administered per treatment session must not exceed 15 units/kg for unilateral lower limb injections or 30 units/kg for bilateral injections. In addition, the total Botulinum Toxin Type A dose per treatment session must not exceed 1000 units or 30 units/kg, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be distributed across more than 1 injection site in any single muscle.

No more than 0.5 ml of Botulinum Toxin Type A should be administered in any single injection site. See below table for recommended dosing:

whichever is lower

Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Repeat Botulinum Toxin Type A treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were re-treated between 16 – 22 weeks; however, some patients had a longer duration of response, i.e. 28 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Botulinum Toxin Type A and muscles to be injected.

Clinical improvement may be expected within two weeks after injection.

Method of administration

When treating lower limb spasticity associated with cerebral palsy in children, Botulinum Toxin Type A is reconstituted with sodium chloride injection B.P. (0.9 % w/v) (see also section 6.6) and is administered by intramuscular injection as detailed above.

Focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age or older:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with botulinum toxins. For treatment initiation, consideration should be given to start with a lower dose.

The maximum dose of Botulinum Toxin Type A administered per treatment session for unilateral upper limb injections must not exceed 16 U/kg or 640 U whichever is lower. When injecting bilaterally, the maximum Botulinum Toxin Type A dose per treatment session must not exceed 21 U/kg or 840 U, whichever is lower.

The total dose administered should be divided between the affected spastic muscles of the upper limb(s). No more than 0.5 ml of Botulinum Toxin Type A should be administered in any single injection site. See table below for recommended dosing:

Botulinum Toxin Type A Dosing by Muscle for Paediatric Upper Limb Spasticity

whichever is lower

Although actual location of the injection sites can be determined by palpation the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Repeat Botulinum Toxin Type A treatment should be administered when the effect of a previous injection has diminished, but no sooner than 16 weeks after the previous injection. A majority of patients in the clinical study were retreated between 16–28 weeks; however. some patients had a longer duration of response, i.e. 34 weeks or more. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Botulinum Toxin Type A and muscles to be injected.

Method of administration

When treating upper limb spasticity associated with cerebral palsy in children, Botulinum Toxin Type A is reconstituted with sodium chloride injection (0.9% w/v) (see section 6.6) and is administered by intramuscular injection as detailed above.

Focal spasticity of upper and lower limbs in paediatric cerebral palsy patients, two years of age or older:

Posology

When treating combined upper and lower spasticity in children aged 2 years or older refer to the posology section for the individual indications above. The dose of Botulinum Toxin Type A to be injected for concomitant treatment should not exceed a total dose per treatment session of 30 U/kg or 1000 U, whichever is lower. Retreatment of the upper and lower limbs combined should be considered no sooner than a 12 to 16-week window after the previous treatment session. The optimal time to retreatment should be selected based on individuals progress and response to treatment.

Method of administration

When treating combined upper and lower spasticity associated with cerebral palsy in children refer to the method of administration section for the individual indications above.

Posology

The doses recommended for torticollis are applicable to adults of all ages, provided the adults are of normal weight with no evidence of reduced neck muscle mass. A lower dose may be appropriate if the patient is markedly underweight or in the elderly, where reduced muscle mass may exist.

The initial recommended dose for the treatment of spasmodic torticollis is 500 units per patient given as a divided dose and administered into the two or three most active neck muscles.

For rotational torticollis distribute the 500 units by administering 350 units into the splenius capitis muscle, ipsilateral to the direction of the chin/head rotation and 150 units into the sternomastoid muscle, contralateral to the rotation.

For laterocollis, distribute the 500 units by administering 350 units into the ipsilateral splenius capitis muscle and 150 units into the ipsilateral sternomastoid muscle. In cases associated with shoulder elevation, the ipsilateral trapezoid or levator scapulae muscles may also require treatment, according to visible hypertrophy of the muscle or electromyographic (EMG) findings. Where injections of three muscles are required, distribute the 500 units as follows, 300 units splenius capitis, 100 units sternomastoid and 100 units to the third muscle.

For retrocollis distribute the 500 units by administering 250 units into each of the splenius capitis muscles. Bilateral splenii injections may increase the risk of neck muscle weakness.

All other forms of torticollis are highly dependent on specialist knowledge and EMG to identify and treat the most active muscles. EMG should be used diagnostically for all complex forms of torticollis, for reassessment after unsuccessful injections in non-complex cases, and for guiding injections into deep muscles or in overweight patients with poorly palpable neck muscles.

On subsequent administration, the doses may be adjusted according to the clinical response and side effects observed. Doses within the range of 250 – 1000 units are recommended, although the higher doses may be accompanied by an increase in side effects, particularly dysphagia. The maximum dose administered must not exceed 1000 units.

The relief of symptoms of torticollis may be expected within a week after the injection.

Injections may be repeated approximately every 16 weeks or as required to maintain a response, but not more frequently than every 12 weeks.

Children: The safety and effectiveness of Botulinum Toxin Type A in the treatment of spasmodic torticollis in children have not been demonstrated.

Method of administration

When treating spasmodic torticollis, Botulinum Toxin Type A is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing 500 units per ml of Botulinum Toxin Type A (see section 6.6).

Botulinum Toxin Type A is administered by intramuscular injection as described above.

Posology

In a dose ranging clinical trial on the use of Botulinum Toxin Type A for the treatment of benign essential blepharospasm, a dose of 40 units per eye was significantly effective. Doses of 80 units and 120 units per eye resulted in a longer duration of effect. However, the incidence of local adverse events, specifically ptosis, was dose related. In the treatment of blepharospasm and hemifacial spasm, the maximum dose used must not exceed a total dose of 120 units per eye.

An injection of 10 units (0.05 ml) medially and 10 units (0.05 ml) laterally should be made into the junction between the preseptal and orbital parts of both the upper (3 and 4) and lower orbicularis oculi muscles (5 and 6) of each eye. In order to reduce the risk of ptosis, injections near the levatorpalpebrae superioris should be avoided.

For injections into the upper lid, the needle should be directed away from its centre to avoid the levator muscle. A diagram to aid placement of these injections is provided above. The relief of symptoms may be expected to begin within two to four days with maximal effect within two weeks.

Injections should be repeated approximately every twelve weeks or as required to prevent recurrence of symptoms but not more frequently than every twelve weeks.

On such subsequent administrations, if the response from the initial treatment is considered insufficient, the dose per eye may need to be increased to:

– 60 units: 10 units (0.05 ml) medially and 20 units (0.1 ml) laterally;

– 80 units: 20 units (0.1 ml) medially and 20 units (0.1 ml) laterally; or

– up to 120 units: 20 units (0.1 ml) medially and 40 units (0.2 ml) laterally, above and below each eye in the manner previously described. Additional sites in the frontalis muscle above the brow (1 and 2) may also be injected if spasms here interfere with vision.

In cases of unilateral blepharospasm, the injections should be confined to the affected eye. Patients with hemifacial spasm should be treated as for unilateral blepharospasm. The doses recommended are applicable to adults of all ages including the elderly.

Children: The safety and effectiveness of Botulinum Toxin Type A in the treatment of blepharospasm and hemifacial spasm in children have not been demonstrated.

Method of administration

When treating blepharospasm and hemifacial spasm, Botulinum Toxin Type A is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing 200 units per ml of Botulinum Toxin Type A (see section 6.6).

Botulinum Toxin Type A is administered by subcutaneous injection medially and laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the eyes, as described above.

Posology

The treatment interval depends on the individual patient’s response after assessment. Treatment interval with Botulinum Toxin Type A should not be more frequent than every three months.

Remove any make-up and disinfect the skin with a local antiseptic.

Intramuscular injections should be performed using a sterile 29 – 30 gauge needle. The recommended injection points for glabellar lines and lateral canthal lines are described below:

Glabellar lines:

The recommended dose is 50 units (0.25 ml of reconstituted solution) of Botulinum Toxin Type A to be divided into 5 injection sites, 10 units (0.05 ml of reconstituted solution) are to be administered intramuscularly, at right angles to the skin, into each of the 5 sites: 2 injections into each corrugator muscle and one into the procerus muscle near the nasofrontal angle as shown above.

The anatomical landmarks can be more readily identified if observed and palpated at maximal frown. Before injection, place the thumb or index finger firmly below the orbital rim in order to prevent extravasation below the orbital rim.

The needle should be pointed upward and medially during the injection. In order to reduce the risk of ptosis, avoid injections near the levator palpebrae superioris muscle, particularly in patients with larger brow-depressor complexes (depressor supercilii). Injections in the corrugator muscle must be made into the central part of that muscle, at least 1 cm above the orbital rim.

In clinical studies an optimal effect, in glabellar lines, was demonstrated for up to 4 months after injection. Some patients were still responders at 5 months (see section 5.1).

Lateral canthal lines:

The recommended dose per side is 30 units (60 units for both sides, 0.30 ml of reconstituted solution) of Botulinum Toxin Type A, to be divided into 3 injection sites; 10 units (0.05 ml of reconstituted solution) are to be administered intramuscularly into each injection point.

Injection should be lateral (20 – 30° angle) to the skin and very superficial. All injection points should be at the external part of the orbicularis oculi muscle and sufficiently far from the orbital rim (approximately 1 – 2 cm) as shown above.

The anatomical landmarks can be more readily identified if observed and palpated at maximal smile. Care must be taken to avoid injecting the zygomaticus major/minor muscles to avoid lateral mouth drop and asymmetrical smile.

General information

In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed. In case of treatment failure after the first treatment session, the following approaches may be considered:

Analysis of the causes of failure, e.g. incorrect muscles injected, inappropriate injection technique, and formation of toxin-neutralising antibodies

Re-evaluation of the relevance of treatment with Botulinum Toxin Type A

The efficacy and safety, of repeat injections of Botulinum Toxin Type A, has been evaluated in glabellar lines up to 24 months and up to 8 repeat treatment cycles and for lateral canthal lines up to 12 months and up to 5 repeat treatment cycles.

Children: The safety and effectiveness of Botulinum Toxin Type A, in treating moderate to severe glabellar lines and lateral canthal lines, in individuals under 18 years of age have not been demonstrated.

Method of administration

For moderate to severe glabellar lines or lateral canthal lines, Botulinum Toxin Type A is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing 200 units per ml of Botulinum Toxin Type A (see section 6.6). Botulinum Toxin Type A is administered by intramuscular injection as described above.

Posology

The recommended initial dosage is 100 units per axilla. If the desired effect is not attained, up to 200 units per axilla can be administered for subsequent injections. The maximum dose administered should not exceed 200 units per axilla.

The area to be injected may be determined beforehand using the iodine-starch test. Both axillae should be cleaned and disinfected. Intradermal injections at ten sites, each site receiving 10 units, i.e., to deliver 100 units per axilla, are then administered. The maximum effect should be seen by week two after injection. In many cases, the recommended dose will provide adequate suppression of sweat secretion for approximately 48 weeks. The time point for further applications should be determined on an individual basis according to clinical need. Injections should not be repeated more frequently than every 12 weeks. There is some evidence for a cumulative effect of repeated doses so the time of each treatment for a given patient should be assessed individually.

Children: The safety and effectiveness of Botulinum Toxin Type A in the treatment of axillary hyperhidrosis in children has not been demonstrated.

Method of administration:

When treating axillary hyperhidrosis, Botulinum Toxin Type A is reconstituted with sodium chloride solution B.P. (0.9 % w/v) to yield a solution containing 200 units per ml of Botulinum Toxin Type A (see section 6.6).

Botulinum Toxin Type A is administered by intradermal injection as described above.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Side effects related to spread of toxin distant from the site of administration have been reported (see section 4.8) which, in some cases, was associated with dysphagia, pneumonia and/or significant debility resulting, very rarely, in death. Patients treated with therapeutic doses may present with excessive muscle weakness. The risk of occurrence of such undesirable effects may be reduced by using the lowest effective possible dose and by not exceeding the maximum recommended dose.

Botulinum Toxin Type A should only be used with caution and under close medical supervision in patients with subclinical or clinical evidence of marked defective neuromuscular transmission (e.g. myasthenia gravis). Such patients may have an increased sensitivity to agents such as Botulinum Toxin Type A, which may result in excessive muscle weakness with therapeutic doses. Patients with underlying neurological disorders are at increased risk of this side effect.

Caution should be exercised when treating adult patients especially the elderly, with focal spasticity affecting the lower limbs, who may be at increased risk of fall.

In placebo-controlled clinical studies, where patients were treated for lower limb spasticity, 6.3% and 3.7% of patients experienced a fall in the Botulinum Toxin Type A and placebo groups, respectively.

Dry eye has been reported with the use of Botulinum Toxin Type A in the treatment of glabellar lines, lateral canthal lines, blepharospasm and hemifacial spasm (see section 4.8). Reduced tear production, reduced blinking, and corneal disorders, may occur with the use of botulinum toxins, including Botulinum Toxin Type A.

Very rare cases of death, occasionally in the context of dysphagia, pneumopathy (including but not limited to dyspnoea, respiratory failure, respiratory arrest) and/or in patients with significant asthenia have been reported following treatment with botulinum toxin A or B. Patients with disorders resulting in defective neuromuscular transmission, difficulty in swallowing or breathing are more at risk of experiencing these effects. In these patients, treatment must be administered under the control of a specialist and only if the benefit of treatment outweighs the risk.

Botulinum Toxin Type A should be administered with caution to patients with preexisting swallowing or breathing problems, as these can worsen following the distribution of the effect of toxin into the relevant muscles. Aspiration has occurred in rare cases and is a risk when treating patients who have a chronic respiratory disorder.

The recommended posology and frequency of administration for Botulinum Toxin Type A must not be exceeded (see section 4.2).

Patients and their care-givers must be warned of the necessity to seek immediate medical treatment in case of swallowing, speech or respiratory problems.

Botulinum Toxin Type A should not be used to treat spasticity in patients who have developed a fixed contracture.

As with any intramuscular injection, Botulinum Toxin Type A should only be used where strictly necessary in patients with prolonged bleeding times, infection or inflammation at the proposed site(s) of injection.

Caution should be taken when Botulinum Toxin Type A is used where the targeted muscle shows excessive weakness or atrophy.

Botulinum Toxin Type A should only be used to treat a single patient, during a single session. Specific precautions must be taken during the preparation and administration of the product (see section 4.2) and for the inactivation and disposal of any unused reconstituted solution (see section 6.6).

Antibody formation to botulinum toxin has been noted rarely in patients receiving Botulinum Toxin Type A. Clinically, neutralising antibodies might be suspected by a substantial deterioration in response to therapy and/or the need for consistent use of increased doses.

When treating glabellar lines, it is essential to study the patient’s facial anatomy prior to administration. Facial asymmetry, ptosis, excessive dermatochalasis, scarring and any alterations to this anatomy, as a result of previous surgical interventions should be taken into consideration.

Careful consideration should be given before the injection of patients who have experienced a previous allergic reaction to a product containing botulinum toxin type A. The risk of a further allergic reaction must be considered in relation to the benefit of treatment.

Paediatric use

For the treatment of spasticity associated with cerebral palsy in children, Botulinum Toxin Type A should only be used in children of 2 years of age or over. Postmarketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with comorbidities, predominantly with cerebral palsy. In general, the dose used in these cases was in excess of that recommended (see section 4.8).

There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including following off-label use (e.g. neck area). Extreme caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease. Treatment in patients with poor underlying health status should be administered only if the potential benefit to the individual patient is considered to outweigh the risks.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of botulinum toxin may be potentiated by drugs interfering either directly or indirectly with neuromuscular function (e.g. aminoglycosides, curare-like nondepolarising blockers, muscle relaxants) and such drugs should be used with caution in patients treated with botulinum toxin due to the potential for undesirable effects.

4.6 Fertility, pregnancy and lactationPregnancy:

There are limited data from the use of Clostridium botulinum type A toxinhaemag­glutinin complex in pregnant women. Studies in animals have shown reproductive toxicity at high doses causing maternal toxicity (see section 5.3).

Botulinum Toxin Type A should be used during pregnancy only if the benefit justifies any potential risk to the foetus. Caution should be exercised when prescribing to pregnant women.

It is not known whether Clostridium botulinum type A toxin-haemagglutinin complex is excreted in human milk. The excretion of Clostridium botulinum type A toxinhaemag­glutinin complex in milk has not been studied in animals. The use of Clostridium botulinum type A toxin-haemagglutinin complex during lactation cannot be recommended.

Studies in male and female rats have shown effects on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

There is a potential risk of muscle weakness or visual disturbances which, if experienced, may temporarily impair the ability to drive or operate machinery.

4.8 Undesirable effectsGeneral

Side effects related to spread of toxin distant from the site of administration have been reported, such as dry mouth, exaggerated muscle weakness, dysphagia, aspiration/as­piration pneumonia, with fatal outcome in some very rare cases (see section 4.4). Hypersensitivity reactions have also been reported post-marketing.

The frequency of adverse reactions reported in placebo-controlled trials after a single administration is defined as follows:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to < 1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

The following adverse reactions were seen in patients treated across a variety of indications including blepharospasm, hemifacial spasm, torticollis, spasticity associated with either cerebral palsy or stroke/TBI and axillary hyperhidrosis:

In addition, the following adverse reactions specific to individual indications were reported:

*The frequency for Dysphagia was derived from pooled data from open-label studies. Dysphagia was not observed in the double-blind studies in the Adult Upper Limb (AUL) indication.

Focal spasticity affecting the lower limbs in adults

Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older

Focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age or older

5   PHARMACOLOGICAL PROPERTIES

Three Botulinum Toxin Type A doses were investigated over 1 treatment cycle in a clinical study.

Efficacy was measured by the medians of differences in the Percentage of Normal Activity (PNA) values (derived from the Blepharospasm Disability Scale) between each treatment group and placebo. A dose-dependent improvement in blepharospasm was evident with increasing Botulinum Toxin Type A dose, with all treatment groups being superior to placebo.

[a] p value > 0.001

For the 40 units, 80 units and 120 units Botulinum Toxin Type A treatment groups, the medians of the changes from baseline in PNA values were statistically significantly higher compared to those in placebo group at weeks 4, 8, and 12.

A statistically significant difference compared to placebo group was also observed for the 80 units and 120 units Botulinum Toxin Type A treatment groups at week 16, indicating a greater duration of response at the 80 units and 120 units doses.

The incidence of related Treatment Emergent Adverse Events (TEAEs), specifically ptosis, was higher in the Botulinum Toxin Type A treatment groups than in the placebo treatment group and was dose-dependent with greater incidence seen at higher Botulinum Toxin Type A doses. See table below:

Focal spasticity in paediatric cerebral palsy patients, two years of age or older

Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older

A double-blind, placebo-controlled multicentre study (Study Y-55–52120–141) was conducted in children with dynamic equinus foot deformity due to spasticity in children with cerebral palsy. A total of 235 botulinum toxin naïve or non-naïve patients with a Modified Ashworth Score (MAS) of grade 2 or greater were enrolled to receive Botulinum Toxin Type A 10 units/kg/leg, Botulinum Toxin Type A 15 units/kg/leg or placebo. Forty one percent of patients were treated bilaterally resulting in a total Botulinum Toxin Type A dose of either 20 units/kg or 30 units/kg. The primary efficacy variable was the mean change from baseline in MAS in ankle plantar flexors at Week 4. Secondary efficacy variables were the mean Physicians Global Assessment (PGA) score and Mean Goal Attainment Scaling (GAS) score at Week 4. Patients were followed up for at least 12 weeks post-treatment and up to a maximum of 28 weeks. On completion of this study, patients were offered entry into an openlabel extension study (Study Y-55–52120–147).

p < 0.05; **p < 0.003; *** p < 0.0006 compared to placebo; LS = least square

[a] GAS score measures progress towards goals that were selected at baseline from a list of twelve categories. The five most commonly selected goals were improved walking pattern (70.2%), improved balance (32.3%), decreased frequency of falling (31.1%), decreased frequency of tripping (19.6%) and improved endurance (17.0%)

Improvement in the spasticity of the ankle plantar flexors was observed, as assessed by the Tardieu scale. The spasticity grade (Y) was statistically significantly improved compared to placebo for both the 10 units/kg/leg and 15 units/kg/leg Botulinum Toxin Type A treatment groups at Week 4 and Week 12, and the angle of catch (Xv3) was significant for the 10 units/kg/leg Botulinum Toxin Type A group at Week 12 and at both Week 4 and Week 12 for the 15 units/kg/leg Botulinum Toxin Type A group.

Both Botulinum Toxin Type A treatment groups, 10 units/kg/leg and 15 units/kg/leg, demonstrated a significant improvement from baseline in the Observational Gait Scale (OGS) overall score at Week 4 when compared to placebo and a statistically significantly higher proportion of patients were treatment responders for initial foot contact on the OGS at Week 4 and Week 12.

Parents completed the condition-specific Module for cerebral palsy for the Paediatric Quality of Life Inventory. There was a statistically significant improvement from baseline in fatigue at Week 12 in the Botulinum Toxin Type A 10 units/kg/leg and

15 units/kg/leg Botulinum Toxin Type A treatment groups compared to placebo. No other statistically significant improvements were observed in the other subscales.

On completion of this study, 216 patients entered an open-label extension study (Y-55–52120–147) where they could receive re-treatment based on clinical need. Both distal (gastrocnemius, soleus and tibialis posterior) and proximal (hamstrings and hip adductors) muscles were permitted to be injected, including multilevel injections. Efficacy was observed over repeated treatment sessions for up to 1 year as assessed by MAS, PGA and GAS.

Focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age or older

The efficacy and safety of Botulinum Toxin Type A for the treatment of upper limb spasticity in children was evaluated in a randomised, multi-centre, double-blind, controlled, study in which doses of 8 U/kg and 16 U/kg in the selected study upper limb were compared with a low dose control group of 2 U/kg. A total of 210 botulinum toxin naïve or non-naïve patients with upper limb spasticity due to cerebral palsy (Modified Ashworth Scale (MAS) score >2 in the primary targeted muscle group (PTMG)) were randomised and treated in the study.

The total dose of Botulinum Toxin Type A was injected intramuscularly into the affected upper limb muscles which included the PTMG of either elbow flexors or wrist flexors as well as other upper limb muscles according to the disease presentation. No more than 0.5 ml was allowed to be administered per injection site. However more than one injection site per muscle was permitted.

An Electrical stimulation (ES) and/or ultrasound was used to assist muscle localisation for injection.

After the initial treatment, up to 3 further treatments of Botulinum Toxin Type A could be administered at planned doses of either 8 U/kg or 16 U/kg, although the investigator could elect to increase or decrease the dose (but not exceeding 16 U/kg). The minimum retreatment interval was 16 weeks. For treatment cycles 2, 3 and 4, injection into the lower limbs and the non-study upper limb was also allowed at the same time as the study upper limb was injected. Subjects were followed-up for a minimum of 1 year to a maximum of 1 year 9 months after entry into the study.

The primary efficacy variable was the mean change from baseline in MAS in PTMG at Week 6. Secondary efficacy variables were the mean Physicians Global Assessment (PGA) score and mean Goal Attainment Scale (GAS) score at Week 6.

MAS Change from Baseline at Week 6 and Week 16, PGA and GAS at Week 6 and Week 16 – Treatment Cycle 1 (mITT)

LS=least square

PTMG: elbow flexors or wrist flexors

* p< 0.05; **p< 0.001; *** p< 0.0001; compared to 2 U/kg dose group

[a] The four most commonly selected primary goals were Reaching, Grasp and release, Use of limb as a helping hand to stabilise and Involving affected arm more in daily activities.

Improvement in the spasticity of the PTMG was observed, as assessed by the Tardieu scale. In the PTMG elbow flexors, the angle of catch (Xv3) was statistically significantly improved compared with Botulinum Toxin Type A 2 U/kg at Week 6 for both the 8 and 16 U/kg treatment groups and also at Week 16 for the Botulinum Toxin Type A 16 U/kg group. In addition, a statistically significant decrease from Baseline in spasticity grade (Y) at Week 6 and 16 was observed for the Botulinum Toxin Type A 16 U/kg group compared with Botulinum Toxin Type A 2 U/kg. In the PTMG wrist flexors, statistically significant improvements from Baseline in Xv3 and Y were observed in the Botulinum Toxin Type A 16 U/kg group compared with the Botulinum Toxin Type A 2 U/kg group at Week 6 but not for the 8 U/kg group.

Parents completed the condition-specific Module for Cerebral Palsy for the Paediatric Quality of Life Inventory. At Week 16, there was a statistically significant improvement from Baseline in fatigue (p=0.0251) in the Botulinum Toxin Type A 8 U/kg group and, in movement and balance (p=0.0253) in the 16 U/kg group compared with the Botulinum Toxin Type A 2 U/kg group. No other statistically significant improvements were observed in the other subscales.

The majority of subjects treated with Botulinum Toxin Type A were retreated by Week 28 (62.3% in the Botulinum Toxin Type A 8 U/kg group and 61.4% in the Botulinum Toxin Type A 16 U/kg group), though more than 24% of subjects in both treatment groups had not yet required retreatment by Week 34.

Following repeated treatment, efficacy was generally maintained across treatment cycles for both Botulinum Toxin Type A 8 U/kg and 16 U/kg groups.

During the clinical development of Botulinum Toxin Type A, for the treatment of moderate to severe glabellar lines and lateral canthal lines, more than 4500 patients were included in the different clinical trials and approximately 3800 patients were exposed to Botulinum Toxin Type A.

Glabellar lines:

In clinical studies, 2032 patients with moderate to severe glabellar lines have been treated at the recommended dose of 50U of Botulinum Toxin Type A. Of these, 305 were treated with 50U in two pivotal Phase III double-blind placebo-controlled studies and 1200 treated with 50U in a long-term open-label repeated dose Phase III study. The remaining patients were treated in supportive and dose-ranging studies.

The median time to onset of response was 2 to 3 days following treatment, with the maximum effect observed at day thirty. In both pivotal placebo-controlled phase III studies, Botulinum Toxin Type A injections significantly reduced the severity of glabellar lines for up to 4 months. The effect was still significant after 5 months in one of the two pivotal studies.

Thirty days after injection, the assessment of the investigators showed that 90% (273/305) of patients had responded to treatment (exhibited no or mild glabellar lines at maximum frown), compared to 3% (4/153) placebo-treated patients. Five months after injection, 17% (32/190) of patients treated with Botulinum Toxin Type A were still responding to treatment compared to 1% (1/92) of placebo treated patients in the concerned study. The patients’ own assessment at maximum frown after thirty days gave a response rate of 82% (251/305) for those treated with Botulinum Toxin Type A and 6% (9/153) for those treated with placebo. The proportion of patients exhibiting a two-grade improvement according to the investigator assessment at maximum frown, was 77% (79/103) in the one pivotal Phase III study where this was assessed.

A subset of 177 patients had moderate or severe glabellar lines at rest prior to treatment. Assessment by investigators of this population, thirty days after treatment, showed that 71% (125/177) of Botulinum Toxin Type A-treated patients were considered responders versus 10% (8/78) of placebo-treated patients.

The long-term repeat dose open-label study showed that the median time to onset of response of 3 days was maintained across repeated dose cycles. The responder rate at maximum frown as determined by the investigator at day 30 was maintained over repeated cycles (ranging between 80% and 91% over the 5 cycles). The responder rate at rest over repeated dose cycles was also consistent with the single dose studies, with 56% to 74% of Botulinum Toxin Type A-treated patients considered by investigators to be responders thirty days after treatment.

Lateral canthal lines:

In clinical studies, 308 patients with moderate to severe lateral canthal lines at maximum smile have been treated at the recommended dose of 30 units per side in double-blind studies. Of these, 252 were treated in a Phase III double-blind placebo controlled study and 56 patients were treated in a double-blind Phase II dose-ranging study.

In the phase III study, Botulinum Toxin Type A injections significantly reduced the severity of lateral canthal lines compared with placebo (p<0.001) at 4, 8 and 12 weeks (assessed at maximum smile by the investigators). For the subjects’ assessment of satisfaction with the appearance of their lateral canthal lines, there was a statistically significant difference between Botulinum Toxin Type A and placebo (p<0.010) in favour of Botulinum Toxin Type A at 4, 8, 12 and 16 weeks.

The primary efficacy endpoint was at 4 weeks following injection: the assessment of the investigators showed that 47.2% (119/252) of patients had responded to treatment (exhibited no or mild lateral canthal lines at maximum smile), compared to 7.2% (6/83) placebo-treated patients.

In a post-hoc analysis, at the same time point, 4 weeks following injection, 75% (189/252) of Botulinum Toxin Type A treated patients had at least 1 grade improvement at maximum smile compared with only 19% (16/83) of placebo-treated subjects.

A total of 315 subjects entered the open label extension phase of the Phase III study in which they could be treated concomitantly for both lateral canthal lines and glabellar lines.

Patients treated with Botulinum Toxin Type A in the double-blind and open label phases of the Phase III received a median of 3 treatments for lateral canthal lines. The median interval between injections for lateral canthal lines, which was largely determined by the protocol design, ranged from 85 to 108 days. The results showed that efficacy is maintained with repeated treatments over the period of one year. The patient satisfaction levels at weeks 4, 16 and 52 show after the first treatment with Botulinum Toxin Type A that 165/252 subjects (65.5%) were either very satisfied or satisfied with the appearance of their LCLs.

At week 16, 4 weeks after either a second Botulinum Toxin Type A treatment for those randomised to Botulinum Toxin Type A in Part A or the first treatment for those randomised to placebo the proportion who were very satisfied or satisfied was 233/262 (89.0%). At week 52 when subjects could have had up to five cycles of Botulinum Toxin Type A treatment with the last one being at week 48 the proportion of very satisfied/satisfied subjects was 255/288 (84.7%).

No patient tested positive for toxin-neutralising antibodies after receiving repeated treatments with Botulinum Toxin Type A over one year.

The efficacy and safety of Botulinum Toxin Type A for the treatment of Axillary Hyperhidrosis was evaluated in a multi-centre, randomised, double-blind clinical study that included 152 adult patients with Axillary Hyperhidrosis who had symptoms for greater than one year and had failed standard therapy. Patients were injected with 200U in one axilla and placebo into the other. Two weeks later patients were injected with 100U Botulinum Toxin Type A in the axilla previously injected with placebo.

At the primary end point i.e. two weeks after treatment with Botulinum Toxin Type A, efficacy was measured as PCF (Proportional Change Function of sweat production on gravimetric analysis mg/min) relative to baseline. The results are shown below:

PCF = proportional change function; SD = standard deviation; U = units; vs =versus *Paired t-test Botulinum Toxin Type A 200U vs placebo: p<0.0001

#Paired t-test Botulinum Toxin Type A 200U vs Botulinum Toxin Type A 100U: p=0.0416

In the same study, absolute sweat production was a secondary endpoint: 200U Botulinum Toxin Type A treatment resulted in an average absolute sweat production decrease from 165 ± 112 mg/min to 24 ± 27 mg/min 2 weeks after injection, and 86.2 % of patients achieved an absolute sweat rate of less than 50 mg/min. The 100U treatment resulted in an average absolute sweat production decrease from 143 ± 111mg/min to 31 ± 48 mg/min 2 weeks after injection, and 83.4 % of patients achieved an absolute sweat rate of less than 50 mg/min. The placebo treatment resulted in an average absolute sweat production decrease from 173 ± 131mg/min to 143 ± 111 mg/min 2 weeks after injection, and 3.9 % of patients achieved an absolute sweat rate of less than 50 mg/min.

Efficacy was observed for up to 48 weeks. Subsequent injections under a follow up open label study showed a similar decrease in sweating though there was some evidence that duration of effect may persist for longer in subsequent treatment cycles.

5.2 Pharmacokinetic properties

Pharmacokinetic studies with botulinum toxin pose problems in animals because of the high potency, the minute doses involved, the large molecular weight of the compound and the difficulty of labelling toxin to produce sufficiently high specific activity. Studies using I125 labelled toxin have shown that the receptor binding is specific and saturable, and the high density of toxin receptors is a contributory factor to the high potency. Dose and time responses in monkeys showed that at low doses there was a delay of 2 – 3 days with peak effect seen 5 – 6 days after injection. The duration of action, measured by changes of ocular alignment and muscle paralysis, varied between 2 weeks and 8 months. This pattern is also seen in man, and is attributed to the process of binding, internalisation and changes at the neuromuscular junction.

5.3 Preclinical safety data

In a chronic toxicity study performed in rats, up to 12 units/animal, there was no indication of systemic toxicity. Reproductive toxicity studies in pregnant rats and rabbits given Clostridium botulinum type A toxin-haemagglutinin complex by daily intramuscular injection, at doses of 6.6 units/kg (79 units/kg total cumulative dose) and 3.0 units/kg (42 units/kg total cumulative dose) in rats and rabbits respectively, did not result in embryo/fetal toxicity. Implantation losses at maternally toxic doses were observed at higher doses in both species. Clostridium botulinum type A toxinhaemag­glutinin complex demonstrated no teratogenic activity in either rats or rabbits and no effects were observed in the pre- and post-natal study on the F1 generation in rats. Fertility of male and female rats was decreased due to reduced mating, secondary to muscle paralysis, at doses of 29.4 units/kg weekly in males and increased implantation loss at 20 units/kg weekly in females (see section 4.6).

In a pivotal single dose study, juveniles showed a slight delay in sexual maturation (not observed in the repeat dose study), an effect associated with decreased body weight, but subsequent mating performance and fertility were unaffected. In a pivotal repeated dose juvenile study, rats treated weekly from the age of weaning on Postnatal Day 21 up to 13 weeks of age comparable to children of 2 years old, to young adulthood (11 administrations over 10 weeks, up to total dose of approximately 33 units/kg) do not show adverse effects on postnatal growth (including skeletal evaluation), reproductive, neurological and neurobehavioral development.

The effects in reproduction, juvenile and chronic toxicity non-clinical studies were limited to changes in injected muscles related to the mechanism of action of Clostridium botulinum type A toxin-haemagglutinin complex.

There was no ocular irritation following administration of Clostridium botulinum type A toxin-haemagglutinin complex into the eyes of rabbits.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Human albumin Lactose.

6.2 Incompatibilities

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

6.3 Shelf lifeUnopened vial:

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C –8°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product 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 storageUnopened vial:

Store in a refrigerator (2°C-8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

3 ml vial (type 1 glass) with a stopper (bromobutyl rubber), with an overseal (aluminium), containing 300 units of botulinum toxin type A powder for solution for injection.

Pack sizes of 1 or 2 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

When preparing and handling Botulinum Toxin Type A solutions, the use of gloves is recommended. If Botulinum Toxin Type A dry powder or reconstituted solution should come into contact with the skin or mucous membranes, they should be washed thoroughly with water.

The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.

Each vial is for single use only.

Reconstitution instructions are specific for each of the 300 unit vial and the 500 unit vial. These volumes yield concentrations specific for the use for each indication.

*Preservative-free 0.9 % sodium chloride injection

For paediatric cerebral palsy spasticity, which is dosed using unit per body weight, further dilution may be required to achieve the final volume for injection.

Appearance of product after reconstitution:

A clear, colourless solution, free from particulate matter.

Immediately after treatment of the patient, any residual Botulinum Toxin Type A which may be present in either vial or syringe should be inactivated with dilute hypochlorite solution (1 % available chlorine).

Spillage of Botulinum Toxin Type A should be wiped up with an absorbent cloth soaked in dilute hypochlorite solution.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ipsen Limited

190 Bath Road,

Slough

Berkshire, SL1 3XE. UK.

8 MARKETING AUTHORISATION NUMBER(S)

PL 34926/0015

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 05 January 2011