Botox 200 IU 1 Vial

Description

1. NAME OF THE MEDICINE  

BOTOX 200 UNITS ALLERGAN, powder for injectable solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION  

Botulinum toxin type A* ¹ ……………………………………………………………. 200 units* ² ALLERGAN

for a bottle.

*1 (from Clostridium botulinum)

*2 One unit corresponds to the lethal dose 50 (LD50) of the reconstituted product injected intraperitoneally in mice.

Botulinum toxin units are not interchangeable between products.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM  

Powder for solution for injection.

White powder.

The BOTOX product appears as a thin white deposit that may be difficult to see at the bottom of the bottle.

4. CLINICAL DATA  

4.1. Therapeutic indications  

Adults

Bladder dysfunction

Treatment of idiopathic overactive bladder associated with symptoms including:

· 3 episodes of urinary incontinence with urgency over 3 days,

And

· urinary frequency defined by a number of urinations ≥ 8 per day and not responding adequately to anticholinergics (after 3 months of treatment) or intolerant to anticholinergic treatment and not responding to well-conducted physiotherapy.

Treatment of neurological detrusor overactivity leading to urinary incontinence not controlled by anticholinergic treatment in:

· spinal cord injured patients,

· patients with multiple sclerosis.

Neurological disorders

Prophylactic treatment of chronic migraine (presence of headaches at least 15 days per month including at least 8 migraine days per month) in adult patients who have not responded to or are intolerant to other migraine prophylactic treatments.

Adults and children over 12 years old

· Oculomotor disorders: strabismus, recent oculomotor paralysis, recent thyroid myopathy.

· Blepharospasm.

· Hemifacial spasm.

· Spasmodic torticollis.

· Severe axillary hyperhidrosis that has resisted local treatments and caused significant psychological and social impact.

Adults and children 2 years and older

· Local symptomatic treatment of spasticity (muscle hyperactivity) of the upper and/or lower limbs.

4.2. Dosage and method of administration  

General recommendations

BOTOX must be administered as part of a comprehensive multidisciplinary approach by specialist physicians who already have good experience in the use of the toxin in these indications and with an appropriate technical platform.

The recommended doses of BOTOX are not interchangeable with other botulinum toxin preparations. They are expressed in ALLERGAN UNITS ( see section 4.4 ) and are different from other botulinum toxin preparations.

If different presentations of BOTOX are used in an injection procedure, care must be taken to use the correct amount of solvent by reconstituting the number of units per 0.1 ml determined. The amount of solvent varies between BOTOX 50 UNITS ALLERGAN, BOTOX 100 UNITS ALLERGAN and BOTOX 200 UNITS ALLERGAN. Each syringe will be labeled accordingly.

In case of a history of neurogenic facial damage, it is recommended to reduce the dosage during the first injection session ( see section 4.4 ).

Elderly patients

Initial treatment should be initiated with the lowest dose recommended for the indication. Elderly patients with significant medical history and concomitant medications should be treated with caution.

Pediatric population

The safety and efficacy of BOTOX in indications other than those described in section 4.1 of the Summary of Product Characteristics for the pediatric population have not been established. In the pediatric population, no dosage recommendations can be made for indications other than the local symptomatic treatment of spasticity. For this indication, BOTOX should only be administered by physicians experienced in the evaluation and local symptomatic treatment of pediatric spasticity and as part of a structured rehabilitation program.

Currently available data in the paediatric population are described in sections 4.2, 4.4, 4.8, 5.1 of the Summary of Product Characteristics as shown in the table below.

Oculomotor disorders	12 years (see sections 4.4 and 4.8)
Blepharospasm/Hemifacial spasm	12 years (see sections 4.4 and 4.8)
Cervical dystonia	12 years (see sections 4.4 and 4.8)
Local symptomatic treatment of spasticity	2 years (see sections 4.2, 4.4 and 4.8)
Severe axillary hyperhidrosis	12 years (limited experience in adolescents aged 12 to 17 years, see sections 4.4, 4.8 and 5.1)
Neurological detrusor overactivity in children	5-17 years (see sections 4.8 and 5.1)
Overactive bladder in children	12-17 years (see sections 4.8 and 5.1)

Minimum interval between 2 injection sessions

The presence of antibodies against botulinum toxin type A may reduce the effectiveness of BOTOX treatment. Therefore, as a precautionary measure, a minimum interval between 2 injection sessions should be respected:

· For the indication in severe axillary hyperhidrosis that has resisted local treatments: 4 months.

· For the indication of local symptomatic treatment of spasticity (muscle hyperactivity) of the upper and/or lower limbs in adults and children aged 2 years and over: 3 months.

· For other indications in adults and children over 12 years: 2 months and 10 weeks for the treatment of spasmodic torticollis.

· For the indication in overactive bladder in adults: when the benefits of the previous injection have faded (generally 6 months) and respecting a minimum interval of 3 months.

· For the indication in neurological detrusor overactivity in adults: when the benefits of the previous injection fade (generally 9 months) and respecting a minimum interval of 3 months.

· For indication in chronic migraine in adults: 3 months.

Injection technique

Strict intramuscular or strict intradermal route depending on the indication. Refer to the specific recommendations for each indication, described below.

Generally, the optimal dose and number of injection sites per muscle have not been established for all indications. In this case, dosage regimens should be established individually by the practitioner. Optimal doses should always be established by titration and should not exceed the maximum recommended dose.

After disinfecting the skin, the diluted dose of BOTOX is injected using a sterile needle of a gauge adapted to the muscle to be injected.

Electromyographic guidance can increase injection accuracy: electrical activity recorded by the injection needle tip is used as a guide for positioning in the target muscle.

This guidance is imperative in the treatment of strabismus.

In children, botulinum toxin injections should be administered by specialized physicians with extensive experience in this treatment in children. This drug treatment should be included in a comprehensive multidisciplinary approach (involving a neurologist, pediatrician, physical medicine and rehabilitation physician, orthopedic surgeon, etc.) and combined with rehabilitation care.

In adult patients with overactive bladder, this drug treatment by injection into the detrusor should be included in a comprehensive multidisciplinary management involving a urologist and a gynecologist-obstetrician who has received specific training in the use of botulinum toxin for this indication under the supervision of a urologist. Botulinum toxin injections should be performed under cystoscopic visualization, via a flexible or rigid cystoscope, avoiding the trigone.

In adult patients with neurological detrusor overactivity, this drug treatment by injection into the detrusor should be included in a comprehensive multidisciplinary management involving a urologist and a physical medicine and rehabilitation physician who has received specific training in the use of botulinum toxin for this indication under the supervision of a urologist. Botulinum toxin injections should be performed under cystoscopic visualization, via a flexible or rigid cystoscope, avoiding the trigone.

For instructions on reconstitution of the medicinal product before administration, handling and disposal, see section 6.6.

After reconstitution, BOTOX should only be used for a single injection session for a single patient.

BLEPHAROSPASM

1) Preparation of the product

Prepare a solution containing 2.5 units per 0.1 ml.

2) Dosage and method of administration

Use a 27 or 30 gauge (0.40 or 0.30 mm) needle.

Electromyographic guidance is not necessary.

The recommended starting dose for the treatment of bilateral blepharospasm is 17.5 units per eye (0.70 ml) with the following distribution:

· 7.5 units (0.30 ml) distributed between three sites (2.5 units per site): internal and external part of the orbicularis muscle of the upper eyelid and external pretarsal part of the orbicularis muscle of the lower eyelid.

· 5 units (0.20 ml) in the brow bone divided into 2 sites (2.5 units per site).

· 5 units (0.20 ml) in the upper facial area.

The initial dose should not exceed 25 units (1 ml) per orbicularis.

Avoiding injection near the upper eyelid levator muscle helps reduce the complication of ptosis.

Avoiding injection into the medial lower eyelid, and thus reducing diffusion into the minor oblique, helps reduce the complication of diplopia.

The following diagrams indicate possible injection sites:

Typically, the effect of the injections appears within three days and peaks one to two weeks after treatment. Each treatment lasts approximately three months, after which the procedure can be repeated indefinitely. For reinjections, the dose can be increased up to twofold if the initial treatment result is deemed insufficient. However, there appears to be little benefit from injecting more than 5 Units per site.

The total dose should not exceed 100 Units (4 ml) every 3 months.

Normally, treatment more frequently than every 3 months does not provide any additional benefit.

HEMIFACIAL SPASM

The doses and injection technique are identical to those described for the treatment of unilateral blepharospasm.

Electromyographic monitoring may be necessary to identify small circular muscles.

Patients with hemifacial spasm or VIIth cranial nerve disorders will be treated as for unilateral blepharospasm; other affected facial muscles will be injected as needed.

SPASMODIC TORTICOLLIS

1) Preparation of the product

Prepare a solution containing 10 units per 0.1 ml.

2) Dosage and method of administration

Use a 25, 27 or 30 gauge needle (0.50, 0.40 or 0.30 mm).

In clinical trials, treatment of spastic torticollis typically consisted of injecting BOTOX into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, major complexius, transversus neck, and/or trapezius muscle(s). This list is not exhaustive; any muscle responsible for controlling head position may be involved and therefore require treatment.

Muscle mass and the degree of hypertrophy or atrophy are factors to consider when selecting the appropriate dose. Muscle activation patterns may change spontaneously in spastic torticollis, without changing the clinical presentation of dystonia.

If it is difficult to isolate the muscles to be injected, injections should be made with electromyographic assistance.

· The recommended initial doses are as follows:

· sternocleidomastoid: 40 to 75 Units (0.40 to 0.75 ml), splenius: 75 Units – 50 to 150 Units (0.75 ml) and trapezius: 75 Units – 50 to 100 Units (0.75 ml). For each muscle, the dose will be divided into 3 sites.

· elevator of the scapula: 50 Units (0.5 ml) divided into 2 sites;

· scalene: 25 Units (0.25 ml).

In initial controlled clinical trials to establish safety and efficacy in spastic torticollis (cervical dystonia), doses of reconstituted BOTOX solution ranged from 140 to 280 Units. In more recent studies, doses ranged from 95 to 360 Units (with an approximate mean of 240 Units). As with any drug therapy, the initial dose in a treatment-naïve patient will be the lowest effective dose.

Do not administer more than 50 units (0.50 ml) per site.

To minimize the risk of dysphagia, the sternocleidomastoid should not be injected bilaterally, nor receive more than 100 units (1 ml) per session.

The total dose should never exceed 200 units (2 ml) during the first session.

Adjustments may be made during subsequent sessions depending on the initial response, without exceeding a total dose of 300 units (3 ml) per session.

The optimal number of injection sites depends on muscle size.

Clinical improvement usually appears within two weeks of injection. Clinical benefit usually appears around the sixth week after injection. A repeat injection may be given when the clinical effect of the previous injection has diminished.

The duration of beneficial effect reported in clinical trials has shown significant variation (from 2 to 33 weeks), with a more common duration of 3 months, depending on the symptoms and individual patient responses. The dosage regimen should therefore be tailored to the needs of each patient.

Injection sessions should be repeated depending on the duration of the clinical effect. They should always be spaced at least 10 weeks apart.

STRABISMUS

1) Preparation of the product

Prepare a solution containing 2.5 units per 0.1 ml.

2) Dosage and method of administration

Use a 27 gauge needle that is 40 mm long.

BOTOX is intended to be injected into the extraocular muscles using electromyographic guidance (see Injection Technique).

To prepare the eye for BOTOX injection, it is recommended to administer a few drops of local anesthetic and eye decongestant a few minutes before the injection.

Initial doses: Use the smaller doses for treating small deviations and the larger doses for large deviations.

For vertical muscles and for horizontal strabismus of less than 20 prismatic diopters: 1.25 units to 2.5 units (from 0.05 ml to 0.10 ml) regardless of the muscle.

For horizontal strabismus of 20 to 50 prismatic diopters: 2.5 units to 5 units (from 0.10 ml to 0.20 ml) regardless of the muscle.

For persistent external motor nerve paralysis lasting one month or more: 1.25 units to 2.5 units (0.05 ml to 0.10 ml) in the medial rectus.

Initial doses of diluted BOTOX usually cause paralysis of the injected muscles one to two days after injection; the intensity of this paralysis increases during the first week. The paralysis lasts 2 to 6 weeks and gradually resolves over a roughly equivalent period. Overcorrections lasting more than 6 months are rare.

About half of patients will require additional doses, either because of insufficient muscle paralysis after the initial dose, or because of mechanical factors such as significant deviations or restrictions, or because of lack of binocular motor fusion to stabilize alignment.

ADULT: LOCAL SYMPTOMATIC TREATMENT OF SPASTICITY (MUSCULAR HYPERACTIVITY) OF THE UPPER AND/OR LOWER LIMBS

1) Preparation of the product

Prepare a solution with a dilution appropriate to the dosage.

2) Dosage and method of administration

Dosage

The exact dosage and number of injection sites should be individualized based on the size, number, and location of the muscles involved, the severity of spasticity, the presence of localized muscle weakness, and the patient’s response to previous treatment.

Average dosages per injected muscle:

In clinical trials, the total dose administered per injection session did not exceed 360 Units. The total dose should be divided among the selected muscles.

Generally, the maximum total dose is set at 6 Units/kg.

Mode of administration

Use a 25, 27, or 30 gauge needle for superficial muscles and a longer needle for deeper muscles.

Electromyographic guidance or nerve stimulation techniques may be helpful in isolating the affected muscles. Choosing multiple injection sites per muscle allows for more even distribution of BOTOX and is particularly useful for larger muscles.

Clinical improvement in muscle hypertonia is generally observed within two weeks following the injection session. The maximum clinical effect generally appears four to six weeks after treatment. Injection sessions may be repeated if necessary, but should always be spaced at least three months apart.

In clinical trials, the interval between 2 injection sessions was between 12 and 16 weeks.

During a new injection session, the intensity and type of muscle spasticity may lead to modifying the dose of BOTOX administered and the choice of muscles to be injected.

CHILDREN AGED 2 YEARS AND OLDER: LOCAL SYMPTOMATIC TREATMENT OF SPASTICITY (MUSCULAR HYPERACTIVITY) OF THE UPPER AND/OR LOWER LIMBS

1) Preparation of the product

Prepare a solution with a dilution appropriate to the dosage.

2) Dosage and method of administration

After reconstitution, BOTOX is injected with a sterile 27 or 30 gauge needle of a length adapted to the targeted muscles.

To locate the affected muscles, the use of electromyographic (EMG) guidance or nerve stimulation techniques may be helpful.

The exact dosage and number of injection sites should be individualized based on the size, number, and location of the muscles involved, the severity of spasticity, the presence of local muscle weakness, and the patient’s response to previous treatment. In clinical trials, doses per muscle ranging from 0.5 to 2.0 Units/kg body weight for the upper limb and 2.0 to 4.0 Units/kg body weight for the lower limb were administered at each treatment session.

Do not exceed the initial dose recommended when initiating treatment.

In the treatment of equinus foot, two injections are made into each of the medial (internal) and lateral (external) heads of the affected gastrocnemius (gastrocnemius) muscle.

In case of hemiplegia, the recommended initial dose is 4 Units per kg injected into the affected limb.

In case of diplegia, the recommended initial dose is 6 Units per kg, to be divided between the two affected limbs.

The recommended initial dose should be strictly adhered to in children, particularly those:

· who have associated comorbidities, particularly those with pre-existing swallowing or respiratory disorders,

· whose muscles to be treated are underdeveloped,

· which require multi-site injection,

· who benefit from injections under general anesthesia.

For guidance, the table below provides guidelines for BOTOX injection in the treatment of local spasticity in children aged 2 years and older.

In all cases, when choosing the dose, an individual benefit/risk assessment should be considered, in order to reduce the risk of adverse effects, in particular the risk of diffusion of the toxin away from the administration site ( see sections 4.4 and 4.8 ). Depending on the response to previous treatment, the dose may be increased above the recommended initial dose with extreme caution, without, however, exceeding the maximum dose per session indicated below. The dose and treatment plan should be re-evaluated if adverse effects occur.

Clinical improvement usually occurs within two weeks of the injection session. Injection sessions should be repeated depending on the duration of the clinical effect.

They will always be spaced at least 3 months apart. An appropriate dosage should allow for an interval of at least 6 months between two sessions.

AXILLARY HYPERHIDROSIS

1) Preparation of the product

Prepare a solution containing 100 Units per 4 ml or 2.5 Units per 0.1 ml.

2) Dosage and method of administration

Use a 30 gauge needle.

Inject 50 Units of BOTOX by strict intradermal injection, evenly distributed in several sites of the hyperhidrosis area of ​​each armpit separated from each other by approximately 1 to 2 cm. The area of ​​hyperhidrosis can be determined using standardized methods, such as the Minor method (iodine test). Doses other than 50 Units per armpit have not been studied and therefore cannot be recommended.

Clinical improvement generally occurs within the first week following the injection session.

The response to treatment is greater than 4 months and can last 1 year or more. Additional injections may be given when the clinical effect of previous injections diminishes, but it is necessary to respect a minimum interval of 4 months between 2 injection sessions.

ADULTS: BLADDER DYSFUNCTIONS

1) Preparation of the product

Prepare a solution with a dilution appropriate to the dosage (see section 6.6).

2) Dosage and method of administration

At the time of treatment, patients should not have a urinary tract infection (see section 4.3).

A cyto-bacteriological examination of urine must be systematically carried out 5 days before treatment. In case of sterility, prophylactic antibiotic therapy must be administered to the patient 1 to 3 days before treatment, on the day of treatment and 1 to 3 days after treatment. In case of asymptomatic bacterial colonization, appropriate antibiotic therapy must be initiated at least 2 days before, continued on the day of treatment and at least 2 days after.

Discontinuation of antiplatelet therapy is recommended at least 3 days prior to the injection procedure. Patients on anticoagulants should be managed appropriately to reduce the risk of bleeding.

ADULTS: OVERACTIVE BLADDER

Patients should be informed that clean intermittent catheterization to empty their bladder may be necessary. They or those around them should be able to perform this (see section 4.4).

Intravesical instillation of a dilute anesthetic solution with or without associated sedation may be performed prior to injection according to local practice. If local anesthetic is instilled, the bladder should be drained and flushed with sterile sodium chloride solution before proceeding with the injection procedure.

Start treatment with a dose of 50 Units of BOTOX. If the response is insufficient, the study dose of 100 Units of BOTOX could be used for subsequent injections.

The reconstituted BOTOX solution (see section 6.6) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with sufficient sodium chloride solution to allow adequate visualization of the injections, while avoiding excessive distension.

The needle should be filled with approximately 1 ml of reconstituted BOTOX solution (depending on the needle length) before starting injections to empty the air from the dead volume.

The needle should be inserted approximately 2 mm into the detrusor muscle, and the 0.5 ml injections should be given at 20 sites approximately 1 cm apart (see diagram below). The last injection should be given with 1 ml of sterile sodium chloride solution to ensure that the full dose has been injected. After the injections have been given, the sodium chloride solution used for bladder wall visualization should not be drained so that the patient can demonstrate the ability to void before leaving the healthcare facility. The patient should remain under observation for at least 30 minutes after the injection session and until spontaneous voiding returns.

Clinical improvement is generally observed within the first 2 weeks following the injection. A new injection may be considered when the clinical benefit of the previous injection fades (average observed duration of effect, based on a patient request for retreatment, in the Phase III studies with 100 Units of BOTOX: 166 days (approximately 24 weeks)), and respecting a minimum interval of 3 months. For patients who received 100 Units of BOTOX in the Phase III studies and then in the open-label extension study (N=438), the average observed duration of effect, based on a patient request for retreatment, was 212 days (approximately 30 weeks).

ADULTS: NEUROLOGICAL DETRUSOR HYPERACTIVITY

Patients should be informed that if they did not self-catheterize prior to BOTOX treatment, clean intermittent catheterization may be necessary to empty their bladder during and after treatment. They or those around them should be able to perform this (see section 4.4).

Intravesical instillation of a dilute anesthetic solution with or without associated sedation, or general anesthesia may be administered prior to injection according to local practice. If local anesthetic is instilled, the bladder should be drained and flushed with sterile sodium chloride solution before proceeding with the injection procedure.

In spinal cord injuries, the recommended dose is 200 Units of BOTOX.

In patients with multiple sclerosis, the recommended starting dose is 100 Units of BOTOX. In patients using self-catheterization as a voiding method, a dose of 200 Units of BOTOX may be considered. The injection is performed under cystoscopic visualization, via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with a sufficient amount of sodium chloride solution to allow adequate visualization of the injections, while avoiding excessive distension.

The needle should be filled with approximately 1 ml of reconstituted BOTOX solution (depending on the needle length) before starting injections to empty the air from the dead volume.

The needle should be inserted approximately 2 mm into the detrusor muscle, and the 1 ml injections should be given at 30 sites approximately 1 cm apart (see diagram). The last injection should be given with 1 ml of sterile sodium chloride solution to ensure that the full dose has been injected. After the injections have been made, the sodium chloride solution used for visualizing the bladder walls should be drained. The patient should remain under observation for at least 30 minutes after the injection session.

Clinical improvement is generally observed within the first 2 weeks following the injection. A new injection may be considered when the clinical benefit of the previous injection fades, approximately 9 months later (average observed duration of effect, based on a patient-expressed retreatment request, in the phase III studies: 256 to 295 days with 200 Units of BOTOX (approximately 36-42 weeks)), and respecting a minimum interval of 3 months. For patients who received 200 Units of BOTOX in the phase III studies and then in the open-label extension study (N=174), the average observed duration of effect, based on a patient-expressed retreatment request, was 253 days (approximately 36 weeks).

ADULTS: CHRONIC MIGRAINE

1) Preparation of the product

Prepare a solution with a dilution appropriate to the dosage.

2) Dosage and method of administration

Use a 30 gauge needle that is 13 mm long.

Injections should be distributed over 7 specific muscle areas of the head/neck as shown in the table below. A 25mm needle may be required in the neck area for patients with extremely thick neck muscles.

With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscles should be injected bilaterally, with half of the injection sites administered on the left side and the other half on the right side of the head and neck. If one or more sites are more painful, additional injections may be administered unilaterally or bilaterally in up to 3 specific muscle groups (occipitalis, temporalis, and trapezius), but not exceeding the maximum dose per muscle indicated in the table below.

The recommended interval between treatments is 3 months. After the first two treatment cycles, the appropriateness of continuing treatment in the absence of efficacy should be reassessed before each new treatment session.

The injection sites are listed in the diagrams below:

The muscle groups recommended for optional additional injections are shown in the diagrams below:

The recommended dose is between 155 units and 195 units administered intramuscularly as 0.1 ml (5 units) injections at 31 to 39 injection sites.

Dosages per injected muscle:

	Recommended dose
Head/Neck Areas	Total dose (number of injection sites a )
Corrugator b	10 Units (2 sites)
Procerus	5 Units (1 site)
Frontalis b	20 Units (4 sites)
Temporalis b	40 Units (8 sites) to 50 Units (up to 10 sites)
Occipitalis b	30 Units (6 sites) to 40 Units (up to 8 sites)
Paraspinal cervical muscles b	20 Units (4 sites)
Trapezius b	30 Units (6 sites) to 50 Units (up to 10 sites)
Total dose between :	155 Units to 195 Units (31 to 39 sites)

¹ intramuscular injection site = 0.1 ml = 5 Units of BOTOX

^b Doses distributed bilaterally

All therapeutic indications :

In the event of failure after a first treatment session, i.e. in the absence, one month after the session, of significant functional improvement compared to the initial assessment, it is necessary to:

· clinically verify, and ideally by electromyographic examination in a specialized environment, the action of the toxin on the injected muscle(s),

· analyze the causes of failure:

o poor selection of injected muscles,

o insufficient dose,

o unsuitable injection technique,

o appearance of a fixed retraction,

o antagonist muscles too weak,

o formation of neutralizing antibodies,

· reassess the relevance of treatment with botulinum toxin type A,

· in the absence of any adverse effects following the first treatment session, perform a second injection as follows:

o adjust the dose taking into account data from the analysis of the failure of the previous treatment,

o use electromyographic guidance,

o respect the 3-month interval between the first and second injection.

In case of treatment failure or reduction of effect after repeated injections, alternative treatments should be used.