Posology : מינונים

4.2   Posology and method of administration

Posology
Refer to specific recommendations for each indication described below.
Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan Units are different from other botulinum toxin preparations.

Elderly patients
No specific dose adjustment is required for use in the elderly. Initial dosing should begin at the lowest recommended dose for the specific indication. For repeat injections the lowest effective dose with the longest clinically indicated interval between injections is recommended. Elderly patients with significant medical history and concomitant medications should be treated with caution. There are limited clinical data in patients older than 65 years treated for post-stroke spasticity of the ankle and foot with BOTOX. see sections 4.4, 4.8 and 5.1 for further information).

There is limited phase 3 clinical data with BOTOX in patients older than 65 years for the following indications: vertical lines between the eyebrows seen at maximum frown (Glabellar Lines), lateral canthal lines seen at maximum smile (Crow’s Feet Lines) and forehead lines seen at maximum eyebrow elevation: (see section 5.1).

Paediatric population

The safety and efficacy of BOTOX in indications other than those described for the paediatric population in section 4.1 have not been established. No recommendation on posology can be made for indications other than focal spasticity associated with paediatric cerebral palsy. Currently available data per indication are described in section 4.2, 4.4, 4.8 and 5.1, as shown in the table below.


• Blepharospasm/Hemifacial spasm                          12 years
• Strabismus                                              12 years
• Cervical dystonia                                       12 years
• Cerebral palsy                                          2 years
• Upper and lower limb spasticity associated with         18 years stroke
• Chronic migraine (CM)                                   18 years
• Overactive Bladder (OAB) and Neurogenic                 18 years
Detrusor Overactivity (NDO)
• Primary hyperhidrosis of the axillae                    12 years
(limited experience in adolescents between
12 and 17 years, see section 4.4, 4.8 and
5.1))
• Glabellar lines seen at maximum frown                   18 years
• Crow’s Feet lines seen at maximum smile                 18 years • Glabellar lines seen at maximum frown treated at        18 years the same time as Crow's feet lines seen at maximum smile

The safety and effectiveness of BOTOX in the treatment of glabellar lines seen at maximum frown, crow’s feet lines seen at maximum smile, or forehead lines seen at maximum eyebrow elevation in individuals under 18 years of age have not been demonstrated. The use of BOTOX is not recommended in individuals under 18 years (see section 4.4).

BOT API MAR23 CL-2                                2/44
The following information is important:

If different vial sizes of BOTOX are being used as part of one injection procedure, care should be taken to use the correct amount of diluent when reconstituting a particular number of units per 0.1 ml. The amount of diluent varies between BOTOX 50 Allergan Units, BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe should be labelled accordingly.

BOTOX must only be reconstituted with sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection). The appropriate amount of diluent (see dilution table below) should be drawn up into a syringe.

This product is for single use only and any unused solution should be discarded.

For instructions on use, handling and disposal of vials please refer to section 6.6.

Dilution table for BOTOX 50, 100 and 200 Allergan Units vial size for all indications except bladder disorders:

50 Unit vial             100 Unit vial                    200 Unit vial Resulting      Amount of diluent sterile Amount of diluent sterile            Amount of diluent dose        unpreserved normal saline unpreserved normal saline            sterile unpreserved (Units per      solution (0.9% sodium     solution (0.9% sodium            normal saline solution 0.1 ml)         chloride solution for     chloride solution for           (0.9% sodium chloride injection) added in a 50  injection) added in a 100          solution for injection) Unit vial                 Unit vial                added in a 200 Unit vial     20 Units                0.25 ml                    0.5 ml                            1 ml
10 Units                 0.5 ml                     1 ml                             2 ml 5 Units                  1 ml                      2 ml                             4 ml      4 Units                1.25 ml                    2.5ml                              5ml
2.5 Units                 2 ml                      4 ml                             8 ml
1.25 Units                 4 ml                      8 ml                              ---- 

Overactive bladder:
It is recommended that a 100 Unit or two 50 Unit vials are used for convenience of reconstitution.

Dilution instructions using two 50 Unit vials:
• Reconstitute two 50 Unit vials of BOTOX each with 5 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix the vials gently.
• Draw the 5 ml from each of the vials into a single 10 ml syringe.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Dilution instructions using a 100 Unit vial:
• Reconstitute a 100 Unit vial of BOTOX with 10 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix gently.
• Draw the 10 ml from the vial into a 10 ml syringe.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Dilution instructions using a 200 Unit vial:
• Reconstitute a 200 Unit vial of BOTOX with 8 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix gently.
BOT API MAR23 CL-2                                 3/44
• Draw 4 ml from the vial into a 10 ml syringe.
• Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) into the 10 ml syringe and mix gently.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

This product is for single use only and any unused reconstituted product should be disposed of.

Urinary incontinence due to neurogenic detrusor overactivity:
It is recommended that a 200 Unit vial or two 100 Unit vials are used for convenience of reconstitution.

Dilution instructions using four 50 Unit vials:
• Reconstitute four 50 Unit vials of BOTOX, each with 3 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix the vials gently.
• Draw 3 ml from the first vial and 1 ml from the second vial into one 10 ml syringe.
• Draw 3 ml from the third vial and 1 ml from the fourth vial into a second 10 ml syringe.
• Draw the remaining 2 ml from the second and fourth vials into a third 10 ml syringe.
• Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) into each of the three 10 ml syringes, and mix gently.
This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX.
Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Dilution instructions using two 100 Unit vials:
• Reconstitute two 100 Unit vials of BOTOX, each with 6 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix the vials gently.
• Draw 4 ml from each vial into each of two 10 ml syringes.
• Draw the remaining 2 ml from each vial into a third 10 ml syringe.
• Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) into each of the three 10 ml syringes, and mix gently.
This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX.
Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Dilution instructions using a 200 Unit vial:
• Reconstitute a 200 Unit vial of BOTOX with 6 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) and mix the vial gently.
• Draw 2 ml from the vial into each of three 10 ml syringes.
• Complete the reconstitution by adding 8 ml of sterile unpreserved normal saline solution (0.9% sodium chloride solution for injection) into each of the 10 ml syringes, and mix gently.
This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Method of Administration

Refer to specific guidance for each indication described below.
BOTOX should only be given by physicians with appropriate qualifications, and expertise in the treatment and the use of the required equipment.

Generally valid optimum dose levels and number of injection sites per muscle have not been established for all indications. In these cases, individual treatment regimens should therefore be drawn 

BOT API MAR23 CL-2                               4/44
up by the physician. Optimum dose levels should be determined by titration but the recommended maximum dose should not be exceeded.

BOTOX, after reconstitution, must be used only for one session of injection(s) per patient. The excess of unused product must be disposed of as detailed in section 6.6.

Particular precautions should be taken for product preparation and administration as well as for the inactivation and disposal of the remaining unused solution (see section 4.4 and 6.6).

NEUROLOGIC DISORDERS:

Focal spasticity associated with paediatric cerebral palsy
Recommended needle:            Sterile 23-26 gauge/0.60–0.45 mm needle 
Administration guidance:        To be administered as a divided dose through single injections into the medial and lateral heads of the affected gastrocnemius muscle.

Recommended dose:               Hemiplegia: The initial recommended dose is 4 Units/kg body weight in the affected limb.
Diplegia: The initial recommended dose is 6 Units/kg body weight divided between the affected limbs.

Maximum total dose:             200 Units.

Additional information:         Clinical improvement generally occurs within the first 2 weeks after injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes but not more frequently than every 3 months. It may be possible to adapt the dosage regimen to obtain an interval of at least 6 months between treatment sessions.

Focal upper limb spasticity in adults

Recommended needle:             Sterile 25, 27 or 30 gauge needle. Needle length should be determined based on muscle location and depth.
Administration guidance:        Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. Multiple injection sites may allow BOTOX to have more uniform contact with the innervation areas of the muscle and are especially useful in larger muscles.

Recommended dose:               The exact dosage and number of injection sites should be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, presence of local muscle weakness and the patient response to previous treatment.

In controlled clinical trials the following doses were administered:

Muscle                           Total Dosage; Number of
Sites
Flexor digitorum profundus       15 – 50 Units; 1-2 sites
Flexor digitorum sublimis        15 – 50 Units; 1-2 sites
Flexor carpi radialis            15 – 60 Units; 1-2 sites
Flexor carpi ulnaris             10 – 50 Units; 1-2 sites
Adductor pollicis                20 Units; 1-2 sites
Flexor pollicis longus           20 Units; 1-2 sites
BOT API MAR23 CL-2                                5/44
Maximum total dose:            In controlled and open non-controlled clinical trials doses between 200 and 240 Units divided among selected muscles have been used at a given treatment session. Re-injections should not occur before 12 weeks.

Additional information:        In controlled clinical trials patients were followed for 12 weeks after single treatment. Improvement in muscle tone occurred within 2 weeks with the peak effect generally seen within 4 to 6 weeks. In an open, non-controlled continuation study, most of the patients were re- injected after an interval of 12 to 16 weeks, when the effect on muscle tone had diminished. These patients received up to 4 injections with a maximal cumulative dose of 960 Units over 54 weeks. If it is deemed appropriate by the treating physician, repeat doses may be administered, when the effect of a previous injection has diminished.
The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX and muscles to be injected. The lowest effective dose should be used.

Focal lower limb spasticity in adults
Recommended needle:             Sterile 25, 27 or 30 gauge needle. Needle length should be determined based on muscle location and depth.

Administration guidance:       Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. Multiple injection sites may allow BOTOX to have more uniform contact with the innervation areas of the muscle and are especially useful in larger muscles.

The following diagram indicates the injection sites for adult lower limb spasticity:



Recommended dose:              The recommended dose for treating adult lower limb spasticity involving the ankle and foot is 300 Units to 400 Units divided among up to 6 muscles, as listed in the following table. The maximum recommended dose at one treatment is 400 Units.

BOTOX Dosing by Muscle for Adult Lower Limb Spasticity:
Muscle                    Recommended Dose
Total Dosage; Number of Sites
Gastrocnemius
Medial head                    75 Units; 3 sites
Lateral head                   75 Units; 3 sites
Soleus                       75 Units; 3 sites

BOT API MAR23 CL-2                              6/44
Tibialis posterior                      75 Units; 3 sites
Flexor hallucis longus                    50 Units; 2 sites
Flexor digitorum longus                    50 Units; 2 sites
Flexor digitorum brevis                    25 Units; 1 site
Additional information:          If it is deemed appropriate by the treating physician, the patient should be considered for re-injection when the clinical effect of the previous injection has diminished, no sooner than 12 weeks after the previous injection.


Blepharospasm/hemifacial spasm
Recommended needle:              Sterile, 27-30 gauge/0.40–0.30 mm needle.

Administration guidance:         Electromyographic guidance is not necessary.

Recommended dose:                The initial recommended dose is 1.25-2.5 Units injected into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if spasms here interfere with vision.

Maximum total dose:              The initial dose should not exceed 25 Units per eye. In the management of blepharospasm total dosing should not exceed
100 Units every 12 weeks.

Additional information:          Avoiding injection near levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. The following diagrams indicate the possible injection sites:



In general, the initial effect of the injections is seen within 3 days and reaches a peak at 1 to 2 weeks post-treatment. Each treatment lasts approximately 3 months, following which the procedure can be repeated as needed. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. Normally no additional benefit is conferred by treating more frequently than every 3 months.

Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles (e.g. zygomaticus major, orbicularis oris) being injected as needed.

Strabismus

BOT API MAR23 CL-2                                 7/44
Recommended needle:        27-gauge/1.5" (40 mm) needle

Administration guidance:   Prepare a solution containing 2.5 units per 0.1 mL.
BOTOX is intended for injection into the extra-ocular muscles, with electromyographic guidance required. Electromyographic guidance may enhance injection precision. The electrical activity recorded by the tip of the injection needle is used as a guide to position it in the target muscle. This guidance is mandatory for treating strabismus.

To prepare the eye for the BOTOX injection, a few drops of local anaesthetic and ocular decongestant solution should be administered a few minutes before the injection.

Recommended dose:          Initial doses: use the lowest doses for treatment of mild deviations and higher doses for more marked deviations.

For vertical muscles and for horizontal strabismus of less than 20 prism diopters: 1.25 to 2.5 units (0.05 to 0.10 mL) for any type of muscle.

For horizontal strabismus of 20 to 50 prism diopters: 2.5 to 5 units
(0.10 to 0.20 mL) for any type of muscle.
For paralysis of the external oculomotor nerve persisting for a month or more: 1.25 to 2.5 units (0.05 to 0.10 mL) in the medial rectus.

Maximum total dose:        The maximum recommended dose as a single injection for any one muscle is 25 units. The recommended volume of BOTOX injected for treatment of strabismus is 0.05mL to 0.15mL per muscle.

Additional information:

The initial doses of diluted BOTOX usually induce paralysis of the injected muscles 1 or 2 days post-injection. The intensity of the paralysis increases over the first week. Paralysis lasts 2 to 6 weeks and gradually attenuates over an approximately equivalent period.
Overcorrections lasting more than 6 months are rare.

Approximately half of the patients treated will require additional doses due to insufficient paralysis of the muscle following the initial dose or because of mechanical factors such as marked deviations or restrictions, or because of the absence of motor binocular fusion to stabilize alignment.

It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.

Subsequent doses for patients experiencing adequate paralysis of the target muscle should be comparable to the initial dose. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to two-fold compared to the previously administered dose. Subsequent injections should not be administered until the effects of the previous dose have dissipated, as evidenced by the return of function to the injected and adjacent muscle.



BOT API MAR23 CL-2                          8/44
Cervical dystonia

Recommended needle:        Appropriately sized needle (usually 25-30 gauge/0.50–0.30 mm).
Administration guidance:   In clinical trials the treatment of cervical dystonia has typically included injection of BOTOX into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, semispinalis, longissimus and/or the trapezius muscle(s). This list is not exhaustive as any of the muscles responsible for controlling head position may be involved and therefore require treatment.

The muscle mass and the degree of hypertrophy or atrophy are factors to be taken into consideration when selecting the appropriate dose.
Muscle activation patterns can change spontaneously in cervical dystonia without a change in the clinical presentation of dystonia.

In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance.

Recommended dose:          No more than 200 Units total should be injected for the first course of therapy, with adjustments made in subsequent courses dependent on the initial response.

In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of reconstituted BOTOX ranged from 140 to
280 Units. In more recent studies, the doses have ranged from 95 to
360 Units (with an approximate mean of 240 Units). As with any drug treatment, initial dosing in a naïve patient should begin at the lowest effective dose. No more than 50 Units should be given at any one site.
No more than 100 Units should be given to the sternomastoid. To minimise the incidence of dysphagia, the sternomastoid should not be injected bilaterally.

Maximum total dose:        A total dose of 300 Units at any one sitting should not be exceeded.
The optimal number of injection sites is dependent upon the size of the muscle. Treatment intervals of less than 10 weeks are not recommended.

Additional information:    Clinical improvement generally occurs within the first 2 weeks after injection. The maximum clinical benefit generally occurs approximately 6 weeks post-injection. The duration of beneficial effect reported in clinical trials showed substantial variation (from 2 to 33 weeks) with a typical duration of approximately 12 weeks.


Chronic Migraine
Recommended needle:        Sterile 30-gauge, 0.5 inch needle

Administration guidance:   Chronic migraine should be diagnosed by, and BOTOX should be exclusively administered under the supervision of neurologists who are experts in the treatment of chronic migraine.

Injections should be divided across 7 specific head/neck muscle areas as specified in the table below. A 1-inch needle may be needed in the 
BOT API MAR23 CL-2                           9/44
neck region 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 the number of injections sites administered to the left, and half to the right side of the head and neck. If there is a predominant pain location(s), additional injections to one or both sides may be administered in up to 3 specific muscle groups (occipitalis, temporalis, and trapezius), up to the maximum dose per muscle as indicated in the table below.

The following diagrams indicate the injection sites:



The following diagrams indicate recommended muscle groups for optional additional injections: 


Recommended dose:               155 Units to 195 Units administered intramuscularly as 0.1 ml (5 Units) injections to 31 and up to 39 sites.

BOTOX Dosing By Muscle for Chronic Migraine:

Recommended Dose
Head/Neck Area                          Total Dosage (number of sites*) Frontalis**                             20 Units (4 sites)
Corrugator**                            10 Units (2 sites)
Procerus                                5 Units (1 site)
Occipitalis**                           30 Units (6 sites) up to 40 Units (up to 8 sites)

BOT API MAR23 CL-2                              10/44
Temporalis**                            40 Units (8 sites) up to 50 Units (up to 10 sites)
Trapezius**                             30 Units (6 sites) up to 50 Units (up to 10 sites)
Cervical Paraspinal Muscle
20 Units (4 sites)
Group**
Total Dose Range:                                   155 Units to 195 Units 31 to 39 sites
*
1 IM injection site = 0.1 ml = 5 Units BOTOX
**
Dose distributed bilaterally

Additional information:        The recommended retreatment schedule is every 12 weeks.


BLADDER DISORDERS:

Patients should not have a urinary tract infection at the time of treatment.
Prophylactic antibiotics should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment.

It is recommended that patients discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding.

For the management of urinary incontinence, BOTOX should be administered by physicians who are experienced in the assessment and treatment of bladder dysfunction (eg, urologists and urogynaecologists).

Overactive bladder

Recommended needle:            A flexible or rigid cystoscope can be used. The injection needle should be filled (primed) with approximately 1 ml of the reconstituted BOTOX prior to the start of the injections (depending on the needle length) to remove any air.

Administration guidance:       Prior to injection an intravesical instillation of diluted local anaesthetic, with or without sedation, may be used, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before the next steps of the procedure.

Reconstituted BOTOX (100 Units/10 ml) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone and base. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but over-distension should be avoided.

The needle should be inserted approximately 2 mm into the detrusor,
and 20 injections of 0.5 ml each (total volume 10 ml) should be spaced approximately 1 cm apart (see figure below). For the final injection, approximately 1 ml of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should not be drained so that 
BOT API MAR23 CL-2                                11/44
patients can demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post- injection and until a spontaneous void has occurred.



Recommended dose:              The recommended dose is 100 Units of BOTOX, as 0.5 ml (5 Units) injections across 20 sites in the detrusor.

Additional information:        Clinical improvement may occur within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in phase 3 clinical studies was 166 days [~24 weeks] based on patient request for re-treatment),
but no sooner than 3 months from the prior bladder injection.

Urinary incontinence due to neurogenic detrusor overactivity

Recommended needle:            A flexible or rigid cystoscope can be used. The injection needle should be filled (primed) with approximately 1 ml prior to the start of the injections (depending on the needle length) to remove any air.

Administration guidance:       Prior to injection, either an intravesical instillation of diluted anaesthetic (with or without sedation) or general anaesthesia may be used, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and rinsed with sterile saline before the next steps of the injection procedure.

Reconstituted BOTOX (200 Units/30 ml) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone and base. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but over-distension should be avoided.

The needle should be inserted approximately 2 mm into the detrusor,
and 30 injections of 1 ml each (total volume 30 ml) should be spaced approximately 1 cm apart (see figure above). For the final injection, approximately 1 ml of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should be drained. The patient should be observed for at least 30 minutes post-injection.
BOT API MAR23 CL-2                              12/44
Recommended dose:              The recommended dose is 200 Units of BOTOX, as 1 ml (~6.7 Units) injections across 30 sites in the detrusor.

Additional information:        Clinical improvement generally occurs within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in phase 3 clinical studies was 256-295 days (~36-42 weeks) for BOTOX 200 Units based on patient request for re-treatment, but no sooner than 3 months from the prior bladder injection.


SKIN AND SKIN APPENDAGE DISORDER:
Primary hyperhidrosis of the axillae

Recommended needle:            Sterile 30-gauge needle

Administration guidance:       The hyperhidrotic area may be defined by using standard staining techniques, e.g. Minor´s iodine-starch test.

Recommended dose:              50 Units of BOTOX is injected intradermally, evenly distributed in multiple sites approximately 1-2 cm apart within the hyperhidrotic area of each axilla.

Maximum total dose:            Doses other than 50 Units per axilla cannot be recommended.
Injections should not be repeated more frequently than every 16 weeks (see section 5.1).

Additional information:        Clinical improvement generally occurs within the first week after injection. Repeat injection of BOTOX can be administered when the clinical effect of a previous injection diminishes and the treating physician deems it necessary.


Glabellar lines seen at maximum frown
Recommended needle:             Sterile 30-gauge needle

Administration guidance:        Care should be taken to ensure that BOTOX is not injected into a blood vessel (see section 4.4).

Reconstituted BOTOX (50 U/1.25 ml, 100 U/2.5 ml or 200 U/5 ml) is injected using a sterile 30 gauge needle. 0.1 mL (4 U) is administered in each of the 5 injection sites (see Figure 1): 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 U.

Before injection, the thumb or index finger is to be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection. In order to reduce the risk of eyelid ptosis, the maximum dose of 4 U for each injection site as well as the number of injection sites should not be exceeded. In addition, injections near the levator palpebrae superioris muscle must be avoided, particularly in patients with larger brow-depressor complexes (depressor supercilii).

BOT API MAR23 CL-2                              13/44
Injections in the corrugator muscle must be done in the central part of that muscle, a distance of at least 1 cm above the arch of the eyebrows.
Figure 1:



Recommended dose:             The recommended injection volume per muscle site is 0.1 ml.
Treatment intervals should not be more frequent than every 3 months.

Maximum total dose:            20 Units
Additional information:       Improvement of severity of glabellar lines seen at maximum frown generally occurs within 1 week after treatment.
The effect was demonstrated for up to 4 months after injection.


Crow’s Feet lines seen at maximum smile
Recommended needle:           Sterile 30-gauge needle

Administration guidance:      Care should be taken to ensure that BOTOX is not injected into a blood vessel (see section 4.4).

Reconstituted BOTOX (50 U/1.25 ml, 100 U/2.5 ml or 200 U/5 ml) is injected using a sterile 30 gauge needle. 0.1 ml (4 U) is administered in each of the 3 injection sites per side (total of
6 injection sites) in the lateral orbicularis oculi muscle, for a total dose of 24 U in a total volume of 0.6 ml (12 U per side).

In order to reduce the risk of eyelid ptosis, the maximum dose of 4 U for each injection site as well as the number of injection sites should not be exceeded. In addition, injections should be made temporal to the orbital rim, thereby maintaining a safe distance from the muscle controlling eyelid elevation.

Injections should be given with the needle tip bevel up and oriented away from the eye. The first injection (A) should be made approximately 1.5 to 2.0 cm temporal to the lateral canthus and just temporal to the orbital rim. If the lines in the crow’s feet region are above and below the lateral canthus, inject as shown in Figure 2.


BOT API MAR23 CL-2                            14/44
Alternatively, if the lines in the crow’s feet region are primarily below the lateral canthus, inject as shown in Figure 3.

Figure 2:                                                            Figure 3: 


Recommended dose:             The recommended injection volume per muscle site is 0.1 ml.
Treatment intervals should not be more frequent than every 3 months.

Maximum total dose:          24 U
For simultaneous treatment with glabellar lines seen at maximum frown, the dose is 24 U for crow’s feet lines seen at maximum smile and 20 U for glabellar lines (see Administration Instructions for
Glabellar Lines, and Figure 1) for a total dose of 44 U in a total volume of 1.1 ml.

Additional information:       Improvement of severity of crow’s feet lines seen at maximum smile, when assessed by the investigator, occurred within 1 week of treatment. The effect was demonstrated for a median of 4 months after injection.

Forehead Lines seen at maximum eyebrow elevation:

Recommended needle:          Sterile 30-gauge needle

Administration guidance:      Care should be taken to ensure that BOTOX is not injected into a blood vessel (see section 4.4).

Reconstituted BOTOX (50 Units/1.25 ml, 100 Units/2.5 ml or 200
U/5 ml) is injected using a sterile 30 gauge needle. 0.1 ml (4 Units) is administered in each of the 5 injection sites in the frontalis muscle, for a total dose of 20 Units in a total volume of 0.5 ml (see Figure 4).
To identify the location of the appropriate injection sites in the frontalis muscle, the overall relationship between the size of the subject’s forehead, and the distribution of frontalis muscle activity should be assessed.

BOT API MAR23 CL-2                            15/44
The following horizontal treatment rows should be located by light palpation of the forehead at rest and maximum eyebrow elevation:

• Superior Margin of Frontalis Activity: approximately 1 cm above the most superior forehead crease
• Lower Treatment Row: midway between the superior margin of frontalis activity and the eyebrow, at least 2 cm above the eyebrow
• Upper Treatment Row: midway between the superior margin of frontalis activity and lower treatment row


The 5 injections should be placed at the intersection of the horizontal treatment rows with the following vertical landmarks:

• On the lower treatment row at the midline of the face, and 0.5 – 1.5 cm medial to the palpated temporal fusion line (temporal crest); repeat for the other side.
• On the upper treatment row, midway between the lateral and medial sites on the lower treatment row; repeat for the other side.

Figure 4:



Recommended dose:              The recommended injection volume per muscle site is 0.1 ml.
Treatment intervals should not be more frequent than every three months.
Maximum total dose: 20 U       The total dose for treatment of forehead lines (20 Units) in conjunction with glabellar lines (20 Units) is 40 Units/1.0 mL.
For simultaneous treatment with glabellar lines and crow’s feet lines, the total dose is 64 Units, comprised of 20 Units for forehead lines, 20 Units for glabellar lines (see Administration Instructions for Glabellar Lines, and Figure 1), and 24 Units for crow’s feet lines (see Crows Feet Lines Administration, and Figures 2 and 3).


BOT API MAR23 CL-2                              16/44
Additional information:          Improvement of severity of forehead lines seen at maximum eyebrow elevation occurred within 1 week of treatment. The effect was demonstrated for approximately 4 months after injection.


ALL INDICATIONS:
In case of treatment failure after the first treatment session, i.e. absence, at one month after injection, of significant clinical improvement from baseline, the following actions should be taken: -      Clinical verification, which may include electromyographic examination in a specialist setting, of the action of the toxin on the injected muscle(s);
-      Analysis of the causes of failure, e.g. bad selection of muscles to be injected, insufficient dose, poor injection technique, appearance of fixed contracture, antagonist muscles too weak, formation of toxin-neutralising antibodies;
-      Re-evaluation of the appropriateness of treatment with botulinum toxin type A; -      In the absence of any undesirable effects secondary to the first treatment session, instigate a second treatment session as following: i) adjust the dose, taking into account the analysis of the earlier treatment failure ii) use EMG; and iii) maintain a 3-month interval between the two treatment sessions.

In the event of treatment failure or diminished effect following repeat injections alternative treatment methods should be employed.
In treating adult patients, including when treating for multiple indications, the maximum cumulative dose should not exceed 400 Units, in a 12-week interval.

The efficacy and safety of repeat injections has not been evaluated, beyond 12 months, in patients being treated with BOTOX for glabellar and/or crow’s feet lines and/or forehead lines.