4.1. Therapeutic indications

BOTOX is indicated for:

Neurologic disorders:

BOTOX is indicated for the symptomatic treatment of:

• treatment of focal spasticity, including:

elbow, wrist and hand in paediatric cerebral palsy patients, two years of age or older as an adjunct to rehabilitative therapy

ankle and foot in ambulant paediatric cerebral palsy patients, two years of age or older as an adjunct to rehabilitative therapy

upper limb spasticity in adults

ankle and foot disability due to lower limb spasticity in adults

• symptomatic relief of blepharospasm, hemifacial spasm and idiopathic cervical dystonia (spasmodic torticollis)

• prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine)

Bladder disorders:

• management of bladder dysfunctions in adult patients who are not adequately managed with anticholinergics

overactive bladder with symptoms of urinary incontinence, urgency and frequency

neurogenic detrusor overactivity with urinary incontinence due to subcervical spinal cord injury (traumatic or non-traumatic), or multiple sclerosis

Skin and skin appendage disorders

• management of severe hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics

• temporary improvement in the appearance of:

moderate to severe vertical lines between the eyebrows seen at maximum frown (glabellar lines) and/or,

moderate to severe lateral canthal lines (crow's feet lines) seen at maximum smile and/or,

moderate to severe forehead lines seen at maximum eyebrow elevation,

moderate to severe platysma prominence seen at maximum contraction,

when the severity has an important psychological impact in adult patients.

4.2. Posology and method of administration

Posology

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

Dosages for elderly patients are the same as for younger adults. Initial dosing should begin at the lowest recommended dose for the specific indication. Elderly patients with significant medical history and concomitant medications should be treated with caution.

There are limited data in patients older than 65 years managed with BOTOX for urinary incontinence with neurogenic detrusor overactivity, ankle and foot disability due to lower limb spasticity, as well as for facial lines and platysma prominence (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 paediatric focal spasticity associated with cerebral palsy. For this indication, BOTOX should only be administered by appropriately qualified healthcare practitioners who are experienced in the assessment and treatment of paediatric focal spasticity and as part of a structured program of rehabilitation.

Currently available data in paediatric populations are described in section 4.2, 4.4, 4.8 and 5.1, as shown in the table below.

• Focal spasticity in paediatric patients

2 years (see section 4.2, 4.4 and 4.8)

• Blepharospasm/Hemifacial spasm/ Idiopathic Cervical dystonia

12 years (see section 4.4 and 4.8)

• Primary hyperhidrosis of the axillae

12 years

(limited experience in adolescents between 12 and 17 years, see sections 4.4, 4.8 and 5.1)

• Paediatric neurogenic detrusor overactivity

5 - 17 years (see section 4.8 and 5.1)

• Paediatric overactive bladder

12 - 17 years (see section 4.8 and 5.1)

Method of Administration

BOTOX 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.

This product is for single use only and any unused solution should be discarded. The most appropriate vial size should be selected for the indication.

A decrease or increase in the BOTOX dose is possible by administering a smaller or larger injection volume. The smaller the injection volume the less discomfort and less spread of toxin in the injected muscle occurs. This is of benefit in reducing effects on nearby muscles when small muscle groups are being injected.

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

Refer to specific guidance for each indication described below.

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 up by an appropriately qualified healthcare practitioner. Optimum dose levels should be determined by titration but the recommended maximum dose should not be exceeded.

NEUROLOGIC DISORDERS

Focal spasticity of the upper limb in paediatric patients

Recommended needle:

Appropriately sized sterile needle. Needle length should be determined based on muscle location and depth.

Administration guidance:

Localisation of the involved muscles with techniques such as needle electromyographic (EMG) guidance, nerve stimulation, or ultrasound is recommended. Prior to injection, local anaesthesia or local anaesthesia in combination with minimal or moderate sedation may be used, per local site practice. The safety and efficacy of BOTOX in the treatment of paediatric spasticity has not been evaluated under general anaesthesia or deep sedation/analgesia.

The following diagram indicates the injection sites for paediatric upper limb spasticity:

Recommended dose:

The recommended dose for treating paediatric upper limb spasticity is 3 Units/kg to 6 Units/kg body weight divided among the affected muscles.

BOTOX Dosing by Muscle for Paediatric Upper Limb Spasticity

Muscles Injected

BOTOX 3 Units/kg

(maximum Units per muscle)

BOTOX 6 Units/kg

(maximum Units per muscle)

Number of Injection Sites

Elbow Flexor Muscles

Biceps

1.5 Units/kg (50 Units)

3 Units/kg (100 Units)

4

Brachialis

1 Unit/kg (30 Units)

2 Units/kg (60 Units)

2

Brachioradialis

0.5 Units/kg (20 Units)

1 Unit/kg (40 Units)

2

Wrist Muscles

Flexor carpi radialis

1 Unit/kg (25 Units)

2 Units/kg (50 Units)

2

Flexor carpi ulnaris

1 Unit/kg (25 Units)

2 Units/kg (50 Units)

2

Finger Muscles

Flexor digitorum profundus

0.5 Units/kg (25 Units)

1 Unit/kg (50 Units)

2

Flexor digitorum sublimis

0.5 Units/kg (25 Units)

1 Unit/kg (50 Units)

2

Maximum dose:

The total dose of BOTOX administered per treatment session in the upper limb should not exceed 6 Units/kg body weight or 200 Units, whichever is lower. If it is deemed appropriate by the treating healthcare practitioner, 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. When treating the upper and lower limbs in combination, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 12-week interval.

Additional information:

Treatment with BOTOX is not intended to substitute for usual standard of care rehabilitation regimens. Clinical improvement generally occurs within the first two weeks after injection. Repeat treatment should be administered when the clinical effect of a previous injection diminishes but not more frequently than every 12 weeks.

Focal spasticity of the lower limb in paediatric patients

Recommended needle:

Appropriately sized sterile needle. Needle length should be determined based on muscle location and depth.

Administration guidance:

Localisation of the involved muscles with techniques such as needle electromyographic guidance, nerve stimulation, or ultrasound is recommended. Prior to injection, local anaesthesia or local anaesthesia in combination with minimal or moderate sedation may be used, per local site practice. The safety and efficacy of BOTOX in the treatment of paediatric spasticity has not been evaluated under general anaesthesia or deep sedation/analgesia.

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

Recommended dose:

The recommended dose for paediatric lower limb spasticity is 4 Units/kg to 8 Units/kg body weight divided among the affected muscles.

BOTOX Dosing by Muscle for Paediatric Lower Limb Spasticity

Muscles Injected

BOTOX 4 Units/kg

(maximum Units

per muscle)

BOTOX 8 Units/kg

(maximum Units

per muscle)

Number of

Injection Sites

Gastrocnemius medial head

1 Unit/kg (37.5 Units)

2 Units/kg (75 Units)

2

Gastrocnemius lateral head

1 Unit/kg (37.5 Units)

2 Units/kg (75 Units)

2

Soleus

1 Unit/kg (37.5 Units)

2 Units/kg (75 Units)

2

Tibialis Posterior

1 Unit/kg (37.5 Units)

2 Units/kg (75 Units)

2

Maximum dose:

The total dose of BOTOX administered per treatment session in the lower limb should not exceed 8 Units/kg body weight or 300 Units, whichever is lower. If it is deemed appropriate by the treating healthcare practitioner, 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. When treating both lower limbs or the upper and lower limbs in combination, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 12-week interval.

Additional information:

Treatment with BOTOX is not intended to substitute for usual standard of care rehabilitation regimens. Clinical improvement generally occurs within the first two weeks after injection. Repeat treatment should be administered when the clinical effect of a previous injection diminishes but not more frequently than every 12 weeks.

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 techniques such as electromyographic guidance, nerve stimulation, or ultrasound is recommended. 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 upper limb spasticity:

Recommended dose:

The recommended dose for treating adult upper limb spasticity is up to 400 Units divided among the affected muscles as listed in the following table.

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

Muscle

Recommended Dose; Number of Sites

Shoulder*

Pectoralis major

Teres major

Latissimus dorsi

75 – 125 Units; 3 sites

30 – 50 Units; 2 sites

45 – 75 Units; 3 sites

Elbow

Biceps brachii

Brachioradialis

Brachialis

70 Units; 2 sites

45 Units; 1 site

45 Units; 1 site

Forearm

Pronator quadratus

Pronator teres

10 – 50 Units; 1 site

15 – 25 Units; 1 site

Wrist

Flexor carpi radialis

Flexor carpi ulnaris

15 – 60 Units; 1-2 sites

10 – 50 Units; 1-2 sites

Fingers/Hand

Flexor digitorum profundus

Flexor digitorum sublimis/superficialis

Lumbricals**

Interossei**

15 – 50 Units; 1-2 sites

15 – 50 Units; 1-2 sites

5 – 10 Units;1 site

5 – 10 Units;1 site

Thumb

Adductor pollicis

Flexor pollicis longus

Flexor pollicis brevis

Opponens pollicis

20 Units; 1-2 sites

20 Units; 1-2 sites

5 – 25 Units; 1 site

5 – 25 Units; 1 site

*When injecting the shoulder muscles in combination, the recommended maximum dose is 250 U.

**When injecting both lumbricals and/or interossei, the recommended maximum dose is 50 U per hand.

Maximum dose:

400 Units in total

Additional information:

If it is deemed appropriate by the treating healthcare practitioner, the patient should be considered for re-injection when the clinical effect of the previous injection has diminished. Re-injections should occur no sooner than 12 weeks after the previous injection. 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 techniques such as electromyographic guidance, nerve stimulation, or ultrasound is recommended. 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 diagrams indicate the injection sites for adult lower limb spasticity:

Recommended dose:

300 Units to 400 Units divided among up to 6 muscles, as listed in the following table.

Muscle

Recommended Dose

Total Dosage; Number of Sites

Gastrocnemius

Medial head

Lateral head

75 Units; 3 sites

75 Units; 3 sites

Soleus

75 Units; 3 sites

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

Maximum dose:

400 Units in total

Additional information:

If it is deemed appropriate by the treating healthcare practitioner, 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.

Administrative guidance:

Electromyographic guidance is not necessary.

Recommended dose:

The initial recommended dose is 1.25-2.5 Units (0.05-0.1 ml volume at each site) 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.

The following diagrams indicate the possible injection sites:

Maximum dose:

The initial dose should not exceed 25 Units per eye. In the management of blepharospasm total dosing should not exceed 100 Units in total 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.

In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated indefinitely. Normally no additional benefit is conferred by treating more frequently than every three months.

At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient – usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injecting more than 5 Units per site.

Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles being injected as needed. Electromyographic control may be necessary to identify affected small circumoral muscles.

Cervical dystonia

Recommended needle:

A 25, 27 or 30 gauge/0.50-0.30 mm needle may be used for superficial muscles, and a 22 gauge needle may be used for deeper musculature.

Administrative guidance:

The treatment of cervical dystonia typically may include 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 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.

Multiple injection sites allow BOTOX to have more uniform contact with the innervation areas of the dystonic muscle and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated.

Recommended dose:

Dosing must be tailored to the individual patient based on the patient' s head and neck position, location of pain, muscle hypertrophy, patient' s body weight, and patient response.

Initial dosing in a naïve patient should begin at the lowest effective dose.

To minimise the incidence of dysphagia, the sternomastoid should not be injected bilaterally.

The following doses are recommended:

Type I

Head rotated toward side of shoulder elevation

Sternomastoid

Levator scapulae

Scalene

Splenius capitis

Trapezius

50 – 100 Units; at least 2 sites

50 Units; 1 – 2 sites

25 – 50 Units; 1 – 2 sites

25 – 75 Units; 1 – 3 sites

25 – 100 Units; 1 – 8 sites

Type II

Head rotation only

Sternomastoid

25 – 100 Units; at least 2 sites if >25 Units given

Type III

Head tilted toward side of shoulder elevation

Sternomastoid

Levator scapulae

Scalene

Trapezius

25 – 100 Units at posterior border; at least 2 sites if >25 Units given

25 – 100 Units; at least 2 sites

25 – 75 Units; at least 2 sites

25 – 100 Units; 1 – 8 sites

Type IV

Bilateral posterior cervical muscle spasm with elevation of the face

Splenius capitis and cervicis

50 – 200 Units; 2 – 8 sites, treat bilaterally

(This is the total dose and not the dose for each side of the neck)

Maximum dose:

No more than 50 Units should be given at any one injection site.

No more than 100 Units should be given to the sternomastoid.

No more than 200 Units in total should be injected for the first course of therapy, with adjustments made in subsequent courses dependent on the initial response, up to a maximum total dose of 300 Units.

Additional information:

Treatment intervals of less than 10 weeks are not recommended.

Chronic migraine

Recommended needle:

Sterile 30 gauge, 0.5 inch needle.

A 1 inch needle may be needed in the neck region for patients with extremely thick neck muscles.

Administration guidance:

Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams below. 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 injection sites administered to the left, and half to the right side of the head and neck.

The following diagrams indicate the injection sites:

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 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.

Recommended Dose

Head/Neck Area

Total Dosage (number of sites*)

Corrugator**

10 Units (2 sites)

Procerus

5 Units (1 site)

Frontalis**

20 Units (4 sites)

Temporalis**

40 Units (8 sites) up to 50 Units (up to 10 sites)

Occipitalis**

30 Units (6 sites) up to 40 Units (up to 8 sites)

Cervical Paraspinal Muscle Group**

20 Units (4 sites)

Trapezius**

30 Units (6 sites) up to 50 Units (up to 10 sites)

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 re-treatment schedule is every 12 weeks.

BLADDER DISORDERS

Overactive bladder

Recommended needle:

The injection needle should be filled (primed) with approximately 1 ml of the reconstituted BOTOX solution prior to the start of the injections (depending on the needle length) to remove any air.

Administration guidance:

The reconstituted solution of BOTOX (100 Units/10 ml) is injected 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 and avoid backflow of the product, 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 unpreserved normal saline (0.9% sodium chloride for injection) should be injected so the full dose is delivered.

Recommended dose:

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

Additional information:

For the patient preparation and monitoring, see section 4.4.

After the injections are given, the saline used for bladder wall visualisation should not be drained so that the 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.

Patients should be considered for reinjection when the clinical effect of the previous injection has diminished but no sooner than 3 months from the prior bladder injection.

Urinary incontinence due to neurogenic detrusor overactivity

Recommended needle:

The injection needle should be filled (primed) with approximately 1 ml of the reconstituted BOTOX solution prior to the start of the injections (depending on the needle length) to remove any air.

Administration guidance:

The reconstituted solution of BOTOX (200 Units/30 ml) is injected 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 and avoid backflow of the product, 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 unpreserved normal saline (0.9% sodium chloride for injection) should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should be drained.

Recommended dose:

The recommended dose is 200 Units of BOTOX, as 1 ml (~6.7 Units) injections across 30 sites in the detrusor muscle.

Additional information:

For the patient preparation and monitoring, see section 4.4.

Patients should be considered for reinjection when the clinical effect of the previous injection has diminished, but no sooner than 3 months from the prior bladder injection.

No urodynamic data beyond 2 treatments and no histopathological data after repeated treatment are currently available.

Patients should not receive multiple treatments in the event of limited symptomatic improvement.

SKIN AND SKIN APPENDAGE DISORDERS

Primary hyperhidrosis of the axillae

Recommended needle:

Sterile 30 gauge needle.

Administration guidance:

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

Recommended dose:

50 Units of BOTOX is injected intradermally to each axilla, evenly distributed in multiple sites approximately 1-2 cm apart.

The recommended injection volume for intradermal injection is 0.1-0.2 ml.

Maximum dose:

Doses other than 50 Units per axilla cannot be recommended.

Additional information:

Clinical improvement generally occurs within the first week after injection and persists for 4-7 months.

Repeat injection of BOTOX can be administered when the clinical effect of a previous injection diminishes and the treating healthcare practitioner deems it necessary. Injections should not be repeated more frequently than every 16 weeks.

Glabellar lines seen at maximum frown

Recommended needle:

Sterile 30 gauge needle.

Administration guidance:

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 addition, injections near the levator palpebrae superioris muscle must be avoided, particularly in patients with larger brow-depressor complexes (depressor supercilii). 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 (see figure).

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the glabellar lines seen at maximum frown, see section 4.4.

Recommended dose:

A volume of 0.1 ml (4 Units) is administered in each of the 5 injection sites (see Figure): 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 Units.

Maximum dose:

In order to reduce the risk of eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded.

Additional Information

Treatment intervals should not be more frequent than every three months. In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed.

In case of insufficient dose a second treatment session should be initiated by adjusting the total dose up to 40 or 50 Units, taking into account the analysis of the previous treatment failure (see information in All indications).

The efficacy and safety of repeat injections of BOTOX for the treatment of glabellar lines beyond 12 months has not been evaluated.

Crow's feet lines seen at maximum smile

Recommended needle:

Sterile 30 gauge needle.

Administration guidance:

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 1. Alternatively, if the lines in the crow's feet region are primarily below the lateral canthus, inject as shown in Figure 2.

In order to reduce the risk of eyelid ptosis, injections should be made temporal to the orbital rim, thereby maintaining a safe distance from the muscle controlling eyelid elevation.

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the crow's feet lines seen at maximum smile (see section 4.4).

Recommended dose:

A volume of 0.1 ml (4 Units) 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 Units in a total volume of 0.6 ml (12 Units per side).

For simultaneous treatment with glabellar lines seen at maximum frown, the dose is 24 Units for crow's feet lines seen at maximum smile and 20 Units for glabellar lines (see Administration guidance for glabellar lines) for a total dose of 44 Units in a total volume of 1.1 ml.

Maximum dose:

In order to reduce the risk of eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded.

Additional information:

Treatment intervals should not be more frequent than every 3 months.

The efficacy and safety of repeat injections of BOTOX for the treatment of crow’s feet lines beyond 12 months has not been evaluated.

Forehead Lines seen at maximum eyebrow elevation

Recommended needle:

Sterile 30 gauge needle.

Administration guidance:

To identify the location of the appropriate injection sites in the frontalis muscle, assess the overall relationship between the size of the subject's forehead, and the distribution of frontalis muscle activity should be assessed.

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 3:

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the forehead lines seen at maximum eyebrow elevation (see section 4.4).

Recommended dose:

A volume of 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 3).

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 Recommended dose for Glabellar Lines and Figure), and 24 Units for crow's feet lines (see Recommended dose for Crow's Feet Lines and Figures 1 and 2).

Additional information:

Treatment intervals should not be more frequent than every 3 months.

The efficacy and safety of repeat injections of BOTOX for the treatment of forehead lines beyond 12 months has not been evaluated.

Platysma Prominence seen at maximum contraction

Recommended needle:

Appropriately sized sterile needle (recommended range 30-33 gauge needle).

Administration guidance:

Identify the treatment location: For each side, the 4 jawline injections to the upper platysma muscle should be approximately 1 to 2 cm inferior and parallel to the lower mandibular border. The anterior injection site should be in line with the oral commissure, and the posterior injection site should be slightly anterior to the angle of the mandible. The remaining 2 injections should be equidistant (approximately 1 to 2 cm apart) between the anterior and posterior injection points (see Figures 4 and 5).

For each vertical neck band, 1 to 2 per side, distribute 5 injections vertically approximately 1 to 2 cm apart (see Figures 4 and 5). The most superior injection site should be approximately 1 to 2 cm inferior to the jawline injections.

The platysma muscle is a thin muscle sheet just below the surface of the skin. Therefore, all platysma muscle injections should be administered superficially and intramuscularly with the needle perpendicular to the surface of the skin. For vertical neck band injections, each band should be identified while the patient is contracting their platysma. Gently pinch the band to isolate the muscle from nearby anatomical structures during administration (see Table below).

Figure 4: Injection Sites for Platysma Prominence (2 Bands)

Figure 5: Injection Sites for Platysma Prominence (1 Band)

To reduce injection-related complications, including facial paresis and dysphagia, injection should be at least 1 cm inferior to the lower mandibular border and do not inject into structures deep to the platysma muscle, particularly in the anterior region of the neck.

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the platysma muscles seen at maximum contraction (see section 4.4).

Recommended dose:

Using an appropriately sized sterile syringe, needle and aseptic technique, 2 Units/0.05 ml of reconstituted BOTOX is injected into each of the 4 sites in the upper segment of platysma muscle, below the jawline on each side. In addition, 1 Unit/0.025 ml of reconstituted BOTOX is injected into each of the 5 sites along each vertical neck band, 1 to 2 vertical neck bands per side.

Dosing for Platysma Prominence

Jawline Injection (Inferior to the Lower Mandibular Border)

Vertical Neck Band Injection

Total Dose (Number of Injection Sites)

2 Units/0.05 ml into each of the 4 sites on each side (16 Units in 8 sites)

1 Unit/0.025 ml into each of the 5 sites per band (1 to 2 bands/side)

1 band on both sides(10 Units in 10 sites)

26 Units

(18 sites)

1 band on one side, and 2 bands on the other side(15 Units in 15 sites)

31 Units(23 sites)

2 bands on both sides(20 Units in 20 sites)

36 Units(28 sites)

Maximum dose:

No more than 2 Units should be given for each injection site at the jawline, and no more than 1 Unit should be given for each injection site along the vertical neck bands. The number of injection sites should not be exceeded.

Depending on platysma prominence severity, the total dose should not exceed 26 Units (1 band/side), 31 Units (1 band on one side, 2 bands on the other side), or 36 Units (2 bands/side) (see Table above and Figures 4 and 5).

Additional information:

Treatment intervals should not be more frequent than every 3 months.

The efficacy and safety of dosing with BOTOX more frequently than every 3 months for the treatment of platysma prominence have not been evaluated.

The efficacy and safety of repeat injections of BOTOX for the treatment of platysma prominence beyond 12 months have not been evaluated.

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 three-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.

When treating adult patients for multiple indications, the maximum cumulative dose should not exceed 400 Units in a 12-week interval.

In treating paediatric patients, including when treating for multiple indications, the maximum cumulative dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 12-week interval.

4.3. Contraindications

- known hypersensitivity to botulinum toxin type A or to any of the excipients listed in section 6.1;

- presence of infection at the proposed injection site(s).

For the management of bladder disorders:

- urinary tract infection at the time of treatment;

- acute urinary retention at the time of treatment, in patients who are not routinely catheterising;

- patients who are not willing and/or able to initiate catheterisation post-treatment if required;

- presence of bladder calculi.

4.4. Special warnings and precautions for use

The recommended dosages and frequencies of administration of BOTOX should not be exceeded due to the potential for overdose, exaggerated muscle weakness, distant spread of toxin and the formation of neutralising antibodies. Initial dosing in treatment naïve patients should begin with the lowest recommended dose for the specific indication.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium free”.

Prescribers and patients should be aware that side effects can occur despite previous injections being well tolerated. Caution should therefore be exercised on the occasion of each administration.

Side effects related to spread of toxin distant from the site of administration have been reported (see section 4.8), sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility.

The symptoms are consistent with the mechanism of action of botulinum toxin and have been reported hours to weeks after injection.

Cases of iatrogenic botulism have been reported following injection of botulinum toxin products. Patients and caregivers should be advised to seek immediate medical advice if they experience any signs or symptoms consistent with the spread of botulinum toxin effect or if swallowing, speech or respiratory disorders arise (see section 4.9).

Most cases have been reported following the use of botulinum toxin containing products when used for unapproved indications and/or administration into unapproved injection sites or following use of higher than recommended doses and the use of unlicensed products.

The risk of symptoms from toxin spread is probably greatest in patients who have underlying conditions and comorbidities that would predispose them to these symptoms, including children and adults treated for spasticity, and are treated with high doses.

Patients treated with therapeutic doses may also experience exaggerated muscle weakness.

Elderly and debilitated patients should be treated with caution. Generally, clinical studies of BOTOX did not identify differences in responses between the elderly and younger patients except for facial lines (see section 5.1). Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

Consideration should be given to the risk-benefit implications for the individual patient before embarking on treatment with BOTOX.

Dysphagia has also been reported following injection to sites other than the cervical musculature (see section 4.4 'Cervical Dystonia').

BOTOX should only be used with extreme caution and under close supervision in patients with subclinical or clinical evidence of defective neuromuscular transmission e.g. myasthenia gravis or Lambert-Eaton Syndrome in patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy) and in patients with underlying neurological disorders. Such patients may have an increased sensitivity to agents such as BOTOX, even at therapeutic doses, which may result in excessive muscle weakness and an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk. Patients with a history of dysphagia and aspiration should be treated with extreme caution.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.

As with any treatment with the potential to allow previously-sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually.

The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and injection into vulnerable anatomic structures must be avoided.

Pneumothorax associated with injection procedure has been reported following the administration of BOTOX near the thorax.

Caution is warranted when injecting in proximity to the lung (particularly the apices) or other vulnerable anatomic structures.

Serious adverse events including fatal outcomes have been reported in patients who had received off-label injections of BOTOX directly into salivary glands, the oro-lingual-pharyngeal region, oesophagus and stomach. Some patients had pre-existing dysphagia or significant debility.

Serious and/or immediate hypersensitivity reactions have been rarely reported including anaphylaxis, serum sickness, urticaria, soft tissue oedema, and dyspnoea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. If such a reaction occurs further injection of BOTOX should be discontinued and appropriate medical therapy, such as epinephrine, immediately instituted. One case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine.

As with any injection, procedure-related injury could occur. An injection could result in localised infection, pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling, erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc.

Caution should be exercised when BOTOX is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle. Caution should also be exercised when BOTOX is used for treatment of patients with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor neuropathy).

There have been reports of adverse events following administration of BOTOX involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease.

New onset or recurrent seizures have been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to botulinum toxin injection has not been established. The reports in children were predominantly from cerebral palsy patients treated for spasticity.

Formation of neutralising antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. Results from some studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. When appropriate, the potential for antibody formation may be minimised by injecting with the lowest effective dose given at the longest clinically indicated intervals between injections.

Clinical fluctuations during the repeated use of BOTOX (as with all botulinum toxins) may be a result of different vial reconstitution procedures, injection intervals, muscles injected and slightly differing potency values given by the biological test method used.

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.

Paediatric use

The safety and efficacy of BOTOX in indications other than those described for the paediatric population in section 4.1 has not been established. Post-marketing 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.

NEUROLOGIC DISORDERS

Focal spasticity in adult and paediatric patients

BOTOX is a treatment of focal spasticity that has only been studied in association with usual standard of care regimens, and is not intended as a replacement for these treatment modalities. BOTOX is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.

BOTOX should only be used for the treatment of focal spasticity in adult patients if muscle tone reduction is expected to result in improved function (e.g. improvements in gait), or improved symptoms (e.g. reduction in muscle spasms or pain), and/or to facilitate care. Improvement in active function may be limited if BOTOX treatment is initiated longer than 2 years post-stroke or in patients with Modified Ashworth Scale (MAS) < 3.

Caution should be exercised when treating adult patients with spasticity who may be at increased risk of fall.

There have been post-marketing reports of death (sometimes associated with aspiration pneumonia) and of possible distant spread of toxin in children with co-morbidities, predominantly cerebral palsy following treatment with botulinum toxin. See warnings under section 4.4, 'Paediatric use'.

Blepharospasm

Reduced blinking following botulinum toxin injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.

Ecchymosis occurs easily in the soft eyelid tissues. This can be minimised by applying gentle pressure at the injection site immediately after injection.

Because of the anticholinergic activity of botulinum toxin, caution should be exercised when treating patients at risk for angle closure glaucoma, including patients with anatomically narrow angles.

Cervical dystonia

Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be very mild, but could be severe. Dysphagia may persist for two to three weeks after injection, but has been reported to last up to five months post-injection. Consequent to the dysphagia there is the potential for aspiration, dyspnoea and occasionally the need for tube feeding. In rare cases dysphagia followed by aspiration pneumonia and death has been reported.

Limiting the dose injected into the sternocleidomastoid muscle to less than 100 Units may decrease the occurrence of dysphagia. Patients with smaller neck muscle mass, or patients who receive bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia. Dysphagia is attributable to the spread of the toxin to the oesophageal musculature. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.

Dysphagia may contribute to decreased food and water intake resulting in weight loss and dehydration. Patients with subclinical dysphagia may be at increased risk of experiencing more severe dysphagia following a BOTOX injection.

Chronic migraine

No efficacy has been shown for BOTOX in the prophylaxis of headaches in patients with episodic migraine (headaches on < 15 days per month).

BLADDER DISORDERS

Patient preparation and monitoring

Prophylactic antibiotics should be administered to patients with sterile urine or asymptomatic bacteriuria in accordance with local standard practice.

The decision to discontinue anti-platelet therapy should be subject to local guidance and benefit/risk consideration for the individual patient. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding.

Appropriate medical caution should be exercised when performing the cystoscopy. The patient should be observed for at least 30 minutes post-injection.

In patients who are not regularly practicing catheterisation, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate. Patients should be instructed to contact their physician if they experience difficulties in voiding as catheterisation may be required.

Overactive bladder

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 rinsed with sterile saline before the next steps of the injection procedure.

Urinary incontinence due to neurogenic detrusor overactivity

BOTOX injection can be performed under general or local anaesthesia with or without sedation. If a local anaesthetic intravesical instillation is performed, the bladder should be drained and rinsed with sterile saline before the next steps of the injection procedure.

Autonomic dysreflexia associated with the procedure can occur and greater vigilance is required in patients known to be at risk.

SKIN AND SKIN APPENDAGE DISORDERS

Primary hyperhidrosis of the axillae

Medical history and physical examination, along with specific additional investigations as required, should be performed to exclude potential causes of secondary hyperhidrosis (e.g. hyperthyroidism, phaeochromocytoma). This will avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of underlying disease.

Glabellar lines seen at maximum frown and/or crow's feet lines seen at maximum smile and/or forehead lines seen at maximum eyebrow elevation or platysma prominence seen at maximum contraction

It is mandatory that BOTOX is used for one single patient treatment only during a single session. 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 6.6).

The use of BOTOX is not recommended in individuals under 18 years. There are limited phase 3 clinical data with BOTOX in patients older than 65 years.

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the glabellar lines seen at maximum frown, in the crow's feet lines seen at maximum smile, in the forehead lines seen at maximum eyebrow elevation, or in the platysma muscles seen at maximum contraction, see section 4.2. When injecting in the platysma muscles, should accidental intravascular injection into the carotid artery or jugular vein occur, monitor the patient closely for signs and symptoms as described under accidental injection in section 4.9.

There is a risk of eyelid ptosis following treatment, refer to Section 4.2 for administration instructions on how to minimise this risk.

4.5. Interaction with other medicinal products and other forms of interaction

Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking agents).

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

No interaction studies have been performed. No interactions of clinical significance have been reported.

There are no data available on the concomitant use of anticholinergics with BOTOX injections in the management of overactive bladder.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of botulinum toxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for humans is unknown. BOTOX is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There is no information on whether BOTOX is excreted in human milk. The use of BOTOX during breast-feeding cannot be recommended.

Fertility

There are no adequate data on the effects on fertility from the use of botulinum toxin type A in women of childbearing potential. Studies in male and female rats have shown fertility reductions (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, BOTOX may cause asthenia, muscle weakness, somnolence, dizziness and visual disturbance, which could affect driving and the operation of machinery.

4.8. Undesirable effects

a) General

In controlled clinical trials adverse events considered by the investigators to be related to BOTOX were reported in 35% patients with blepharospasm, 28% with cervical dystonia, 8% with paediatric spasticity, 11% with primary hyperhidrosis of the axillae, 9% in adults with focal spasticity of the upper limb, 11% in adults with focal spasticity of the lower limb, 26% with overactive bladder, 32% in adults with neurogenic detrusor overactivity and 6.2% in paediatric patients with neurogenic detrusor overactivity. In clinical trials for chronic migraine, the incidence was 26% with the first treatment and declined to 11% with a second treatment.

In controlled clinical trials for glabellar lines seen at maximum frown, adverse events considered by the investigators to be related to BOTOX were reported in 23% (placebo 19%) of patients. In treatment cycle 1 of the pivotal controlled clinical trials for crow's feet lines seen at maximum smile, such events were reported in 8% (24 Units for crow's feet lines alone) and 6% (44 Units: 24 Units for crow's feet lines administered simultaneously with 20 Units for glabellar lines) of patients compared to 5% for placebo.

In treatment cycle 1 of clinical trials for forehead lines seen at maximum eyebrow elevation, adverse events considered by the investigators to be related to BOTOX were reported in 20.6% of patients treated with 40 Units (20 Units to the frontalis with 20 Units to the glabellar complex), and 14.3% of patients treated with 64 Units (20 Units to the frontalis with 20 Units to the glabellar complex and 24 Units to the lateral canthal lines areas), compared to 8.9% of patients who received placebo.

In treatment cycle 1 of clinical trials for platysma prominence seen at maximum contraction, adverse events considered by investigators to be related to BOTOX were reported in 4.7% of patients treated with 26 Units, 31 Units, or 36 Units, compared to 5.0% of patients who received placebo.

Adverse reactions may be related to treatment, injection technique or both. In general, adverse reactions occur within the first few days following injection and, while generally transient, may have a duration of several months or, in rare cases, longer.

Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue. However, weakness of adjacent muscles and/or muscles remote from the site of injection has been reported.

As is expected for any injection procedure, localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope. Fever and flu syndrome have also been reported after injections of botulinum toxin.

b) Adverse reactions - frequency by indication

The frequency of adverse reactions reported in the clinical trials 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).

NEUROLOGIC DISORDERS

Focal spasticity of the upper limb in paediatric patients

System Organ Class

Preferred Term

Frequency

Infections and infestations

Upper respiratory tract infection

Common

Gastrointestinal disorders

Nausea

Common

Musculoskeletal and connective tissue disorders

Muscular weakness

Common

General disorders and administration site conditions

Injection site pain

Common

Focal spasticity of the lower limb in paediatric patients

System Organ Class

Preferred Term

Frequency

Skin and subcutaneous tissue disorders

Rash

Common

Musculoskeletal and connective tissue disorders

Muscular weakness

Uncommon

General disorders and administration site conditions

Gait disturbance, injection site pain,

Common

Injury, poisoning and procedural complications

Ligament sprain, skin abrasion

Common

Focal upper limb spasticity in adult patients

System Organ Class

Preferred Term

Frequency

Gastrointestinal disorders

Nausea

Common

Musculoskeletal and connective tissue disorders

Pain in extremity, muscular weakness

Common

General disorders and administration site conditions

Fatigue, peripheral oedema

Common

No change was observed in the overall safety profile with repeat dosing.

Injection of BOTOX for spasticity of the upper limb in patients with decreased pulmonary function has been associated with small but statistically significant decreases in forced vital capacity (FVC) and/or forced expiratory volume 1 second (FEV1) that were subclinical and were not correlated with any adverse clinical pulmonary reactions.

Focal lower limb spasticity in adult patients

System Organ Class

Preferred Term

Frequency

Skin and subcutaneous tissue disorders

Rash

Common

Musculoskeletal and connective tissue disorders

Arthralgia, musculoskeletal stiffness, muscular weakness

Common

General disorders and administration site conditions

Peripheral oedema

Common

Injury, poisoning and procedural complications

Fall

Common

Blepharospasm/hemifacial spasm

System Organ Class

Preferred Term

Frequency

Nervous system disorders

Dizziness, facial paresis, facial palsy

Uncommon

Eye disorders

Eyelid ptosis

Very Common

Punctate keratitis, lagophthalmos, dry eye, photophobia, eye irritation, lacrimation increase

Common

Keratitis, ectropion, diplopia, entropion, visual disturbance, blurred vision

Uncommon

Eyelid oedema

Rare

Corneal ulceration, corneal epithelium defect, corneal perforation

Very Rare

Skin and subcutaneous tissue disorders

Ecchymosis

Common

Rash/dermatitis

Uncommon

General disorders and administration site conditions

Irritation, face oedema

Common

Fatigue

Uncommon

Cervical dystonia

System Organ Class

Preferred Term

Frequency

Infections and infestations

Rhinitis, upper respiratory infection

Common

Nervous system disorders

Dizziness, hypertonia, hypoaesthesia, somnolence, headache

Common

Eye disorders

Diplopia, eyelid ptosis

Uncommon

Respiratory, thoracic and mediastinal disorders

Dyspnoea, dysphonia

Uncommon

Gastrointestinal disorders

Dysphagia

Very common

Dry mouth, nausea

Common

Musculoskeletal and connective tissue disorders

Muscular weakness

Very common

Musculoskeletal stiffness and musculoskeletal soreness

Common

General disorders and administration site conditions

Pain

Very common

Asthenia, influenza-like illness, malaise

Common

Pyrexia

Uncommon

Chronic migraine

System Organ Class

Preferred Term

Frequency

Nervous system disorders

Headache*, migraine*, including worsening of migraine, facial paresis

Common

Eye disorders

Eyelid ptosis

Common

Eyelid oedema

Uncommon

Gastrointestinal disorders

Dysphagia

Uncommon

Skin and subcutaneous tissue disorders

Pruritis, rash

Common

Pain of skin

Uncommon

Musculoskeletal and connective tissue disorders

Neck pain, myalgia, musculoskeletal pain, musculoskeletal stiffness, muscle spasms, muscle tightness, muscular weakness

Common

Pain in jaw

Uncommon

Mephisto sign (lateral elevation of eyebrows)

Not known

General disorders and administration site conditions

Injection site pain

Common

* In placebo-controlled trials, headache and migraine, including serious cases of intractable or worsening of headache/migraine, were reported more frequently with BOTOX (9%) than with placebo (6%). They typically occurred within the first month after the injections and their incidence declined with repeated treatments.

BLADDER DISORDERS

Adult overactive bladder

System Organ Class

Preferred Term

Frequency

Infections and infestations

Urinary tract infection

Very common

Bacteriuria

Common

Renal and urinary disorders

Dysuria†

Very common

Urinary retention, pollakiuria, leukocyturia

Common

Investigations

Residual urine volume*

Common

*elevated post-void residual urine volume (PVR) not requiring catheterisation

†procedure-related adverse reactions

In the phase 3 clinical trials urinary tract infection was reported in 25.5% of patients treated with BOTOX 100 Units and 9.6% of patients treated with placebo. Urinary retention was reported in 5.8% of patients treated with BOTOX 100 Units and in 0.4% of patients treated with placebo. Clean intermittent catheterisation was initiated in 6.5% of patients following treatment with BOTOX 100 Units versus 0.4% in the placebo group.

Overall, 42.5% of patients (n = 470) were ≥ 65 years of age and 15.1% (n = 167) were ≥ 75 years of age. No overall difference in the safety profile following BOTOX treatment was observed between patients ≥ 65 years compared to patients < 65 years in these studies, with the exception of urinary tract infection where the incidence was higher in elderly patients in both the placebo and BOTOX groups compared to the younger patients.

No change was observed in the overall safety profile with repeat dosing.

Paediatric overactive bladder

System Organ Class

Preferred Term

Frequency

Infections and infestations

Urinary tract infection

Common

Renal and urinary disorders

Dysuria*, urethral pain*

Common

Gastrointestinal disorders

Abdominal pain, abdominal pain lower

Common

* procedure-related adverse reaction

In one double-blind, parallel-group, randomised, multi-centre clinical study conducted in 55 patients aged 12 to 17 years, the adverse reactions were generally comparable with the known safety profile in adult overactive bladder however events of urethral and abdominal pain were also noted in this small paediatric OAB study.

See sections 4.2 and 5.1.

Adult urinary incontinence due to neurogenic detrusor overactivity

System Organ Class

Preferred Term

Frequency

Infections and infestations

Urinary tract infectiona, b, bacteriuriab

Very Common

Investigations

Residual urine volume**b

Very Common

Psychiatric disorders

Insomnia†a

Common

Gastrointestinal disorders

Constipation†a

Common

Musculoskeletal and connective tissue disorders

Muscular weakness†a, muscle spasma

Common

Renal and urinary disorders

Urinary retentiona, b

Very Common

Haematuria*a, b, bladder diverticuluma, dysuria*b

Common

General disorders and administration site conditions

Fatigue†a, gait disturbance†a

Common

Injury, poisoning and procedural complications

Autonomic dysreflexia*a, fall†a

Common

* procedure-related adverse reactions

** elevated PVR not requiring catheterisation

† only in multiple sclerosis

a Adverse reactions occurring in the Phase 2 and pivotal Phase 3 clinical trials

b Adverse reactions occurring in the post-approval study of BOTOX 100U in MS patients not catheterising at baseline

In the phase 3 clinical trials, urinary tract infection was reported in 49% of patients treated with BOTOX 200 Units and in 36% of patients treated with placebo (in multiple sclerosis patients: 53% vs. 29%, respectively; in spinal cord injury patients: 45% vs. 42%, respectively). Urinary retention was reported in 17% of patients treated with BOTOX 200 Units and in 3% of patients treated with placebo (in multiple sclerosis patients: 29% vs. 4%, respectively; in spinal cord injury patients: 5% vs. 1%, respectively). Among patients who were not catheterising at baseline prior to treatment, catheterisation was initiated in 39% following treatment with BOTOX 200 Units versus 17% on placebo. The risk of urinary retention increased in patients older than 65 years.

No change in the type and frequency of adverse reactions was observed following 2 treatments.

In the post-approval study of BOTOX 100 Units in MS patients not catheterising at baseline, no difference on the MS exacerbation annualised rate (i.e. number of MS exacerbation events per patient-year) was observed (BOTOX=0, placebo=0.07).

Catheterisation was initiated in 15.2% of patients following treatment with BOTOX 100 Units versus 2.6% on placebo (refer to section 5.1).

Paediatric neurogenic detrusor overactivity

System Organ Class

Preferred Term

Frequency

Infections and infestations

Bacteriuria

Very Common

Urinary tract infection, leukocyturia

Common

Renal and urinary disorders

Haematuria

Common

No change was observed in the overall safety profile with repeat dosing.

See sections 4.2 and 5.1.

SKIN AND SKIN APPENDAGE DISORDERS

Primary hyperhidrosis of the axillae

System Organ Class

Preferred Term

Frequency

Nervous system disorders

Headache, paraesthesia

Common

Vascular disorders

Hot flushes

Common

Gastrointestinal disorders

Nausea

Uncommon

Skin and subcutaneous tissue disorders

Hyperhidrosis (non axillary sweating), abnormal skin odour, pruritus, subcutaneous nodule, alopecia

Common

Musculoskeletal and connective tissue disorders

Pain in extremity

Common

Muscular weakness, myalgia, arthropathy

Uncommon

General disorders and administration site conditions

Injection site pain

Very common

Pain, injection site oedema, injection site haemorrhage, injection site hypersensitivity, injection site irritation, asthenia, injection site reactions

Common

Increase in non axillary sweating was reported in 4.5% of patients within 1 month after injection and showed no pattern with respect to anatomical sites affected. Resolution was seen in approximately 30% of the patients within four months.

Weakness of the arm has been also reported uncommonly (0.7%) and was mild, transient, did not require treatment and recovered without sequelae. This adverse event may be related to treatment, injection technique, or both. In the uncommon event of muscle weakness being reported a neurological examination may be considered. In addition, a re-evaluation of injection technique prior to subsequent injection is advisable to ensure intradermal placement of injections.

In an uncontrolled safety study of BOTOX (50 Units per axilla) in paediatric patients 12 to 17 years of age (n= 144), adverse reactions occurring in more than a single patient (2 patients each) comprised injection site pain and hyperhidrosis (non-axillary sweating).

Facial lines in adults

The following table represent the adverse reactions that have been reported during the double-blind, placebo-controlled clinical studies following injection of BOTOX for Glabellar lines, Crow's Feet Lines with or without Glabellar Lines, Forehead Lines and Glabellar Lines with or without Crow's Feet Lines.

System Organ Class

Preferred Term

Glabellar Lines

Crow's Feet Lines with or without Glabellar Lines

Forehead Lines and Glabellar Lines with or without Crow's Feet Lines

Infections and infestations

Infection

Uncommon

n/a

n/a

Psychiatric disorders

Anxiety

Uncommon

n/a

n/a

Nervous system disorders

Headache

Common

n/a

Common

Paraesthesia

Common

n/a

n/a

Dizziness

Uncommon

n/a

n/a

Eye disorders

Eyelid ptosis

Common

n/a

Common1

Blepharitis, eye pain, visual disturbance (includes vision blurred)

Uncommon

n/a

n/a

Eyelid oedema

Uncommon

Uncommon

n/a

Gastrointestinal disorders

Nausea

Common

n/a

n/a

Oral dryness

Uncommon

n/a

n/a

Skin and subcutaneous tissue disorders

Erythema

Common

n/a

n/a

Skin tightness

Common

n/a

Common

Oedema (face, periorbital), photosensitivity reaction, pruritus, dry skin

Uncommon

n/a

n/a

Brow Ptosis

n/a

n/a

Common2

Musculoskeletal and connective tissue disorders

Localised muscle weakness

Common

n/a

n/a

Muscle twitching

Uncommon

n/a

n/a

Mephisto sign (lateral elevation of eyebrows)

Uncommon

n/a

Common

General disorders and administration site conditions

Face pain, injection site oedema, ecchymosis, injection site irritation

Common

n/a

n/a

Injection site bruising*

n/a

n/a

Common

Injection site haematoma*

n/a

Common

Common

Flu syndrome, asthenia, fever

Uncommon

n/a

n/a

Injection site haemorrhage*

n/a

Uncommon

n/a

Injection site pain

Common

Uncommon*

Uncommon*

Injection site paraesthesia

n/a

Uncommon

n/a

n/a – not reported as adverse drug reaction

*procedure-related adverse reactions

1The median time to onset of eyelid ptosis was 9 days following treatment

2The median time to onset of brow ptosis was 5 days following treatment

No change was observed in the overall safety profile following repeat dosing.

Platysma Prominence

The safety of BOTOX was evaluated in the double-blind, placebo-controlled clinical studies for the improvement of platysma prominence. No adverse reactions were reported by ≥1% of BOTOX treated subjects that were also more frequent than in placebo-treated subjects.

The safety of up to 4 BOTOX treatments for platysma prominence was also assessed. Eligible subjects who received BOTOX or placebo in the lead-in double-blind, placebo-controlled study received up to 3 additional BOTOX treatments in its open-label extension study. The following adverse reactions were reported during open-label treatment of platysma prominence:

System Organ Class

Preferred Term

Frequency

Gastrointestinal disorders

Dysphagia

Uncommon

Nervous System disorders

Facial paresis

Uncommon

No change was observed in the overall safety profile with repeat dosing of up to 4 BOTOX treatments.

c) Additional information

The following list includes adverse drug reactions or other medically relevant adverse events that have been reported since the drug has been marketed, regardless of indication, and may be in addition to those cited in section 4.4 (Special warnings and precautions for use), and section 4.8 (Undesirable effects).

System Organ Class

Preferred Term

Immune system disorders

Anaphylaxis, angioedema, serum sickness, urticaria

Metabolism and nutrition disorders

Anorexia

Nervous system disorders

Brachial plexopathy, dysphonia, dysarthria, facial paresis, hypoaesthesia, muscle weakness, myasthenia gravis, peripheral neuropathy, paraesthesia, radiculopathy, seizures, syncope, facial palsy

Eye disorders

Angle-closure glaucoma (for treatment of blepharospasm), eyelid ptosis, lagophthalmos, strabismus, blurred vision, visual disturbance, dry eye, eyelid oedema

Ear and labyrinth disorders

Hypoacusis, tinnitus, vertigo

Cardiac disorders

Arrhythmia, myocardial infarction

Respiratory, thoracic and mediastinal disorders

Aspiration pneumonia (some with fatal outcome), dyspnoea, respiratory depression, respiratory failure

Gastrointestinal disorders

Abdominal pain, diarrhoea, constipation, dry mouth, dysphagia, nausea, vomiting

Skin and subcutaneous tissue disorders

Alopecia, brow ptosis, dermatitis psoriasiform, erythema multiforme, hyperhidrosis, madarosis, pruritus, rash

Musculoskeletal and connective tissue disorders

Muscle atrophy, myalgia, localised muscle twitching/ involuntary muscle contractions

General disorders and administration site conditions

Denervation atrophy, malaise, pyrexia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose of BOTOX is a relative term and depends upon dose, site of injection, and underlying tissue properties. No cases of systemic toxicity resulting from accidental injection of BOTOX have been observed. Excessive doses may produce local, or distant, generalised and profound neuromuscular paralysis. No cases of ingestion of BOTOX have been reported.

Signs and symptoms of overdose are not apparent immediately post-injection. Should accidental injection or ingestion occur or overdose or spread of toxin be suspected, the patient should be medically monitored for up to several weeks for progressive signs and symptoms of muscular weakness, which could be local or distant from the site of injection and may include ptosis, diplopia, dysphagia, dysarthria, generalised weakness or respiratory failure. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalisation.

If the musculature of the oropharynx and oesophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralysed or sufficiently weakened, intubation and assisted respiration will be required until recovery takes place and may involve the need for a tracheostomy and prolonged mechanical ventilation, in addition to other general supportive care.