BOTOX Powder for solution for injection Ref.[6581] Active ingredients: Botulinum toxin type A

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.

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. The risk of symptoms 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 used 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 post-stroke 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 post-stroke 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

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 is 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 seen at maximum frown, in the crow’s feet lines seen at maximum smile , or in the forehead lines seen at maximum eyebrow elevation, see section 4.2. There is a risk of eyelid ptosis following treatment, refer to Section 4.2 for administration instructions on how to minimise this risk.

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.

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).

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.

General

In controlled clinical trials adverse events considered by the investigators to be related to BOTOX were reported in 35% of the patients with blepharospasm, 28% with cervical dystonia, 17% with paediatric cerebral palsy, 11% with primary hyperhidrosis of the axillae, 16% with focal spasticity of the upper limb associated with stroke, 15% with focal spasticity of the lower limb associated with stroke, 26% with overactive bladder, and 32% 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 that 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.

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).

NEUROLOGIC DISORDERS

Focal spasticity of the upper limb in paediatric patients:

Focal spasticity of the lower limb in paediatric patients:

Focal upper limb spasticity associated with stroke in adult patients:

Some of the uncommon events may be disease related.

Focal lower limb spasticity associated with stroke in adult patients:

Blepharospasm/hemifacial spasm:

Nervous system disorders

Cervical dystonia:

Chronic migraine:

* 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

Overactive bladder:

* 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.

Adult urinary incontinence due to neurogenic detrusor overactivity:

* 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:

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

SKIN AND SKIN APPENDAGE DISORDERS

Primary hyperhidrosis of the axillae:

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).

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.

n/a – not reported as adverse drug reaction
^* procedure-related adverse reactions
¹ The median time to onset of eyelid ptosis was 9 days following treatment
² The median time to onset of brow ptosis was 5 days following treatment

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

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).

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.

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