Botulinum toxin type A

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).

Caution should be used when botulinum toxin type A 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 botulinum toxin type A is used for treatment of patients with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor neuropathy).

Botulinum toxin type A 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 botulinum toxin type A, 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.

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

There is no information on whether botulinum toxin type A is excreted in human milk. The use of botulinum toxin type A 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.

No studies on the effects on the ability to drive and use machines have been performed. However, botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A (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 botulinum toxin type A 100 Units and 9.6% of patients treated with placebo. Urinary retention was reported in 5.8% of patients treated with botulinum toxin type A 100 Units and in 0.4% of patients treated with placebo. Clean intermittent catheterisation was initiated in 6.5% of patients following treatment with botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 botulinum toxin type A 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 (botulinum toxin type A=0, placebo=0.07).

Catheterisation was initiated in 15.2% of patients following treatment with botulinum toxin type A 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 botulinum toxin type A (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 botulinum toxin type A 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.