Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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, 17% with paediatric cerebral palsy, 11% with primary hyperhidrosis of the axillae, 16% with focal spasticity of the upper limb associated with stroke and 15% with focal spasticity of the lower limb associated with stroke. In 
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clinical trials for overactive bladder the incidence was 26% with the first treatment and 22% with a second treatment. In clinical trials for urinary incontinence due to neurogenic detrusor overactivity, the incidence was 32% with the first treatment and declined to 18% with a second treatment. 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 23.5% (placebo: 19.2%) 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 7.6% (24 U for crow’s feet lines alone) and 6.2% (44 U: 24 U for crow’s feet lines administered simultaneously with 20 U for glabellar lines) of patients compared to 4.5% 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. Blepharoptosis, which may be technique-related, is consistent with the pharmacological action of BOTOX, when used for cosmetic indications.

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.

The side effects are classified into the following categories, depending on how often they occur: 
Very common          affects more than 1 user in 10
Common               affects 1 to 10 users in 100
Uncommon             affects 1 to 10 users in 1,000
Rare                 affects 1 to 10 users in 10,000
Very rare            affects less than 1 user in 10,000
Not known            cannot be estimated from the available data

Below are lists of side effects which vary depending on the part of the body where BOTOX is injected.

NEUROLOGIC DISORDERS:

Focal spasticity associated with paediatric cerebral palsy
System Organ Class                      Preferred Term                                   Frequency Infections and infestations             Viral infection, ear infection                   Very Common Nervous system disorders                Somnolence, gait disturbance, paraesthesia       Common Skin and subcutaneous tissue            Rash                                             Common 
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disorders
Musculoskeletal and connective        Myalgia, muscular weakness, pain in            Common tissue disorders                      extremity
Renal and urinary disorders           Urinary incontinence                           Common Injury, poisoning and procedural      Fall                                           Common complications
General disorders and                 Malaise, injection site pain, asthenia         Common administration site conditions

Focal upper limb spasticity associated with stroke

System Organ Class                Preferred Term                                     Frequency Psychiatric disorders             Depression, insomnia                               Uncommon Nervous system disorders          Hypertonia                                         Common Hypoasthesia, headache, paraesthesia,              Uncommon incoordination, amnesia
Ear and labyrinth disorders       Vertigo                                            Uncommon Vascular disorders                Orthostatic hypotension                            Uncommon Gastrointestinal disorders        Nausea, paraesthesia oral                          Uncommon Skin and subcutaneous tissue      Ecchymosis, purpura                                Common disorders                         Dermatitis, pruritus, rash                         Uncommon Musculoskeletal and connective    Pain in extremity, muscle weakness                 Common tissue disorders                  Arthralgia, bursitis                               Uncommon General disorders and             Injection site pain, pyrexia, influenza-like       Common administration site conditions    illness, injection site haemorrhage, injection site irritation
Asthenia, pain, injection site hypersensitivity,   Uncommon malaise, oedema peripheral
Some of the uncommon events may be disease related.

Focal lower limb spasticity associated with stroke in adults

System Organ Class                    Preferred Term                                 Frequency Skin and subcutaneous tissue          Rash                                           Common disorders
Musculoskeletal and connective        Arthralgia, musculoskeletal stiffness,         Common tissue disorders                      muscular weakness
General disorders and                 Oedema peripheral                              Common administration site conditions
Injury, poisoning and procedural      Fall                                           Common complications
.
No change was observed in the overall safety profile with repeat dosing.

Blepharospasm, hemifacial spasm and associated dystonias

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,    Common photophobia, eye irritation, lacrimation increase
Keratitis, ectropion, diplopia, entropion,     Uncommon visual disturbance, vision blurred
Eyelid oedema                                  Rare

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Ulcerative keratitis, corneal epithelium         Very Rare defect, corneal perforation
Skin and subcutaneous tissue          Ecchymosis                                       Common disorders                             Rash/dermatitis                                  Uncommon General disorders and                 Irritation, face oedema                          Common administration site conditions        Fatigue                                          Uncommon 
Strabismus

Safety data compiled from clinical trials involving approximately 2058 patients treated with Botox, the following adverse reactions were reported.

System Organ Class                    Preferred Term                                   Frequency Eye disorders                         Eyelid ptosis, eye movement disorder             Very Common Ocular retrobulbar haemorrhages, eye             Uncommon penetration, Holmes-Adie pupil
Vitreous haemorrhage                             Rare

Cervical dystonia

System Organ Class                    Preferred Term                                   Frequency Infections and infestations           Rhinitis, upper respiratory tract infection      Common Nervous system disorders              Dizziness, hypertonia, hypoaesthesia,            Common somnolence, headache
Eye disorders                         Diplopia, eyelid ptosis                          Uncommon Respiratory, thoracic and             Dyspnoea, dysphonia                              Uncommon mediastinal disorders
Gastrointestinal disorders            Dysphagia                                        Very common Dry mouth, nausea                                Common
Musculoskeletal and connective        Muscular weakness                                Very common tissue disorders                      Musculoskeletal stiffness, soreness              Common General disorders and                 Pain                                             Very common administration site conditions        Asthenia, influenza-like illness, malaise        Common Pyrexia                                          Uncommon

Chronic migraine

System Organ Class                    Preferred Term                                   Frequency Nervous system disorders              Headache, migraine, including worsening of       Common migraine, facial paresis
Eye disorders                         Eyelid ptosis                                    Common Skin and subcutaneous tissue          Pruritis, rash                                   Common disorders                             Pain of skin                                     Uncommon 
Musculoskeletal and connective        Neck pain, myalgia, musculoskeletal pain,        Common tissue disorders                      musculoskeletal stiffness, muscle spasms, muscle tightness, muscular weakness
Pain in jaw                                      Uncommon
Mephisto sign (lateral elevation of eyebrows)    Not known
General disorders and                 Injection site pain                              Common administration site conditions
Gastrointestinal disorders            Dysphagia                                        Uncommon 


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The discontinuation rate due to adverse events in these phase 3 trials was 3.8% for BOTOX vs. 1.2% for placebo.

BLADDER DISORDERS:

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 that occurred with a common frequency were dysuria and haematuria.
Clean intermittent catheterisation was initiated in 6.5% of patients following treatment with BOTOX 100 Units versus 0.4% in the placebo group.

Of 1242 patients in the placebo-controlled clinical studies, 41.4% of patients (n = 514) were ≥ 65 years of age and 14.7% (n = 182) 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

System Organ Class                     Preferred Term                                   Frequency Infections and infestations            Urinary tract infection a,b, bacteriuria b       Very Common Investigations                         Residual urine volume **b                        Very Common Psychiatric disorders                  Insomnia a                                       Common Gastrointestinal disorders             Constipation a                                   Common Musculoskeletal and connective         Muscular weakness a, muscle spasm a              Common tissue disorders
Renal and urinary disorders            Urinary retention a,b                            Very Common Haematuria* a,b, dysuria* a,b, bladder           Common diverticulum a
General disorders and                  Fatigue a, gait disturbance a                  Common administration site conditions
Injury, poisoning and procedural        Autonomic dysreflexia* a, fall a              Common complications
* procedure-related adverse reactions
** elevated PVR not requiring catheterisation 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 clinical trials urinary tract infection was reported in 49.2% of patients treated with 200 Units BOTOX and in 35.7% of patients treated with placebo (53.0% of multiple sclerosis patients treated with 200 Units vs. 29.3% with placebo; 45.4% of spinal cord injury patients treated with 200 Units vs.
41.7% with placebo). Urinary retention was reported in 17.2% of patients treated with 200 Units
BOTOX and in 2.9% of patients treated with placebo (28.8% of multiple sclerosis patients treated with 200 Units vs. 4.5% with placebo; 5.4% of spinal cord injury patients treated with 200 Units vs. 1.4% with placebo).

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No change in the type of adverse reactions was observed with repeat dosing.

No difference on the multiple sclerosis (MS) exacerbation annualised rate (i.e., number of MS exacerbation events per patient-year) was observed (BOTOX=0.23, placebo=0.20) in the MS patients enrolled in the pivotal studies, nor in the post-approval study of BOTOX 100 Units in MS patients not catheterising at baseline (BOTOX=0, placebo=0.07).


In the pivotal studies, among patients who were not catheterising at baseline prior to treatment, catheterisation was initiated in 38.9% following treatment with BOTOX 200 Units versus 17.3% on placebo.
In the post-approval study of BOTOX 100 Units in MS patients not catheterising at baseline, catheterisation was initiated in 15.2% of patients following treatment with BOTOX 100 Units versus 2.6% on placebo (refer to Section 5.1).

SKIN AND SKIN APPENDAGE DISORDER:

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          Hyperhidrosis (non axillary sweating), skin           Common disorders                             odour abnormal, pruritus, subcutaneous nodule, alopecia
Musculoskeletal and connective        Pain in extremity                                     Common tissue disorders                      Muscular weakness, myalgia, arthropathy               Uncommon General disorders and                 Injection site pain                                   Very Common administration site conditions        Pain, injection site oedema, injection site           Common haemorrhage, injection site hypersensitivity,
injection site irritation, asthenia, injection site reactions

In the management of primary axillary hyperhidrosis, 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 U 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).

Glabellar Lines

The following adverse drug reactions were reported in the double-blind, placebo-controlled clinical studies following injection of Botox 20 Units for glabellar lines alone: 
System Organ Class                    Preferred Term                                        Frequency 
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Infections and infestations           Infection                                        Uncommon Psychiatric disorders                 Anxiety                                          Uncommon Nervous system disorders              Headache, paraesthesia                           Common Dizziness                                        Uncommon
Eye disorders                         Eyelid ptosis                                    Common Blepharitis, Eye pain, visual disturbance        Uncommon
(includes vision blurred)
Gastrointestinal disorders            Nausea                                           Common Oral dryness                                     Uncommon
Skin and subcutaneous tissue          Erythema, skin tightness                         Common disorders                             Oedema (face, eyelid, periorbital),              Uncommon photosensitivity reaction, pruritis, dry skin
Musculoskeletal and connective        Localised muscle weakness                        Common tissue disorders                      Muscle twitching, Mephisto sign (lateral         Uncommon elevation of eyebrows)
General disorders and                 Face pain, injection site oedema, ecchymosis,    Common administration site conditions        injection site pain, injection site irritation Flu syndrome, asthenia, fever                    Uncommon


Crow’s Feet Lines with or without Glabellar lines
The following adverse drug reactions were reported in the double-blind, placebo-controlled clinical studies following injection of BOTOX for crow’s feet lines with or without glabellar lines: 
System Organ Class                    Preferred Term                                   Frequency Eye disorders                         Eyelid oedema                                    Uncommon General disorders and                 injection site haematoma*                        Common administration site conditions        Injection site haemorrhage*, Injection site      Uncommon pain*, injection site paraesthesia


*procedure-related adverse reactions
Forehead Lines and Glabellar Lines with or without Crow’s Feet Lines 
The following adverse drug reactions were reported in double-blind, placebo-controlled clinical studies following injection of BOTOX for simultaneous treatment of forehead lines and glabellar lines with or without crow’s feet lines:

System Organ Class                  Preferred Term                     Frequency Nervous System Disorders            Headache                           Common 1
Eye Disorders                       Eyelid Ptosis                      Common Skin and subcutaneous tissue        Skin tightness                     Common disorders                                        2
Brow Ptosis                        Common
Musculoskeletal and connective      Mephisto sign (lateral elevation Common tissue disorders                    of eyebrows)
General disorders and               Injection site bruising*           Common administration site conditions      Injection site haematoma*          Common Injection site pain*               Uncommon
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 *procedure-related adverse reactions


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No change was observed in the overall safety profile following repeat dosing.
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
Cardiac disorders                       Arrhythmia, myocardial infarction Ear and labyrinth disorders             Hypoacusis, tinnitus, vertigo Eye disorders                           Angle-closure glaucoma (for treatment of blepharospasm), eyelid ptosis, lagophthalmos, strabismus, vision blurred, visual disturbance, dry eye (associated with periocular injections), eyelid oedema
Gastrointestinal disorders              Abdominal pain, diarrhoea, constipation, dry mouth, dysphagia, nausea, vomiting
General disorders and administration    Denervation atrophy, malaise, pyrexia site conditions
Immune system disorders                 Anaphylaxis, angioedema, serum sickness, urticaria Metabolism and nutrition disorders      Anorexia
Musculoskeletal and connective          Muscle atrophy, myalgia, localized muscle twitching/involuntary tissue disorders                        muscle contractions

Nervous system disorders                Brachial plexopathy, dysphonia, dysarthria, facial paresis, hypoaesthesia, muscle weakness, myasthenia gravis, peripheral neuropathy, paraesthesia, radiculopathy, seizures, syncope, facial palsy
Respiratory, thoracic and mediastinal   Aspiration pneumonia (some with fatal outcome), dyspnoea, disorders                               bronchospasm, respiratory depression, respiratory failure Skin and subcutaneous tissue            Alopecia, dermatitis psoriasiform, erythema multiforme, disorders                               hyperhidrosis, madarosis, pruritus, rash, brow ptosis 
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/