DYSPORT SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are discussed below and elsewhere in labeling:

• Distant Spread of Toxin Effect
• Lack of Interchangeability between Botulinum Toxin Products
• Spread of Toxin Effect
• Hypersensitivity Reactions
• Dysphagia and Breathing Difficulties
• Facial Anatomy in the Treatment of Glabellar Lines
• Dry Eye with the Treatment of Glabellar Lines
• Pre-existing Neuromuscular Disorders
• Human Albumin and Transmission of Viral Diseases
• Intradermal Immune Reaction

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cervical Dystonia

The data described below reflect exposure to DYSPORT in 446 cervical dystonia patients in 7 studies. Of these, two studies were randomized, double-blind, single treatment, placebo-controlled studies with subsequent optional openlabel treatment in which dose optimization (250 to 1000 Units per treatment) over the course of 5 treatment cycles was allowed.

The population was almost entirely Caucasian (99%) with a median age of 51 years (range 18-82 years). Most patients (87%) were less than 65 years of age; 58.4% were women.

Common Adverse Reactions

The most commonly reported adverse reactions (occurring in 5% or more of patients who received 500 Units of DYSPORT in the placebo-controlled clinical trials) in cervical dystonia patients were: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, musculoskeletal pain, dysphonia, injection site pain and eye disorders (consisting of blurred vision, diplopia, and reduced visual acuity and accommodation). Other than injection site reactions, most adverse reactions became noticeable about one week after treatment and lasted several weeks.

The rates of adverse reactions were higher in the combined controlled and open-label experience than in the placebocontrolled trials.

During the clinical studies, two patients (<1%) experienced adverse reactions leading to withdrawal. One patient experienced disturbance in attention, eyelid disorder, feeling abnormal and headache, and one patient experienced dysphagia.

Table 1 compares the incidence of the most frequent adverse reactions from a single treatment cycle of 500 Units of DYSPORT compared to placebo,

Table 1: Most Common Adverse Reactions (≥ 5%) and Greater than Placebo in the Pooled, Double-blind, Placebo-Controlled Phase of Clinical Trials in Patients with Cervical Dystonia

 

Adverse Reactions	DYSPORT 500 Units (N=173) %	Placebo (N=182) %
Any Adverse Reaction	61	51
General disorders and administration site conditions	30	23
Injection site discomfort	13	8
Fatigue	12	10
Injection site pain	5	4
Musculoskeletal and connective tissue disorders	30	18
Muscular weakness	16	4
Musculoskeletal pain	7	3
Gastrointestinal disorders	28	15
Dysphagia	15	4
Dry Mouth	13	7
Nervous system disorders	16	13
Headache	11	9
Infections and infestations	13	9
Respiratory, thoracic and mediastinal disorders	12	8
Dysphonia	6	2
Eye Disorders *	7	2
*The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus.

 

Dose-response relationships for common adverse reactions in a randomized multiple fixed-dose study in which the total dose was divided between two muscles (the sternocleidomastoid and splenius capitis) are shown in Table 2.

Table 2: Common Adverse Reactions by Dose in Fixed-dose Study in Patients with Cervical Dystonia

 

Adverse Reactions	DYSPORT Dose
	Placebo	250 Units	500 Units	1000 Units
Any Adverse Event	30%	37%	65%	83%
Dysphagia	5%	21%	29%	39%
Dry Mouth	10%	21%	18%	39%
Muscular Weakness	0%	11%	12%	56%
Injection Site Discomfort	10%	5%	18%	22%
Dysphonia	0%	0%	18%	28%
Facial Paresis	0%	5%	0%	11%
Eye Disorder *	0%	0%	6%	17%
*The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus

 

Injection Site Reactions

Injection site discomfort and injection site pain were common adverse reactions following DYSPORT administration.

Less Common Adverse Reactions

The following adverse reactions were reported less frequently (<5%).

Breathing Difficulty

Breathing difficulties were reported by approximately 3% of patients following DYSPORTadministration and in 1% of placebo patients in clinical trials during the double-blind phase. These consisted mainly of dyspnea. The median time to onset from last dose of DYSPORT was approximately one week, and the median duration was approximately three weeks.

Other adverse reactions with incidences of less than 5% in the DYSPORT 500 Units group in the double-blind phase of clinical trials included dizziness in 3.5% of DYSPORT-treated patients and 1% of placebo-treated patients, and muscle atrophy in 1% of DYSPORT-treated patients and in none of the placebo-treated patients.

Laboratory Findings

Patients treated with DYSPORTexhibited a small increase from baseline (0.23 mol/L) in mean blood glucose relative to placebo-treated patients. This was not clinically significant among patients in the development program but could be a factor in patients whose diabetes is difficult to control.

Electrocardiographic Findings

ECG measurements were only recorded in a limited number of patients in an open-label study without a placebo or active control. This study showed a statistically significant reduction in heart rate compared to baseline, averaging about three beats per minute, observed thirty minutes after injection.

Glabellar Lines

In placebo-controlled clinical trials of DYSPORT, the most common adverse reactions(≥2%) following injection of DYSPORTwere nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine.

Table 3 reflects exposure to DYSPORT in 398 patients 19 to 75 years of age who were evaluated in the randomized, placebo-controlled clinical studies that assessed the use of DYSPORT for the temporary improvement in the appearance of glabellar lines. Adverse reactions of any cause occurred in 48% of the DYSPORT treated patients and 33% of the placebo-treated patients.

Table 3: Most Common Adverse Reactions with > 1% Incidence in Pooled, Placebo-Controlled Trials for Glabellar Lines

 

Adverse Reactions by Body System	DYSPORT (N=398) %*	Placebo (N=496) %*
Any Adverse Reaction	48	33
Eye Disorders
Eyelid Edema	2	0
Eyelid Ptosis	2	<1
Gastrointestinal Disorders
Nausea	2	1
General Disorders and Administrative Site Conditions
Injection Site Pain	3	2
Injection Site Reaction	3	< 1
Infections and Infestations
Nasopharyngitis	10	4
Upper Respiratory Tract Infection	3	2
Sinusitis	2	1
Investigations Blood Present in Urine	2	< 1
Nervous System Disorders
Headache	9	5
*Patients who received treatment with placebo and DYSPORT are counted in both treatment columns.

 

In the clinical trials safety database, where some patients received up to twelve treatments with DYSPORT, adverse reactions were reported for 57% (1425/2491) of patients. The most frequently reported of these adverse reactions were headache, nasopharyngitis, injection site pain, sinusitis, URI, injection site bruising, and injection site reaction (numbness, discomfort, erythema, tenderness, tingling, itching, stinging, warmth, irritation, tightness, swelling).

Adverse reactions that occurred after repeated injections in 2-3% of the population included bronchitis, influenza, pharyngolaryngeal pain, cough, contact dermatitis, injection site swelling, and injection site discomfort.

The incidence of eyelid ptosis did not increase in the long-term safety studies with multiple re-treatments at intervals ≥ three months. The majority of the reports of eyelid ptosis were mild to moderate in severity and resolved over several weeks.

Spasticity In Adults

Injection Site Reactions

Injection site reactions (e.g. pain, bruising, hemorrhage, erythema/hematoma etc.) have occurred following administration of DYSPORT in adults treated for spasticity.

Upper Limb Spasticity In Adults

Table 4 lists the most frequently reported adverse reactions (≥ 2%) in any DYSPORT dose group and more frequent than placebo in double-blind studies evaluating the treatment of upper limb spasticity in adults with DYSPORT.

Table 4: Most Common Adverse Reactions Observed in at Least 2% of Patients Treated in Pooled, Double-Blind Trials of Adult Patients with Upper Limb Spasticity Reported More Frequently than with Placebo

 

Adverse Reaction	DYSPORT		Placebo (N=279) %
	500 Units (N=197) %	1000 Units (N=194) %
Infections and infestations
Nasopharyngitis	4	1	1
Urinary tract infection	3	1	2
Influenza	1	2	1
Infection	1	2	1
Musculoskeletal and connective tissue disorders
Muscular weakness	2	4	1
Pain in extremity	0	2	1
Musculoskeletal pain	3	2
Back pain	1	2	1
Nervous system disorders
Headache	1	2	1
Dizziness	3	1	1
Convulsion	2	2	1
Syncope	1	2	0
Hypoesthesia	0	2	<1
Partial seizures	0	2	0
General disorders and administration site conditions
Fatigue	2	2	0
Asthenia	2	1	<1
Injury, poisoning and procedural complications
Fall	2	3	2
Injury	2	2	1
Contusion	1	2	<1
Gastrointestinal disorders
Diarrhea	1	2	<1
Nausea	2	1	1
Constipation	0	2	1
Investigation
Blood triglycerides increased	2	1	0
Respiratory, thoracic and mediastinal disorders
Cough	1	2	1
Vascular disorders
Hypertension	1	2	<1
Psychiatric disorders
Depression	2	3	1

 

Less Common Adverse Reactions

In a pooled analysis of clinical studies, adverse reactions with an incidence of less than 2% reported in DYSPORT treatment groups included dysphagia 0.5%, gait disturbance 0.5%, hypertonia 0.5%, and sensation of heaviness 0.3%.

Lower Limb Spasticity In Adults

The data described below reflect exposure to DYSPORT in 255 adult patients with lower limb spasticity. Of this population, 89% were Caucasian, 66% male, and the median age was 55 years (range 23-77 years). Table 9 lists the adverse reactions that occurred in ≥ 2% of patients in any DYSPORT dose group and more frequent than placebo in the double-blind study evaluating the treatment of lower limb spasticity in adults. The most common of these adverse reactions (≥ 5%) in any DYSPORT dose group were falls, muscular weakness, and pain in extremity.

Table 5: Adverse Reactions Observed in at Least 2% of Patients Treated in the Double-Blind Trial of Adult Patients with Lower Limb Spasticity and Reported More Frequently than with Placebo

 

Adverse Reactions	Dysport 1000 U (N = 127) %	Dysport 1500 U (N = 128) %	Placebo (N = 130) %
Musculoskeletal and connective tissue disorders
Muscular weakness	2	7	3
Pain in extremity	6	6	2
Arthralgia	4	2	1
Back pain	3	0	2
Injury, poisoning and procedural complications
Fall	9	6	3
Contusion	2	0	0
Wrist fracture	2	0	0
Nervous system disorders
Headache
Epilepsy/Convulsion/Partial seizure/Status	0	3	1
Epilepticus	4	1	2
Infections and infestations
Upper respiratory tract infection	2	1	1
General disorders and administration site conditions
Fatigue	1	4	0
Asthenia	2	1	1
Influenza-like illness	2	0	0
Edema peripheral	2	0	0
Investigations
Alanine aminotransferase increase	2	0	1
Gastrointestinal disorders
Constipation	0	2	1
Dysphagia	2	1	1
Psychiatric disorders
Depression	2	3	0
Insomnia	0	2	0
Vascular disorders
Hypertension	2	1	1

 

In the efficacy and safety studies of DYSPORT for the treatment of lower limb spasticity in adults, muscular weakness was reported more frequently in women (10%) treated with 1500 units of DYSPORT compared to men (5%). Falls were reported more frequently in patients 65 years of age and over.

Lower Limb Spasticity In Pediatric Patients

Table 6 reflects exposure to DYSPORTin 160 patients, 2 to 17 years of age, who were evaluated in the randomized, placebo-controlled clinical study that assessed the use of DYSPORTfor the treatment of unilateral or bilateral lower limb spasticity in pediatric cerebral palsy patients. The most commonly observed adverse reactions (≥ 10% of patients) are: upper respiratory tract infection, nasopharyngitis, influenza, pharyngitis, cough and pryrexia.

Table 6: Adverse Reactions Observed in ≥ 4% of Patients Treated in the Double-Blind Trial of Pediatric Patients with Lower Limb Spasticity and Reported More Frequently than with Placebo

 

Adverse Reactions	Placebo (N=79) %	Unilteral		Bilateral
		Dysport 10 units/kg (N=43) %	Dysport 15 units/kg (N=50) %	Dysport 20 units/kg (N=37) %	Dysport 30 units/kg (N=30) %
Infections and Infestations
Nasopharyngitis	5	9	12	16	10
Upper respiratory tract infection	13	9	20	5	10
Influenza	8	0	10	14	3
Pharyngitis	8	5	0	11	3
Bronchitis	3	0	0	8	7
Rhinitis	4	5	0	3	3
Varicella	1	5	0	5	0
Ear Infection	3	2	4	0	0
Respiratory tract infection viral	0	5	2	0	0
Gastroenteritis viral	0	2	4	0	0
Gastrointestinal disorders
Vomiting	5	0	6	8	3
Nausea	1	0	2	5	0
Respiratory, thoracic and mediastinal disorders
Cough	6	7	6	14	10
Oropharyngeal pain	0	2	4	0	0
General disorders and administration site conditions
Pyrexia	5	7	12	8	7
Musculoskeletal and connective tissue disorders
Pain in extremity	5	0	2	5	7
Muscular weakness	1	5	0	0	0
Nervous system disorders
Convulsion/Epilepsy	0	7	4	0	7

 

Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post-approval use of DYSPORT: vertigo, photophobia, influenza-like illness, amyotrophy, burning sensation, facial paresis, hypoesthesia, erythema, dry eye, and excessive granulation tissue. Hypersensitivity reactions including anaphylaxis have been reported.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products in this class may be misleading.

Cervical Dystonia

About 3% of subjects developed antibodies (binding or neutralizing) over time with DYSPORT treatment.

Glabellar Lines

Testing for antibodies to DYSPORT was performed for 1554 subjects who had up to nine cycles of treatment. Two subjects (0.13%) tested positive for binding antibodies at baseline. Three additional subjects tested positive for binding antibodies after receiving DYSPORT treatment. None of the subjects tested positive for neutralizing antibodies.

Spasticity In Adults

Upper Limb Spasticity

From 230 subjects treated with DYSPORT and tested for the presence of binding antibodies, 5 subjects were positive at baseline and 17 developed antibodies after treatment. Among those 17 subjects, 10 subjects developed neutralizing antibodies. An additional 51 subjects from a separate repeat-dose study were tested for the presence of neutralizing antibodies only. None of the subjects tested positive.

In total, from the 281 subjects treated in the long-term studies and tested for the presence of neutralizing antibodies, 3.6% developed neutralizing antibodies after treatment. In the presence of binding and neutralizing antibodies to DYSPORT some patients continue to experience clinical benefit.

Lower Limb Spasticity

From 367 subjects treated with DYSPORT and tested for the presence of binding antibodies, 4 subjects were positive at baseline and 2 developed binding antibodies after treatment. No subjects developed neutralizing antibodies. An additional 85 subjects from two separate studies were tested for the presence of neutralizing antibodies only. One subject tested positive for the presence of neutralizing antibodies.

In total, from the 452 subjects treated in with DYSORT and tested for the presence of neutralizing antibodies, 0.2% developed neutralizing antibodies after treatment.

Lower Limb Spasticity In Pediatric Patients

From 226 subjects treated with DYSPORT and tested for the presence of binding antibodies, 5 subjects previously receiving botulinum toxins were positive at baseline and 9 patients developed binding antibodies after injections. Among those 9 subjects, 3 subjects developed neutralizing antibodies, while one subject developed neutralizing antibodies from the 5 subjects testing positive for binding antibodies at baseline who previously received botulinum toxin injections.

From a separate repeat-dose study, 203 subjects were tested for the presence of neutralizing antibodies. Two subjects were positive for neutralizing antibodies at baseline and 5 subjects developed neutralizing antibodies after treatments. In total, from the 429 patients tested for the presence of neutralizing antibodies, 2.1% developed neutralizing antibodies after treatment. In the presence of binding and neutralizing antibodies to DYSPORT, some patients continued to experience clinical benefit.

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with DYSPORT.

Patients treated concomitantly with botulinum toxins and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should be observed closely because the effect of the botulinum toxin may be potentiated. Use of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision.

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

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of DYSPORT.