1 INDICATIONS AND USAGE DYSPORT is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for: the treatment of cervical dystonia in adults ( 1.1 ) the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults < 65 years of age ( 1.2 ) The treatment of spasticity in patients 2 years of age and older ( 1.3 ) 1.1 Cervical Dystonia DYSPORT is indicated for the treatment of cervical dystonia in adults.

1.2 Glabellar Lines DYSPORT is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adults less than 65 years of age.

1.3 Spasticity DYSPORT is indicated for the treatment of spasticity in patients 2 years of age and older.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in labeling: Spread of Toxin Effect [ see Warning s and Precautions (5.1)] Lack of Interchangeability between Botulinum Toxin Products [ see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [ see Warnings and Precautions (5.3) ] Dysphagia and Breathing Difficulties [ see Warnings and Precautions (5.4) ] Facial Anatomy in the Treatment of Glabellar Lines [ see Warnings and Precautions (5.5) ] Dry Eye with the Treatment of Glabellar Lines [see Warnings and Precautions (5.6) ] Pre-existing Neuromuscular Disorders [ see Warnings and Precautions (5.7) ] Human Albumin and Transmission of Viral Diseases [ see Warnings and Precautions (5.8) ] Intradermal Immune Reaction [ see Warnings and Precautions (5.9) ] Pre-existing Conditions at the Injection Site [ See Warnings and Precautions (5.10) ] Most commonly observed adverse reactions are ( 6.1 ): Cervical Dystonia (≥ 5%): muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, musculoskeletal pain, dysphonia, injection site pain and eye disorders Glabellar Lines (≥2%): nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine Spasticity in Adults Upper limb spasticity (≥ 4%): muscular weakness Lower limb spasticity (≥ 5%): falls, muscular weakness, and pain in extremity Spasticity in Pediatric Patients Upper limb spasticity (≥10%): upper respiratory tract infection and pharyngitis Lower limb spasticity ((≥10%): nasopharyngitis, cough, and pyrexia To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc.

at 855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 open-label treatment in which dose optimization (250 to 1000 Units per treatment) over the course of 5 treatment cycles was allowed [see Clinical Studies (14.1)].

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 placebo-controlled 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 7 compares the incidence of the most frequent adverse reactions from a single treatment cycle of 500 Units of DYSPORT compared to placebo [ see Clinical Studies (14.1) ].

Table 7: 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 Injection site discomfort 13 8 Fatigue 12 10 Injection site pain 5 4 Musculoskeletal and connective tissue disorders Muscular weakness 16 4 Musculoskeletal pain 7 3 Gastrointestinal disorders Dysphagia 15 4 Dry Mouth 13 7 Nervous system disorders Headache 11 9 Respiratory, thoracic and mediastinal disorders Dysphonia 6 2 Eye Disorders The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus.

7 2 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 8.

Table 8: Common Adverse Reactions by Dose in Fixed-dose Study in Patients with Cervical Dystonia Adverse Reactions DYSPORT Dose 250 Units % 500 Units % 1000 Units % Placebo % Any Adverse Reaction 37 65 83 30 Dysphagia 21 29 39 5 Dry Mouth 21 18 39 10 Muscular Weakness 11 12 56 0 Injection Site Discomfort 5 18 22 10 Dysphonia 0 18 28 0 Facial Paresis 5 0 11 0 Eye Disorder The following preferred terms were reported: vision blurred, diplopia, visual acuity reduced, eye pain, eyelid disorder, accommodation disorder, dry eye, eye pruritus 0 6 17 0 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 DYSPORT administration 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 DYSPORT exhibited 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 DYSPORT were nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine.

Table 9 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 [ see Clinical Studies (14.2 ) ].

Adverse reactions of any cause occurred in 48% of the DYSPORT-treated patients and 33% of the placebo-treated patients.

Table 9: Most Common Adverse Reactions with > 1% Incidence in Pooled, Placebo-Controlled Trials for Glabellar Lines Adverse Reactions by Body System DYSPORT (N=398) % Patients who received treatment with placebo and DYSPORT are counted in both treatment columns.

Placebo (N=496) % Any Adverse Reaction 48 33 Eye Disorders Eyelid Edema Eyelid Ptosis 2 2 0 <1 Gastrointestinal Disorders Nausea 2 1 General Disorders and Administrative Site Conditions Injection Site Pain Injection Site Reaction 3 3 2 < 1 Infections and Infestations Nasopharyngitis Upper Respiratory Tract Infection Sinusitis 10 3 2 4 2 1 Investigations Blood Present in Urine 2 < 1 Nervous System Disorders Headache 9 5 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.

[ see Dosage and Administration (2.4)].

].

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 10 lists the adverse reactions that occurred in ≥ 2% of patients in any DYSPORT dose group and more frequent than placebo in double-blind studies evaluating the treatment of upper limb spasticity in adults.

The most common adverse reactions (≥ 4%) in any DYSPORT dose group was muscular weakness.

Table 10: 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 500 Units (N=197) % 1000 Units (N=194) % (N=279) % Infections and infestations Influenza 1 2 1 Infection 1 2 1 Musculoskeletal and connective tissue disorders Muscular weakness 2 4 1 Pain in extremity 0 2 1 Back pain 1 2 1 Nervous system disorders Headache 1 2 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 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 adults with lower limb spasticity.

Of this population, 89% were Caucasian, 66% male, and the median age was 55 years (range 23-77 years).

Table 11 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 11: Adverse Reactions Observed in at Least 2% of Patients Treated in the Double-Blind Trial of Adults 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 Pain in extremity Arthralgia 2 6 4 7 6 2 3 2 1 Injury, poisoning and procedural complications Fall 9 6 3 Nervous system disorders Headache 0 3 1 Infections and infestations Upper respiratory tract infection 2 1 1 General disorders and administration site conditions Fatigue Influenza-like illness Edema peripheral 1 2 2 4 0 0 0 0 0 Investigations Alanine aminotransferase increase 2 0 1 Gastrointestinal disorders Constipation 0 2 1 Psychiatric disorders Depression Insomnia 2 0 3 2 0 0 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.

[see Use in Specific Populations (8.5) ] Upper Limb Spasticity in Pediatric Patients Table 12 reflects exposure to DYSPORT in 210 patients, 2 to 17 years of age, who were evaluated in a double blind, active-controlled, multicenter study in patients treated for upper limb spasticity [see Clinical Studies (14.4)].

The most commonly observed adverse reactions (≥10% of patients) were: upper respiratory tract infection and pharyngitis.

Table 12: Adverse Reactions Observed in ≥ 3% of Patients Treated in the Double-Blind Study of Pediatric Patients with Upper Limb Spasticity and Reported More Frequently than Control Group Adverse Reactions Dysport 2 Units/kg 1 (N=70) % Dysport 8 Units/kg (N=70) % Dysport 16 Units/kg (N=70) % Infections and infestations Upper respiratory tract infection Influenza Pharyngitis 2 7 1 9 9 1 6 11 3 10 Gastrointestinal disorders Nausea 0 3 1 Musculoskeletal and connective tissue diorders Muscular weakness 1 4 6 Nervous system disorders Headache Epilepsy 0 1 6 0 3 4 1 Low dose active comparator arm 2 Includes pharyngitis, pharyngitis streptococcal, pharyngotosilitis Additional adverse reactions occurring below 3% and considered to be drug related include: myalgia, pain in extremity, fatigue, influenza-like illness, injection site eczema, injection site bruising, injection site rash, injection site pain, and injection site swelling.

Lower Limb Spasticity in Pediatric Patients Table 13 reflects exposure to DYSPORT in 160 patients, 2 to 17 years of age, who were evaluated in the randomized, placebo-controlled clinical study that assessed the use of DYSPORT for the treatment of unilateral or bilateral lower limb spasticity in pediatric cerebral palsy patients [ see Clinical Studies (14.4) ].

The most commonly observed adverse reactions (≥ 10% of patients) are: upper respiratory tract infection, nasopharyngitis, influenza, pharyngitis, cough and pryrexia.

Table 13: 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 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) % Placebo (N=79) % Infections and Infestations Nasopharyngitis 9 12 16 10 5 Bronchitis 0 0 8 7 3 Respiratory, thoracic and mediastinal disorders Cough 7 6 14 10 6 General disorders and administration site conditions Pyrexia 7 12 8 7 5 Musculoskeletal and connective tissue disorders Pain in extremity 0 2 5 7 5 Nervous system disorders Convulsion/Epilepsy 7 4 0 7 0 6.2 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.

Spasticity in Pediatric Patients 2 Years of Age or Older Upper Limb Spasticity From 178 subjects treated with DYSPORT for up to 4 treatment cycles and tested for the presence of binding antibodies at baseline and end of study, 7 subjects previously receiving botulinum toxin injections had binding antibodies after treatment.

Among those 7 subjects, 4 subjects (2.3%) developed neutralizing antibodies when tested in the mice bioassay.

In the presence of binding and/or neutralizing antibodies to DYSPORT some patients continue to experience clinical benefit.

Lower Limb Spasticity 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.

6.3 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, muscle atrophy, burning sensation, facial paresis, hypoesthesia, erythema, dry eye, and excessive granulation tissue.

Hypersensitivity reactions including anaphylaxis have been reported.