DYSPORT

Botulinum toxin type A, the active ingredient in DYSPORT, is a purified neurotoxin type A complex produced by fermentation of the bacterium Clostridium botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation, dialysis, and chromatography steps. The neurotoxin complex is composed of the neurotoxin, hemagglutinin proteins and non-toxin non-hemagglutinin protein. DYSPORT® (abobotulinumtoxinA) for injection is a sterile, lyophilized powder supplied in a single-dose vial for reconstitution intended for intramuscular injection. Each vial contains 300 Units or 500 Units of lyophilized abobotulinumtoxinA, human serum albumin (125 mcg) and lactose (2.5 mg). DYSPORT may contain trace amounts of cow's milk proteins [ see Contraindications (4) and Warnings and Precautions (5.3) ]. ]. The primary release procedure for DYSPORT uses a cell-based potency assay to determine the potency relative to a reference standard. The assay and reference material are specific to DYSPORT. One unit of DYSPORT corresponds to the calculated median lethal intraperitoneal dose (LD 50 ) in mice. Due to specific details of the assay system, such as vehicle, dilution scheme and laboratory protocols, Units of biological activity of DYSPORT cannot be converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method.

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.

Preparation of DYSPORT Solution for Administration ( 2.2 ) Once reconstituted, store in original container in a refrigerator 2°C to 8°C (36°F to 46°F) and use within 24 hours Do not freeze after reconstitution Reconstitution instructions are specific for the 300 Unit and 500 Unit vials Reconstituted DYSPORT is intended for intramuscular injection only. After reconstitution, DYSPORT should be used for only one injection session and for only one patient. Cervical Dystonia ( 2.3 ) • Initial dose is 500 Units given intramuscularly as a divided dose among the affected muscles • Re-treatment every 12 to 16 weeks or longer, as necessary, based on return of clinical symptoms with doses administered between 250 and 1000 Units to optimize clinical benefit • Re-treatment should not occur in intervals of less than 12 weeks • Titrate in 250 Unit steps according to patient's response Glabellar Lines ( 2.4 ) Administer a total dose of 50 Units, divided in five equal aliquots of 10 Units each, intramuscularly to affected muscles to achieve clinical effect Re-treatment should be administered no more frequently than every 3 months Spasticity in Adults ( 2.5 ) Select dose based on muscles affected, severity of spasticity, and treatment and adverse reaction history botulinum toxins Dosing for upper limb spasticity: between 500 Units and 1000 Units Dosing for lower limb spasticity: up to 1500 Units The maximum recommended total dose per treatment session (upper and lower limb combined) in adults is 1500 Units Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 12 weeks Spasticity in Pediatric Patients ( 2.6 ) Select dose based on the affected muscle, severity of spasticity, and treatment and adverse reaction history with all botulinum toxins. Recommended dosing for upper limb spasticity: 8 Units/kg to 16 Units/kg per limb. The maximum recommended total dose administered per treatment session must not exceed 16 Units/kg or 640 Units, whichever is lower. Recommended dosing for lower limb spasticity: 10 Units/kg to 15 Units/kg per limb. Total dose per treatment session must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral injections, or 1000 Units, whichever is lower. The maximum recommended total dose per treatment session is 30 Units/kg or 1000 Units, whichever is lower. Re-treatment, based on return of clinical symptoms, should not occur in intervals of less than 3 months. 2.1 Instructions for Safe Use The potency units of DYSPORT are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [ see Warnings and Precautions (5.2) and Description (11) ]. Reconstituted DYSPORT is intended for intramuscular injection only. 2.2 Preparation of Dysport Solution for Administration DYSPORT is supplied as a dry powder, in single-dose 300 Unit and 500 Unit vials, which must be reconstituted with preservative-free 0.9% Sodium Chloride Injection, USP using aseptic technique prior to intramuscular injection. Table 1 provides dilution instructions for the 300 Unit and 500 Unit vials, depending on the desired final concentration. The desired final concentration after dilution varies depending on the indication (see Table 2 for the recommended solution concentration after dilution). Table 1: Dilution Instructions for DYSPORT Vials (500 Units and 300 Units) Diluent Preservative-free 0.9% Sodium Chloride Injection, USP Only per 500 Unit Vial Resulting Dose Unites per 0.1 mL DIluent per 300 Unit Vial Resulting Dose Units per 0.1 mL 1 mL 50 Units 0.6 mL 50 Units 2 mL 25 Units -- -- 2.5 mL 20 Units 1.5 mL 20 Units -- -- 2.5 mL 12 Units 5 mL ‡ 10 Units 3 mL 10 Units Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the DYSPORT dose is also possible by administering a smaller or larger injection volume (i.e., 0.05 mL (50% decrease in dose), 0.08% (20% decrease in dose) or 0.15 mL (50% increase in dose)). ‡ When using 5 mL of diluent for a 500 Unit vial of DYSPORT, no more than 2.5 mL of 0.9% Sodium Chloride Injection, USP should be introduced into the vial. Complete the following steps: Reconstitute a 500 Unit vial of DYSPORT with 2.5 mL of Preservative-free 0.9% Sodium Chloride Injection, USP, gently mix, and set the vital aside. Withdraw 2.5 mL of Preservative-free 0.9 Sodium Chloride Infection, USP into a 5 mL syringe Take the 5 mL syringe with 2.5 ml Preservative-free Sodium Chloride Injection, USP and draw up the DYSPORT solution from the reconstituted vial without inverting and mix gently. The resulting concentration will be 10 units/0.1 mL Use immediately after reconstitution in the syringe. Dispose of any unused 0.9% Sodium Chloride Injection, USP. Using an appropriately sized sterile syringe, needle and aseptic technique, draw up the required amount of sterile, preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1 ). Insert the needle into the DYSPORT vial. The partial vacuum will begin to pull the saline into the vial. Any remaining required saline should be expressed into the vial manually. Do not use the vial if no partial vacuum is observed. Swirl gently to dissolve. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted DYSPORT should be a clear, colorless solution, free of particulate matter, otherwise it should not be injected. Expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach an appropriately sized new sterile needle for injection. After reconstitution, DYSPORT should be used for only one injection session and for only one patient. Discard any unused portion. Once reconstituted, unused DYSPORT may be stored in the original container, in a refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 24 hours until time of use. It must be discarded if not used within 24 hours. Do not freeze reconstituted DYSPORT. Discard the vial and needle in accordance with local regulations. Table 2: Recommended Solution Concentration and Dosing Range of DYSPORT by Indication Indication Recommended Concentration Recommended DYSPORT Dose Cervical Dystonia, Adults 50 Units/0.1 mL or 25 Units/0.1 mL 500 Units to 1000 Units Glabellar Lines, Adults 12 Units/0.1 mL or 20 Units/0.1 mL 50 Units, divided in five equal aliquots of 10 Units (0.08 mL) each or 50 Units, divided in five equal aliquots of 10 Units (0.05 mL) each Spasticity, Adults* 10 Units/0.1 mL or 20 Units/0.1 mL Upper Limb: 500 Units to 1000 Units Lower Limb: 1000 Units to 1500 Units Maximum total dose per treatment session = 1500 Units Spasticity, Pediatric Patients ‡ 20 Units/0.1 mL or 50 Units/0.1 mL** Upper Limb: 8 Units/kg to 16 Units/kg per limb Maximum total dose per treatment session = 16 Units/kg or 640 Units, whichever is lower Lower Limb: 10 Units/kg to 15 Units/kg per limb Maximum total dose per treatment session for unilateral limb injections = 15 Units/kg or 1000 Units, whichever is lower Maximum total dose per treatment session for bilateral limb injections = 30 Units/kg or 1000 Units, whichever is lower Maximum total dose per treatment session = 30 Units/kg or 1000 Units, whichever is lower * No more than 1 mL should generally be administered at any single injections site ‡ No more than 0.5 mL of DYSPORT should be administered in any single injection site ** Further dilution with preservative-free 0.9% Sodium Chloride Injection, USP, may be required to achieve the final volume for injection. 2.3 Dosing in Cervical Dystonia The recommended initial dose of DYSPORT for the treatment of cervical dystonia in adults is 500 Units given intramuscularly as a divided dose among affected muscles in patients with or without a history of prior treatment with botulinum toxin. (A description of the average DYSPORT dose and percentage of total dose injected into specific muscles in the pivotal clinical trials can be found in Table 15 of Section 14.1, Clinical Studies – Cervical Dystonia.) Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Clinical studies with DYSPORT in cervical dystonia suggest that the peak effect occurs between two and four weeks after injection. Simultaneous guided injection of DYSPORT with EMG and/or ultrasound may be helpful in locating active muscles. Dose Modification Where dose modification is necessary for the treatment of cervical dystonia, uncontrolled open-label studies suggest that dose adjustment can be made in 250 Unit steps according to the individual patient's response, with re-treatment every 12 weeks or longer, as necessary, based on return of clinical symptoms. Uncontrolled open-label studies also suggest that the total dose administered in a single treatment should be between 250 Units and 1000 Units. Re-treatment, if needed, should not occur in intervals of less than 12 weeks. Doses above 1000 Units have not been systematically evaluated. 2.4 Dosing in Glabellar Lines The dose of DYSPORT for the treatment of glabellar lines in adults is a total of 50 Units given intramuscularly in five equal aliquots of 10 Units each to achieve clinical effect (see Figure 1 ). The clinical effect of DYSPORT may last up to four months. Repeat dosing in clinical studies demonstrated continued efficacy with up to four repeated administrations. It should be administered no more frequently than every three months. When used for re-treatment, DYSPORT should be reconstituted and injected using the same techniques as the initial treatment. Injection Technique Glabellar facial lines arise from the activity of the lateral corrugator and vertical procerus muscles. These can be readily identified by palpating the tensed muscle mass while having the patient frown. The corrugator depresses the skin creating a "furrowed" vertical line surrounded by tensed muscle (i.e., frown lines). The location, size, and use of the muscles vary markedly among individuals. Physicians administering DYSPORT must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. Risk of ptosis can be mitigated by careful examination of the upper lid for separation or weakness of the levator palpebrae muscle (true ptosis), identification of lash ptosis, and evaluation of the range of lid excursion while manually depressing the frontalis to assess compensation. In order to reduce the complication of ptosis, the following steps should be taken: Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Medial corrugator injections should be placed at least 1 centimeter above the bony supraorbital ridge. Ensure the injected volume/dose is accurate and where feasible kept to a minimum. Do not inject toxin closer than 1 centimeter above the central eyebrow. To inject DYSPORT, advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim. Inject patients with a total of 50 Units in five equally divided aliquots. Using an appropriately sized needle, inject 10 Units of DYSPORT into each of five sites, two in each corrugator muscle, and one in the procerus muscle (see Figure 1 ). Figure 1 Figure 1 2.5 Dosing in Spasticity in Adults Dosing in initial and subsequent treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse reaction history with botulinum toxins. No more than 1 mL should generally be administered at any single injection site. The maximum recommended total dose (upper and lower limb combined) of DYSPORT for the treatment of spasticity in adults is 1500 Units. Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique (e.g., electromyography, electrical stimulation, or ultrasound) is recommended to target the injection sites. Upper Limb Spasticity In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of upper limb spasticity in adults [ see Clinical Studies (14.3) ], doses of 500 Units and 1000 Units were divided among selected muscles at a given treatment session (see Table 3 and Figure 2 ). Table 3: DYSPORT Dosing by Muscle for Upper Limb Spasticity in Adults Muscles Injected Recommended Dose DYSPORT Recommended Number of Injection(s) per Muscle Flexor carpi radialis (FCR) Flexor carpi ulnaris (FCU) 100 Units to 200 Units 100 Units to 200 Units 1 to 2 1 to 2 Flexor digitorum profundus (FDP) Flexor digitorum superficialis (FDS) 100 Units to 200 Units 100 Units to 200 Units 1 to 2 1 to 2 Brachialis Brachioradialis Biceps Brachii (BB) Pronator Teres 200 Units to 400 Units 100 Units to 200 Units 200 Units to 400 Units 100 Units to 200 Units 1 to 2 1 to 2 1 to 2 1 Figure 2: Muscles for Injection for Upper Limb Spasticity in Adults Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 12-16 weeks; however some patients had a longer duration of response (i.e. 20 weeks). The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. Clinical improvement may be expected one week after administration of DYSPORT. Figure 2 Lower Limb Spasticity In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of lower limb spasticity in adults [ see Clinical Studies (14.3) ], doses of 1000 Units and 1500 Units were divided among selected muscles at a given treatment session (see Table 4 and Figure 3). Table 4: DYSPORT Dosing by Muscle for Lower Limb Spasticity in Adults Muscles Injected Recommended DYSPORT Dose Recommended Number of Injection Sites per Muscle Distal Muscles Gastrocnemius Medial head 100 Units to 150 Units 1 Lateral head 100 Units to 150 Units 1 Soleus 330 Units to 500 Units 3 Tibialis posterior 200 Units to 300 Units 2 Flexor digitorum longus 130 Units to 200 Units 1 to 2 Flexor halluces longus 70 Units to 200 Units 1 Figure 3: Muscle for Injection for Lower Limb Spasticity in Adults Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 12-16 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. figure3_muscles_for_injection_for_lower_limb_spasticity 2.6 Dosing in Spasticity in Pediatric Patients DYSPORT dosing for spasticity in pediatric patients is based on Units per kilogram of body weight. To calculate the total units of DYSPORT required for treatment of one limb, select the dose of DYSPORT in Units/kg and the body weight (kg) of the patient (see Tables 5 and 6). Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient’s response to previous treatment, and/or adverse reaction history with botulinum toxins. No more than 0.5 mL should generally be administered at any single injection site. The maximum recommended total dose of DYSPORT in a single treatment session for spasticity in pediatric patients 2 years or older is 30 Units/kg or 1000 Units in a 3-month interval. Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique (e.g., electromyography or electrical stimulation, or ultrasound) is recommended to target the injection sites. Upper Limb Spasticity in Pediatric Patients 2 Years of Age and Older In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of upper limb spasticity in pediatric patients 2 years of age or older with a weight of at least 10 kg [ see Clinical Studies (14.4) ], doses of 8 Units/kg or 16 Units/kg were divided among selected muscles of the target upper limb at a given treatment session (see Table 5 and Figure 4). Table 5 describes the recommended Units/kg dose of DYSPORT per muscle. The maximum recommended total dose of DYSPORT administered for treatment of upper limb spasticity must not exceed 16 Units/kg or 640 Units, whichever is lower. Table 5: DYSPORT Dosing by Muscle for Upper Limb Spasticity in Pediatric Patients Muscle Recommended Dose Range per muscle per upper limb (units/kg Body Weight) Number of injection sites per muscle Brachialis 3 Units/kg to 6 Units/kg Up to 2 Brachioradialis 1.5 Units/kg to 3 Units/kg 1 Biceps brachii 3 Units/kg to 6 Units/kg Up to 2 Pronator teres 1 Units/kg to 2 Units/kg 1 Prontator quadratus 0.5 Unit/kg to 1 Units/kg 1 Flexor carpi radialis (FCR) 2 Units/kg to 4 Units/kg Up to 2 Flexor carpi ulnaris (FCU) 1.5 Units/kg to 3 Units/kg 1 Flexor digitorum profundus (FDP) 1 Units/kg to 2 Units/kg 1 Flexor digitorum superficialis (FDS) 1.5 Units/kg to 3 Units/kg Up to 4 Total dose 8 Units/kg to 16 Units/kg in upper limbs (and not exceeding 640 Units) Figure 4: Muscles for Injection for Upper Limb Spasticity in Pediatric Patients Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished but no sooner than 16 weeks after the previous injection. A majority of patients in the clinical study were retreated between 16-28 weeks; however, some patients had a longer duration of response (i.e., 34 weeks or more). The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. Lower Limb Spasticity in Pediatric Patients 2 Years of Age and Older In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of lower limb spasticity in pediatric patients 2 years of age or older [see Clinical Studies (14.4)] , doses of 10 Units/kg to 15 Units/kg were divided among selected muscles of the target lower limb at a given treatment session (see Table 6 and Figure 5). Table 6 describes the recommended Units/kg dose of DYSPORT per muscle of the Gastrocnemius-Soleus Complex (GSC). The recommended total DYSPORT dose per treatment session is 10 Units/kg to 15 Units/kg for unilateral lower limb injections or 20 Units/kg to 30 Units/kg for bilateral lower limb injections. However, the total dose of DYSPORT administered in a 3-month interval must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral lower limb injections, or 1000 units, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be distributed across more than 1 injection site in any single muscle (see Table 6). Table 6. DYSPORT Dosing by Muscle for Lower Limb Spasticity in Pediatric Patients Muscle Injected Recommended DYSPORT Dose Range per muscle per leg (Units/kg Body Weight) Recommended number of injections per muscle Gastrocnemius 6 Units/kg to 9 Units/kg the listed individual doses to be injected in the muscles can be used within the range mentioned without exceeding 15 Units/kg total dose for unilateral injection or 30 Units/kg for bilateral injections or 1000 Units whichever is lower. Up to 4 Soleus 4 Units/kg to 6 Units/kg Up to 2 Total 10 Units/kg to 15 Units/kg divided across both muscles Up to 6 Figure 5: Muscles for Injection for Lower Limb Spasticity in Pediatric Patients Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique (e.g. electromyography or electrical stimulation or ultrasound) is recommended to target the injection sites. Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished but no sooner than 12 weeks after the previous injection. A majority of patients in the clinical studies were retreated between 16-22 weeks, however; some had a longer duration of response. The degree and pattern of muscle spasticity and overall clinical benefit at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. The safety and effectiveness of DYSPORT injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established. figure4_upper_limb_pediatric figure4-2_pediatric_spasticity Figure_4_Muscles_Lower_Limb_Spasticity_Pediatric

DYSPORT is contraindicated in patients with: Known hypersensitivity to any botulinum toxin products, cow's milk protein, or to any of the components in the formulation [ see Warnings and Precautions (5.3) ] . This product may contain trace amounts of cow's milk protein [ see Description (11) ] . Infection at the proposed injection site(s). • Hypersensitivity to: • any botulinum toxin product or excipients ( 4 , 5.3 ) • cow's milk protein ( 4 , 5.3 ) • Infection at the proposed injection site(s) ( 4 )

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.

Concomitant use of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission or muscle relaxants, should be observed closely because the effect of DYSPORT may be potentiated (7.1, 7.4) Anticholinergic drugs may potentiate systemic anticholinergic effects (7.2) The effect of administering different botulinum neurotoxins during the course of treatment with DYSPORT is unknown (7.3) 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should only be performed with caution because the effect of the botulinum toxin may be potentiated. If co-administered, observe the patient closely. 7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision. 7.3 Other Botulinum Neurotoxin Products The effect of administering botulinum neurotoxin products including DYSPORT, 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. 7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of DYSPORT.

DYSPORT® (abobotulinumtoxinA) for Injection is a sterile, lyophilized powder supplied in a single-dose, glass vial. Unopened vials of DYSPORT must be stored refrigerated between 2°C to 8°C (36°F to 46°F). Protect from light. Do not use after the expiration date on the vial. All vials, including expired vials, or equipment used with DYSPORT should be disposed of carefully as is done with all medical waste. DYSPORT contains a unique hologram on the carton. If you do not see the hologram, do not use the product. Instead contact 855-463-5127.