Dysport

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.

2 DOSAGE AND ADMINISTRATION 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 D…

5 WARNINGS AND PRECAUTIONS The potency units of DYSPORT are not interchangeable with other preparations of botulinum toxin products ( 5.2 ) Immediate medical attention may be required in cases of respiratory, speech or swallowing difficulties ( 5.4 ) Recommended dose and frequency of administration should not be exceeded ( 5.5 ) Dry eye may occur with glabellar line treatment; if symptoms persist, consider referring patient to an ophthalmologist ( 5.6 ) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment ( 5.7 ) 5.1 Spread of Toxin Effect Postmarketing safety data from DYSPORTand other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses and approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than the maximum recommended total dose. 5.2 Lack of Interchangeability between Botulinum Toxin Products The potency Units of DYSPORT are specific to the preparation and assay method utilized. They 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 Description (11)]. 5.3 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported with DYSPORT. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a serious hypersensitivity reaction occurs, discontinue further injection of DYSPORT and institute appropriate medical therapy immediately. 5.4 Dysphagia and Breathing Difficulties Treatment with DYSPORT and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved [ see Boxed Warning and Warnings and Precautions (5.2) ] . Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several weeks and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Boxed …

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled clinical studies with DYSPORT in pregnant women. DYSPORT should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. DYSPORT produced embryo-fetal toxicity in relation to maternal toxicity when given to pregnant rats and rabbits at doses lower than or similar to the maximum recommended human dose (MRHD) of 1000 Units on a body weight (Units/kg) basis ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data In a study in which pregnant rats received daily intramuscular injections of DYSPORT (2.2, 6.6, or 22 Units/kg on gestation days 6 through 17 or intermittently 44 Units/kg on gestation days 6 and 12 only) during organogenesis, increased early embryonic death was observed with both schedules at the highest tested doses (22 and 44 Units/kg), which were associated with maternal toxicity. The no-effect dose for embryo-fetal developmental toxicity was 2.2 Units/kg (less than maximum recommended human [MRHD] on a body weight basis). In a study in which pregnant rabbits received daily intramuscular injections of DYSPORT® (0.3, 3.3 or 6.7 Units/kg) on gestation days 6 through 19 or intermittently (13.3 Units/kg on gestation days 6 and 13 only) during organogenesis, no embryofetal data were available at the highest dose administered daily (6.7 Units/kg) because of premature death in all does at that dose. At the lower daily doses or with intermittent dosing, no adverse developmental effects were observed. All dosed for which data were available are less than the MRHD on a body weight basis. In a study in which pregnant rats received 6 weekly intramuscular injections of DYSPORT (4.4, 11.1, 22.2, or 44 Units/kg) beginning on day 6 of gestation and continuing through parturition to weaning, an increase in stillbirths was observed at the highest dose tested, which was maternally toxic. The no-effect dose for pre- and post-natal development toxicity was 22.2 Units/kg (similar to the MRHD).

8.2 Lactation Risk Summary There are no data on the presence of DYSPORT in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for DYSPORT and any potential adverse effects on the breastfed infant from DYSPORT or from the underlying maternal condition.

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 Ce…