Slide 1

Blepharospasm:A Rare, Focal Dystonia, and the Role of BOTOX Treatment

Please see Indication and Important Safety Information, includingBoxed Warning, throughout this presentation.##PRESENTATION OBJECTIVE: Help the audience become more knowledgeable about blepharospasm and the role of BOTOX (onabotulinumtoxinA) in treating these patients.

Introduce yourself and review what the talk will be about.1IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGWARNING: DISTANT SPREAD OF TOXIN EFFECTPostmarketing reports indicate that the effects of BOTOX and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, 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. 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 an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and upper limb spasticity and at lower doses.Please see Indication and additional Important Safety Information throughout this presentation.#Review the Important Safety Information, including Boxed Warning.2What Type of Patients Will We Be Discussing Today?IndicationBlepharospasmBOTOX is indicated for the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.Please see Important Safety Information, including Boxed Warning, throughout this presentation.

#IndicationBOTOX (onabotulinumtoxinA) is indicated for the treatment of blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.

3AgendaOverview of blepharospasm and clinical guidelinefor diagnosisClinical trial profile for BOTOX in blepharospasm

Please see Important Safety Information, including Boxed Warning, throughout this presentation.#Review topics to be covered:Overview of blepharospasm and clinical guideline for diagnosisClinical trial profile for BOTOX (onabotulinumtoxinA) in blepharospasm

4Disease Overview, Diagnosis, and TreatmentPlease see Important Safety Information, including Boxed Warning, throughout this presentation.##5*For anatomical reference only.Lines indicate general areas, not the specific injection sites.

Orbicularis oculiCloses, blinks, and squints eyes3Procerus*Pulls the inner angle of the eyebrows downward and produces transverse nasal wrinkles3Corrugator supercilii*Pulls the eyebrows down toward the bridge of the nose resulting in frowning motion3Definition/Involved Muscles1. Ben Simon and McCann. Int Ophthalmol Clin. 2005; 2. Coscarelli. Semin Ophthalmol. 2010; 3. Standring, ed. Grays Anatomy: The Anatomical Basis of Clinical Practice. 2008.Please see Important Safety Information, including Boxed Warning, throughout this presentation.Blepharospasm is a focal dystonia characterized by sustained, involuntary spasms of eyelid closure1Muscles affected are innervated by the temporal division of the facial nerve (VII)2:The image below shows the functional anatomy of muscles involved in blepharospasm. Muscles for anatomical reference only are noted as such

#Blepharospasm is a focal dystonia characterized by sustained, involuntary spasms of eyelid closure.1

HOW TO USE SLIDE BUILD:1.First the bullets appear. On click, muscle illustration appears.2.On click, VIDEO (NO AUDIO) plays showing a blepharospasm patient.

REFERENCES:1. Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin.2005;45(3):49-75.2. Coscarelli JM. Essential blepharospasm. Semin Ophthalmol. 2010;25(3):104-108.3. Standring S, ed. Grays Anatomy: The Anatomical Basis of Clinical Practice. 40th ed. London, England: Churchill Livingstone; 2008.

6A Rare, Focal DystoniaEpidemiological studies have determined blepharospasm is a rare conditionEstimates range from 235 to 22,518 patients with blepharospasm in the United States1,2Onset usually occurs in patients between fifth and seventh decade of life3Blepharospasm can impair many patient activities, such as driving, walking, reading, and watching TV4Due to its rarity, patients may go years before reaching a specialist who is able to diagnose them with blepharospasm1. Nutt et al. Mov Disord. 1988; 2. CDC WONDER website. Census projections request. Accessed 2015; 3. Brin et al. In: Moore and Naumann, eds. Handbook of Botulinum Toxin Treatment. 2003; 4. Ben Simon and McCann. Int Ophthalmol Clin. 2005.Please see Important Safety Information, including Boxed Warning, throughout this presentation.#7Blepharospasm is a rare condition with just 235 to 22,518 patients in the United States. Onset usually occurs in the later years of life.

HOW TO USE SLIDE BUILD:1.First 3 bullets build. On click, callout is shown at bottom of the slide.

REFERENCES:1. Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ 3rd. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord. 1988;3(3):188-194.2. Centers for Disease Control and Prevention. Census projections request. CDC WONDER website. http://wonder.cdc.gov/population-projections.html. Accessed July 1, 2015.3. Brin MF, Danisi F, Blitzer A. Blepharospasm, oromandibular dystonia, Meiges syndrome and hemifacial spasm. In: Moore P, Naumann M, eds. Handbook of Botulinum Toxin Treatment. 2nd ed. Malden, MA: Blackwell Science; 2003:119-141.4. Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin.2005;45(3):49-75.Signs and SymptomsPlease see Important Safety Information, including Boxed Warning, throughout this presentation.1. Coscarelli. Semin Ophthalmol. 2010; 2. Ben Simon and McCann. Int Ophthalmol Clin. 2005.Patients may self-manage these symptoms by wearing dark glasses and using eye drops2Early symptoms include1,2:Dry eyesLight sensitivityIncreased blinkingOcular painSorenessFrequent blinking is a progressive symptom1Bright light, polluted air, and wind can worsen symptoms1

#Symptoms of blepharospasm include dry eyes, light sensitivity, increased blinking, ocular pain, and soreness.1,2 Patients may self-manage symptoms by wearing dark glasses and using eye drops.2

REFERENCES:1. Coscarelli JM. Essential blepharospasm. Semin Ophthalmol. 2010;25(3):104-108.2. Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin. 2005;45(3):49-75.

8Diagnosis Guideline1. Defazio et al. Neurology. 2013. Please see Important Safety Information, including Boxed Warning, throughout this presentation.Adapted from Defazio et al. Neurology. 2013.NoNoPresence of stereotyped, bilateral, and synchronous orbicularis oculi spasms inducing narrowing/closure of the eyelidsReconsider diagnosisIncreased blinkingPresence of effectivesensory trickNoYesYesYesBlepharospasmA guideline for the diagnosis of blepharospasm has been validated and published in Neurology1:

#A guideline for the diagnosis of blepharospasm was recently validated and published in Neurology.1 This guideline can help physicians recognize and diagnose blepharospasm in clinical and research settings.

REFERENCE:1.Defazio G, Hallett M, Jinnah HA, Berardelli A. Development and validation of a clinical guideline for diagnosing blepharospasm. Neurology. 2013;81(3):236-240.

9Conservative:Patient educationSunglassesDry eye treatmentBlepharitis treatmentBotulinum toxinsOral medicationsSympatholysis myectomyChemomyectomyCorrection of eyelid malposition, aesthetic surgeryTreatment Options1Please see Important Safety Information, including Boxed Warning, throughout this presentation.1. Ben Simon and McCann. Int Ophthalmol Clin. 2005.#Treatment options for blepharospasm.1

REFERENCE:1. Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin.2005;45(3):49-75.

10An ophthalmologist, Dr. Alan Scott, began experimenting with the therapeutic use of botulinum toxin in the 1960s1In 1968, he began collaborating with Dr. Edward Schantz and began human testing of BOTOX in the 1970s after years of animal testing1BOTOX was approved by the FDA for the treatment of blepharospasm in 19892Prior to the introduction of BOTOXno treatment had been approved by the FDA for the treatment of blepharospasm3

1. Erbguth. J Neural Transm. 2008; 2. BOTOX Prescribing Information, August 2015; 3. BEBRF website. Blepharospasm pages. Accessed 2015.BOTOX Was the First Therapy Approved for the Treatment of Blepharospasm More Than 25 Years AgoPlease see Important Safety Information, including Boxed Warning, throughout this presentation.

#In 1989, BOTOX (onabotulinumtoxinA) was the first therapy approved by the FDA for the treatment of blepharospasm.2,3

REFERENCES:1. Erbguth FJ. From poison to remedy: the chequered history of botulinum toxin. J Neural Transm. 2008;115(4):559-565.2. BOTOX Prescribing Information, August 2015.3. Benign Essential Blepharospasm Research Foundation (BEBRF). BEBRF blepharospasm pages.Benign Essential Blepharospasm Research Foundation (BEBRF) website. http://www.blepharospasm.org. Updated November 5, 2012. Accessed July 1, 2015.11BOTOX Clinical ProfilePlease see Important Safety Information, including Boxed Warning, throughout this presentation.##12Effect reaches a peak at 1 to 2 weeks post treatment11. BOTOX Prescribing Information, August 2015; 2. Arthurs et al. Can J Ophthalmol. 1987. Rapid and Significant Symptom ImprovementPlease see Important Safety Information, including Boxed Warning, throughout this presentation.In an open-label study, 27 patients with persistent moderate to severe blepharospasm underwent treatment with BOTOX. Six sites on each sidethe medial and lateral brow, the medial and lateral upper lid, the lateral canthal angle, and the lateral lower lidwere injected with2.0 Units of BOTOX using a 27-gauge needle, a total of 12 Units for each eye.1,2BOTOX treatment showed an improvement within 48 hours post injection (n = 27)193%0102030405060708090100Percentage of Patients (%)#BOTOX (onabotulinumtoxinA) provides rapid and significant symptom improvement in patients with blepharospasm. The effect reaches a peak at 1 to 2 weeks post treatment.1

REFERENCES:1. BOTOX Prescribing Information, August 2015.2. Arthurs B, Flanders M, Codre F, Gauthier S, Dresner S, Stone L. Treatment of blepharospasm with medication, surgery, and type A botulinum toxin. Can J Ophthalmol. 1987;22(1):24-28.131. Arthurs et al. Can J Ophthalmol. 1987. Clinical ImprovementPlease see Important Safety Information, including Boxed Warning, throughout this presentation.Eyelid and eyebrow spasm were graded before and after treatment on a 0 to 4 scale: 0 = no spasm, 1 = increased blinking caused byexternal stimuli, 2 = mild fluttering of the lids, 3 = moderate spasm with mild incapacitation, and 4 = severe spasm resulting in incapacitation. Eyelid force* was also graded on a 0 to 4 scale: 0 = separation of the eyelids with minimal effort to 4 = inability to separate the eyelids withthe thumbs.1

*Amount of force exerted against the examiners fingers by voluntary closure of the lids.

Mean Scores for Lid and Brow Spasm and Lid Force in Patients With Blepharospasm Before and After Treatment With BOTOX (n = 27)1 Lid Spasm Brow SpasmLid ForceChange in Mean Score From Baseline2.90.81.13.32.40.94

3

2

1

0Baseline After BOTOX treatment#BOTOX (onabotulinumtoxinA) provides a clinical improvement in lid and brow spasm, as well as lid force.1

REFERENCE:1. Arthurs B, Flanders M, Codre F, Gauthier S, Dresner S, Stone L. Treatment of blepharospasm with medication, surgery, and type A botulinum toxin. Can J Ophthalmol. 1987;22(1):24-28.14Most Frequently Reported Adverse Reactions in a Blepharospasm Trial11. BOTOX Prescribing Information, August, 2015.Adverse ReactionBOTOXPtosis21%Superficial punctate keratitis6%Eye dryness6%Please see Important Safety Information, including Boxed Warning, throughout this presentation.#Most frequently reported adverse reactions in a blepharospasm trial for BOTOX (onabotulinumtoxinA).1

REFERENCE:1. BOTOX Prescribing Information, August 2015.15Dosing in Blepharospasm3 approved regions for BOTOX in the orbicularis oculi muscle11. BOTOX Prescribing Information, August 2015.

Medial pretarsal orbicularis oculi (upper lid)1.25 Units to 2.5 UnitsLateral pretarsal orbicularis oculi (upper lid)1.25 Units to 2.5 UnitsLateral pretarsal orbicularis oculi (lower lid)1.25 Units to 2.5 UnitsNote: These are general areas, not the specific injection sites.Please see Important Safety Information, including Boxed Warning, throughout this presentation.#BOTOX (onabotulinumtoxinA) dosing ranges and regions in the orbicularis oculi.1

Please note: The illustration shows the approved regions of the muscles to inject, not the exact injection sites.

REFERENCE:1. BOTOX Prescribing Information, August 2015.

16

Dosing Units Are Not Interchangeable With Other Botulinum Toxin ProductsThe potency Units of BOTOX are specific to the preparation and assay method utilized and are not interchangeable with other preparations of botulinum toxin products and, therefore, Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin productsassessed with any other specific assay method1Please see Important Safety Information, including Boxed Warning, throughout this presentation.1. BOTOX Prescribing Information, August 2015.#BOTOX (onabotulinumtoxinA) dosing Units are not interchangeable with other botulinum toxin products.1

REFERENCE:1.BOTOX Prescribing Information, August 2015.

17Blepharospasm Dosing ConsiderationsThe initial recommended dose is 1.25 Units to 2.5 Units at each site. Volume of injection: 0.05 mL to 0.1 mL per site1The cumulative dose of BOTOX treatment for blepharospasm in a 30-day period should not exceed 200 Units1Reconstituted BOTOX is injected using a sterile, 27- to 30-gauge needle without electromyographic guidance1Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis1Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis can be prevented by applying pressure at the injection site immediately after injection1Initial effect of the injections is generally seen within 3 days and reaches a peak 1 to 2 weeks post treatment. Each treatment lasts approximately3 months, following which the procedure can be repeated1Please see Important Safety Information, including Boxed Warning, throughout this presentation.1. BOTOX Prescribing Information, August 2015.#Review the blepharospasm dosing considerations.1

REFERENCE:1.BOTOX Prescribing Information, August 2015.

18General Dosing ConsiderationsIndication-specific dosage and administration recommendations should be followed. When initiating treatment, the lowest recommended dose should be used. In treating adult patients for 1 or more indications, the maximum cumulative dose should not exceed 400 Units in a 3-month interval1The safe and effective use of BOTOX depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering BOTOX must understand the relevant neuromuscular and structural anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures and disease, especially when injecting near the lungs1Please see Important Safety Information, including Boxed Warning, throughout this presentation.1. BOTOX Prescribing Information, August 2015.#Review the general dosing considerations.1

REFERENCE:1.BOTOX Prescribing Information, August 2015.

19IMPORTANT SAFETY INFORMATION (continued)CONTRAINDICATIONSBOTOX is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation.WARNINGS AND PRECAUTIONSLack of Interchangeability Between Botulinum Toxin ProductsThe potency Units of BOTOX 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 BOTOX cannot be compared to nor converted into Units of any other botulinum toxin products assessed with any other specific assay method.

Spread of Toxin EffectSee Boxed Warning.

No definitive serious adverse event reports of distant spread of toxin effect associatedwith BOTOX for blepharospasm at the recommended dose (30 Units and below) have been reported.#Review Important Safety Information.20IMPORTANT SAFETY INFORMATION (continued)WARNINGS AND PRECAUTIONS (continued)Serious Adverse Reactions With Unapproved UseSerious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but mayhave resulted from the administration of BOTOX to the site of injection and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities. There is insufficient information to identify factors associated with an increased risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for unapproved uses have not been established.

#Review Important Safety Information.21WARNINGS AND PRECAUTIONS (continued)Hypersensitivity ReactionsSerious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined.

Pre-Existing Neuromuscular DisordersIndividuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, and respiratory compromise from therapeutic doses of BOTOX (see Adverse Reactions).IMPORTANT SAFETY INFORMATION (continued)#Review Important Safety Information.

22WARNINGS AND PRECAUTIONS (continued)Dysphagia and Breathing Difficulties Treatment with BOTOX 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 oropharyngeal muscles that control swallowing or breathing (see Boxed Warning).Corneal Exposure and Ulceration in Patients Treated With BOTOXfor BlepharospasmReduced blinking from BOTOX injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders.Human Albumin and Transmission of Viral DiseasesThis product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.IMPORTANT SAFETY INFORMATION (continued)#Review Important Safety Information.

23ADVERSE REACTIONSThe following adverse reactions to BOTOX for injection are discussed in greater detail in the following sections: Spread of Toxin Effect (see Boxed Warning); Hypersensitivity Reactions (see Contraindications and Warnings and Precautions); Dysphagia and Breathing Difficulties (see Warnings and Precautions).

BlepharospasmThe most frequently reported adverse reactions following injection of BOTOX for blepharospasm include ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%).

Post Marketing Experience There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin. There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established.

IMPORTANT SAFETY INFORMATION (continued)#Review Important Safety Information.24DRUG INTERACTIONSCo-administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects. The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Excessive weakness may alsobe exaggerated by administration of a muscle relaxant before or after administrationof BOTOX.

Please see full Prescribing Information including Boxed Warning and Medication Guide.IMPORTANT SAFETY INFORMATION (continued)#Review Important Safety Information.

25SummaryBlepharospasm is a focal dystonia characterized by sustained, involuntary spasms of eyelid closureA clinical guideline for the diagnosis of blepharospasm has been validated and published in Neurology In 1989, BOTOX became the first therapy approved by the FDA for the treatment of blepharospasm BOTOX provides rapid and significantsymptom improvementPlease see Important Safety Information, including Boxed Warning, throughout this presentation.#RECAP THE PRESENTATION:Blepharospasm is a focal dystonia characterized by sustained, involuntary spasms of eyelid closureA clinical guideline for the diagnosis of blepharospasm has been validated and published in NeurologyIn 1989, BOTOX (onabotulinumtoxinA) became the first therapy approved by the FDA for the treatment of blepharospasmBOTOX provides rapid and significant symptom improvement

26Thank You!27 2015 Allergan. All rights reserved. marks owned by Allergan, Inc. BOTOXMedical.com APC66VF15 152408

##Conclude presentation and workshop.27