BOTOX (onabotulinumtoxina) treatment record for Chronic Migraine patients

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1 (onbotulinumtoxina) tretment record for Chronic Migrine ptients for injection is indicted for the prophylxis of hedches in dult ptients with chronic migrine ( 15 dys per month with hedche lsting 4 hours dy or longer). Importnt Limittions Sfety nd effectiveness hve not been estblished for the prophylxis of episodic migrine (14 hedche dys or fewer per month) in 7 plcebo-controlled studies. Ptient Nme: Tretment Dte: / / Number of hedche dys/month Current: Bseline (if pplicble): Number of hedche hours/dy Current: Bseline (if pplicble): (When determining number of hedche dys, it my be beneficil to sk the ptient how mny hedche-free dys ech month the ptient is experiencing.) Clinicl rtionle for : DOB: / / Weeks since lst tretment (if pplicble): Vil Size/NDC No. 200 Unit Vil/NDC No.: Unit Vil/NDC No.: Dilution (200 Units/4 ml or /2 ml) Lot number(s) Vil expirtion dte(s) Plese check box if n SPP is used. For electronic billing, pyers require n 11-digit NDC number [5-4-2 configurtion] to be reported on the clim form. Therefore, n dditionl zero should be dded to the beginning of the 10-digit NDC listed on the box [eg, ]. Dosing by Muscle Ares for Chronic Migrine A. Corrugtor dosge: 10 Units divided in 2 sites Right: Left: B. Procerus dosge: 5 Units in 1 site C. Frontlis dosge: 20 Units divided in 4 sites Right: Left: D. Temporlis dosge: 40 Units divided in 8 sites Right: Left: E. Occipitlis dosge: 30 Units divided in 6 sites Right: Left: F. Cervicl Prspinl dosge: 20 Units divided in 4 sites Right: Left: G. Trpezius dosge: 30 Units divided in 6 sites Right: Left: Totl Units injected: Totl Units discrded: Physicin signture: Plese document ptient response on reverse side IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING WARNING: DISTANT SPREAD OF TOXIN EFFECT Postmrketing reports indicte tht the effects of nd ll botulinum toxin products my spred from the re of injection to produce symptoms consistent with botulinum toxin effects. These my include stheni, generlized muscle wekness, diplopi, ptosis, dysphgi, dysphoni, dysrthri, urinry incontinence, nd brething difficulties. These symptoms hve been reported hours to weeks fter injection. Swllowing nd brething difficulties cn be life thretening, nd there hve been reports of deth. The risk of symptoms is probbly gretest in children treted for spsticity, but symptoms cn lso occur in dults treted for spsticity nd other conditions, prticulrly in those ptients who hve n underlying condition tht would predispose them to these symptoms. In unpproved uses, including spsticity in children, nd in pproved indictions, cses of spred of effect hve been reported t doses comprble to those used to tret cervicl dystoni nd upper limb spsticity nd t lower doses. Plese see dditionl Importnt Sfety Informtion on reverse side.

2 Post-Injection Follow-Up Evlution Dte: / / Weeks since tretment: Number of hedche dys/month Current: Chnge from bseline: Number of hedche hours/dy Current: Chnge from bseline: Overll ptient response to (onbotulinumtoxina) tretment: Overll ptient response to other tretments nd/or medictions (if pplicble): Physicin signture: IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS (onbotulinumtoxina) is contrindicted in the presence of infection t the proposed injection site(s) nd in individuls with known hypersensitivity to ny botulinum toxin preprtion or to ny of the components in the formultion. WARNINGS AND PRECAUTIONS Lck of Interchngebility Between Botulinum Toxin Products The potency Units of re specific to the preprtion nd ssy method utilized. They re not interchngeble with other preprtions of botulinum toxin products nd, therefore, Units of biologicl ctivity of cnnot be compred to nor converted into Units of ny other botulinum toxin products ssessed with ny other specific ssy method. Spred of Toxin Effect See Boxed Wrning. No definitive serious dverse event reports of distnt spred of toxin effect ssocited with for chronic migrine t the lbeled dose hve been reported. Serious Adverse Rections with Unpproved Use Serious dverse rections, including excessive wekness, dysphgi, nd spirtion pneumoni, with some dverse rections ssocited with ftl outcomes, hve been reported in ptients who received injections for unpproved uses. In these cses, the dverse rections were not necessrily relted to distnt spred of toxin, but my hve resulted from the dministrtion of to the site of injection nd/or djcent structures. In severl of the cses, ptients hd pre-existing dysphgi or other significnt disbilities. There is insufficient informtion to identify fctors ssocited with n incresed risk for dverse rections ssocited with the unpproved uses of. The sfety nd effectiveness of for unpproved uses hve not been estblished. Hypersensitivity Rections Serious nd/or immedite hypersensitivity rections hve been reported. These rections include nphylxis, serum sickness, urticri, soft-tissue edem, nd dyspne. If such rection occurs, further injection of should be discontinued nd pproprite medicl therpy immeditely instituted. One ftl cse of nphylxis hs been reported in which lidocine ws used s the diluent, nd consequently the cusl gent cnnot be relibly determined. Pre-Existing Neuromusculr Disorders Individuls with peripherl motor neuropthic diseses, myotrophic lterl sclerosis or neuromusculr junctionl disorders (e.g., mystheni grvis or Lmbert-Eton syndrome) should be monitored when given botulinum toxin. Ptients with neuromusculr disorders my be t incresed risk of cliniclly significnt effects including generlized muscle wekness, diplopi, ptosis, dysphoni, dysrthri, severe dysphgi nd respirtory compromise from therpeutic doses of (see Adverse Rections). Humn Albumin nd Trnsmission of Virl Diseses This product contins lbumin, derivtive of humn blood. Bsed on effective donor screening nd product mnufcturing processes, it crries n extremely remote risk for trnsmission of virl diseses. A theoreticl risk for trnsmission of Creutzfeldt-Jkob disese (CJD) is lso considered extremely remote. No cses of trnsmission of virl diseses or CJD hve ever been reported for lbumin. ADVERSE REACTIONS The following dverse rections to (onbotulinumtoxina) for injection re discussed in greter detil in the following sections: Spred of Toxin Effect (see Boxed Wrning) nd Hypersensitivity Rections (see Contrindictions nd Wrnings nd Precutions). Chronic Migrine The most frequently reported dverse rections following injection of for chronic migrine include neck pin (9%), hedche (5%), eyelid ptosis (4%), migrine (4%), musculr wekness (4%), musculoskeletl stiffness (4%), bronchitis (3%), injection-site pin (3%), musculoskeletl pin (3%), mylgi (3%), fcil presis (2%), hypertension (2%), nd muscle spsms (2%). Post Mrketing Experience There hve been spontneous reports of deth, sometimes ssocited with dysphgi, pneumoni, nd/or other significnt debility or nphylxis, fter tretment with botulinum toxin. There hve lso been reports of dverse events involving the crdiovsculr system, including rrhythmi nd myocrdil infrction, some with ftl outcomes. Some of these ptients hd risk fctors including crdiovsculr disese. The exct reltionship of these events to the botulinum toxin injection hs not been estblished. DRUG INTERACTIONS Co-dministrtion of nd minoglycosides or other gents interfering with neuromusculr trnsmission (eg, curre-like compounds) should only be performed with cution s the effect of the toxin my be potentited. Use of nticholinergic drugs fter dministrtion of my potentite systemic nticholinergic effects. The effect of dministering different botulinum neurotoxin products t the sme time or within severl months of ech other is unknown. Excessive neuromusculr wekness my be excerbted by dministrtion of nother botulinum toxin prior to the resolution of the effects of previously dministered botulinum toxin. Excessive wekness my lso be exggerted by dministrtion of muscle relxnt before or fter dministrtion of. Plese see ccompnying full Prescribing Informtion including Boxed Wrning nd Mediction Guide Allergn. All rights reserved APC24HD15

3 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (onbotulinumtoxina) for injection, for intrmusculr, intrdetrusor, or intrderml use Initil U.S. Approvl: 1989 WARNING: DISTANT SPREAD OF TOXIN EFFECT See full prescribing informtion for complete boxed wrning. The effects of nd ll botulinum toxin products my spred from the re of injection to produce symptoms consistent with botulinum toxin effects. These symptoms hve been reported hours to weeks fter injection. Swllowing nd brething difficulties cn be life thretening nd there hve been reports of deth. The risk of symptoms is probbly gretest in children treted for spsticity but symptoms cn lso occur in dults, prticulrly in those ptients who hve n underlying condition tht would predispose them to these symptoms. (5.2) RECENT MAJOR CHANGES Indictions nd Usge, Upper Limb Spsticity (1.3) 04/2015 Dosge nd Administrtion (2.1, 2.5) 04/2015 Wrnings nd Precutions, Serious Adverse Rections with Unpproved Use (5.3) 08/2015 INDICATIONS AND USAGE is n cetylcholine relese inhibitor nd neuromusculr blocking gent indicted for: Tretment of overctive bldder (OAB) with symptoms of urge urinry incontinence, urgency, nd frequency, in dults who hve n indequte response to or re intolernt of n nticholinergic mediction (1.1) Tretment of urinry incontinence due to detrusor overctivity ssocited with neurologic condition [e.g., spinl cord injury (SCI), multiple sclerosis (MS)] in dults who hve n indequte response to or re intolernt of n nticholinergic mediction (1.1) Prophylxis of hedches in dult ptients with chronic migrine ( 15 dys per month with hedche lsting 4 hours dy or longer) (1.2) Tretment of upper limb spsticity in dult ptients (1.3) Tretment of cervicl dystoni in dult ptients, to reduce the severity of bnorml hed position nd neck pin (1.4) Tretment of severe xillry hyperhidrosis tht is indequtely mnged by topicl gents in dult ptients (1.5) Tretment of blephrospsm ssocited with dystoni in ptients 12 yers of ge (1.6) Tretment of strbismus in ptients 12 yers of ge (1.6) Importnt limittions: Sfety nd effectiveness of hve not been estblished for: Prophylxis of episodic migrine (14 hedche dys or fewer per month). (1.2) Tretment of upper limb spsticity in peditric ptients, nd for the tretment of lower limb spsticity in dult nd peditric ptients. (1.3) Tretment of hyperhidrosis in body res other thn xillry. (1.5) DOSAGE AND ADMINISTRATION Follow indiction-specific dosge nd dministrtion recommendtions; Do not exceed totl dose of 400 Units dministered in 3 month intervl (2.1) See Preprtion nd Dilution Technique for instructions on reconstitution, storge, nd preprtion before injection (2.2) Overctive Bldder: Recommended totl dose, s 0.5 ml (5 Units) injections cross 20 sites into the detrusor (2.3) Detrusor Overctivity ssocited with Neurologic Condition: Recommended totl dose 200 Units, s 1 ml (~6.7 Units) injections cross 30 sites into the detrusor (2.3) Chronic Migrine: Recommended totl dose 155 Units, s 0.1 ml (5 Units) injections per ech site divided cross 7 hed/neck muscles (2.4) Upper Limb Spsticity: Select dose bsed on muscles ffected, severity of muscle ctivity, prior response to tretment, nd dverse event history; Electromyogrphic guidnce recommended (2.5) Cervicl Dystoni: Bse dosing on the ptient s hed nd neck position, locliztion of pin, muscle hypertrophy, ptient response, nd dverse event history; use lower initil dose in botulinum toxin nïve ptients (2.6) Axillry Hyperhidrosis: 50 Units per xill (2.7) Blephrospsm: 1.25 Units-2.5 Units into ech of 3 sites per ffected eye (2.8) Strbismus: 1.25 Units-2.5 Units initilly in ny one muscle (2.9) DOSAGE FORMS AND STRENGTHS Single-use, sterile or 200 Units vcuum-dried powder for reconstitution only with sterile, preservtive-free 0.9% Sodium Chloride Injection USP prior to injection (3) CONTRAINDICATIONS Hypersensitivity to ny botulinum toxin preprtion or to ny of the components in the formultion (4.1, 5.4, 6) Infection t the proposed injection site (4.2) Intrdetrusor Injections: Urinry Trct Infection or Urinry Retention (4.3) WARNINGS AND PRECAUTIONS Potency Units of re not interchngeble with other preprtions of botulinum toxin products (5.1, 11) Spred of toxin effects; swllowing nd brething difficulties cn led to deth. Seek immedite medicl ttention if respirtory, speech or swllowing difficulties occur (5.2, 5.6) Potentil serious dverse rections fter injections for unpproved uses (5.3) Concomitnt neuromusculr disorder my excerbte clinicl effects of tretment (5.5) Use with cution in ptients with compromised respirtory function (5.6, 5.7, 5.10) Cornel exposure nd ulcertion due to reduced blinking my occur with tretment of blephrospsm (5.8) Retrobulbr hemorrhges nd compromised retinl circultion my occur with tretment of strbismus (5.9) Bronchitis nd upper respirtory trct infections in ptients treted for upper limb spsticity (5.10) Urinry trct infections in ptients treted for OAB (5.12) Urinry retention: Post-void residul urine volume should be monitored in ptients treted for OAB or detrusor overctivity ssocited with neurologic condition who do not ctheterize routinely, prticulrly ptients with multiple sclerosis or dibetes mellitus. (5.13) ADVERSE REACTIONS The most common dverse rections ( 5% nd >plcebo) re (6.1): OAB: urinry trct infection, dysuri, urinry retention Detrusor Overctivity ssocited with neurologic condition: urinry trct infection, urinry retention Chronic Migrine: neck pin, hedche Spsticity: pin in extremity Cervicl Dystoni: dysphgi, upper respirtory infection, neck pin, hedche, incresed cough, flu syndrome, bck pin, rhinitis Axillry Hyperhidrosis: injection site pin nd hemorrhge, non-xillry sweting, phryngitis, flu syndrome To report SUSPECTED ADVERSE REACTIONS, contct Allergn t or FDA t FDA-1088 or DRUG INTERACTIONS Ptients receiving concomitnt tretment of nd minoglycosides or other gents interfering with neuromusculr trnsmission (e.g., curre-like gents), or muscle relxnts, should be observed closely becuse the effect of my be potentited (7) USE IN SPECIFIC POPULATIONS Pregnncy: Bsed on niml dt, my cuse fetl hrm (8.1) Peditric Use: Sfety nd efficcy re not estblished in ptients under 18 yers of ge for the prophylxis of hedches in chronic migrine, tretment of OAB, detrusor overctivity ssocited with neurologic condition, upper limb spsticity, nd xillry hyperhidrosis; in ptients under 16 yers of ge for tretment of cervicl dystoni; nd in ptients under 12 yers of ge for tretment of blephrospsm nd strbismus (8.4) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 08/2015 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DISTANT SPREAD OF TOXIN EFFECT 1 INDICATIONS AND USAGE 1.1 Bldder Dysfunction 1.2 Chronic Migrine 1.3 Upper Limb Spsticity 1.4 Cervicl Dystoni 1.5 Primry Axillry Hyperhidrosis 1.6 Blephrospsm nd Strbismus 2 DOSAGE AND ADMINISTRATION 2.1 Instructions for Sfe Use 2.2 Preprtion nd Dilution Technique 2.3 Bldder Dysfunction 2.4 Chronic Migrine 2.5 Upper Limb Spsticity 2.6 Cervicl Dystoni 2.7 Primry Axillry Hyperhidrosis 2.8 Blephrospsm 2.9 Strbismus

4 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Known Hypersensitivity to Botulinum Toxin 4.2 Infection t the Injection Site(s) 4.3 Urinry Trct Infection or Urinry Retention 5 WARNINGS AND PRECAUTIONS 5.1 Lck of Interchngebility between Botulinum Toxin Products 5.2 Spred of Toxin Effect 5.3 Serious Adverse Rections with Unpproved Use 5.4 Hypersensitivity Rections 5.5 Pre-Existing Neuromusculr Disorders 5.6 Dysphgi nd Brething Difficulties 5.7 Pulmonry Effects of in Ptients with Compromised Respirtory Sttus Treted for Spsticity or for Detrusor Overctivity ssocited with Neurologic Condition 5.8 Cornel Exposure nd Ulcertion in Ptients Treted with for Blephrospsm 5.9 Retrobulbr Hemorrhges in Ptients Treted with for Strbismus 5.10 Bronchitis nd Upper Respirtory Trct Infections in Ptients Treted for Spsticity 5.11 Autonomic Dysreflexi in Ptients Treted for Detrusor Overctivity ssocited with Neurologic Condition 5.12 Urinry Trct Infections in Ptients with Overctive Bldder 5.13 Urinry Retention in Ptients Treted for Bldder Dysfunction 5.14 Humn Albumin nd Trnsmission of Virl Diseses 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 6.3 Post-Mrketing Experience 7 DRUG INTERACTIONS 7.1 Aminoglycosides nd Other Agents Interfering with Neuromusculr Trnsmission 7.2 Anticholinergic Drugs 7.3 Other Botulinum Neurotoxin Products 7.4 Muscle Relxnts 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology 14 CLINICAL STUDIES 14.1 Overctive Bldder (OAB) 14.2 Detrusor Overctivity ssocited with Neurologic Condition 14.3 Chronic Migrine 14.4 Upper Limb Spsticity 14.5 Cervicl Dystoni 14.6 Primry Axillry Hyperhidrosis 14.7 Blephrospsm 14.8 Strbismus 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing informtion re not listed. FULL PRESCRIBING INFORMATION WARNING: DISTANT SPREAD OF TOXIN EFFECT Postmrketing reports indicte tht the effects of nd ll botulinum toxin products my spred from the re of injection to produce symptoms consistent with botulinum toxin effects. These my include stheni, generlized muscle wekness, diplopi, ptosis, dysphgi, dysphoni, dysrthri, urinry incontinence nd brething difficulties. These symptoms hve been reported hours to weeks fter injection. Swllowing nd brething difficulties cn be life thretening nd there hve been reports of deth. The risk of symptoms is probbly gretest in children treted for spsticity but symptoms cn lso occur in dults treted for spsticity nd other conditions, prticulrly in those ptients who hve n underlying condition tht would predispose them to these symptoms. In unpproved uses, including spsticity in children, nd in pproved indictions, cses of spred of effect hve been reported t doses comprble to those used to tret cervicl dystoni nd upper limb spsticity nd t lower doses. [See Wrnings nd Precutions (5.2)] 1 INDICATIONS AND USAGE 1.1 Bldder Dysfunction Overctive Bldder (onbotulinumtoxina) for injection is indicted for the tretment of overctive bldder with symptoms of urge urinry incontinence, urgency, nd frequency, in dults who hve n indequte response to or re intolernt of n nticholinergic mediction. Detrusor Overctivity ssocited with Neurologic Condition is indicted for the tretment of urinry incontinence due to detrusor overctivity ssocited with neurologic condition (e.g., SCI, MS) in dults who hve n indequte response to or re intolernt of n nticholinergic mediction. 1.2 Chronic Migrine is indicted for the prophylxis of hedches in dult ptients with chronic migrine ( 15 dys per month with hedche lsting 4 hours dy or longer). Importnt limittions Sfety nd effectiveness hve not been estblished for the prophylxis of episodic migrine (14 hedche dys or fewer per month) in seven plcebo-controlled studies. 1.3 Upper Limb Spsticity is indicted for the tretment of upper limb spsticity in dult ptients, to decrese the severity of incresed muscle tone in elbow flexors (biceps), wrist flexors (flexor crpi rdilis nd flexor crpi ulnris), finger flexors (flexor digitorum profundus nd flexor digitorum sublimis), nd thumb flexors (dductor pollicis nd flexor pollicis longus). Importnt limittions Sfety nd effectiveness of hve not been estblished for the tretment of other upper limb muscle groups, or for the tretment of lower limb spsticity. Sfety nd effectiveness of hve not been estblished for the tretment of spsticity in peditric ptients under ge 18 yers. hs not been shown to improve upper extremity functionl bilities, or rnge of motion t joint ffected by fixed contrcture. Tretment with is not intended to substitute for usul stndrd of cre rehbilittion regimens. 1.4 Cervicl Dystoni is indicted for the tretment of dults with cervicl dystoni, to reduce the severity of bnorml hed position nd neck pin ssocited with cervicl dystoni. 1.5 Primry Axillry Hyperhidrosis is indicted for the tretment of severe primry xillry hyperhidrosis tht is indequtely mnged with topicl gents. Importnt limittions The sfety nd effectiveness of for hyperhidrosis in other body res hve not been estblished. Wekness of hnd muscles nd blephroptosis my occur in ptients who receive for plmr hyperhidrosis nd fcil hyperhidrosis, respectively. Ptients should be evluted for potentil cuses of secondry hyperhidrosis (e.g., hyperthyroidism) to void symptomtic tretment of hyperhidrosis without the dignosis nd/or tretment of the underlying disese. Sfety nd effectiveness of hve not been estblished for the tretment of xillry hyperhidrosis in peditric ptients under ge Blephrospsm nd Strbismus is indicted for the tretment of strbismus nd blephrospsm ssocited with dystoni, including benign essentil blephrospsm or VII nerve disorders in ptients 12 yers of ge nd bove. 2 DOSAGE AND ADMINISTRATION 2.1 Instructions for Sfe Use The potency Units of (onbotulinumtoxina) for injection re specific to the preprtion nd ssy method utilized. They re not interchngeble with other preprtions of botulinum toxin products nd, therefore, units of biologicl ctivity of cnnot be compred to nor converted into units of ny other botulinum toxin products ssessed with ny other specific ssy method [see Wrnings nd Precutions (5.1) nd Description (11)]. Indiction specific dosge nd dministrtion recommendtions should be followed. When inititing tretment, the lowest recommended dose should be used. In treting dult ptients for one or more indictions, the mximum cumultive dose should not exceed 400 Units, in 3 month intervl. The sfe nd effective use of depends upon proper storge of the product, selection of the correct dose, nd proper reconstitution nd dministrtion techniques. An understnding of stndrd electromyogrphic techniques is lso required for tretment of strbismus nd of upper limb spsticity, nd my be useful for the tretment of cervicl dystoni. Physicins dministering must understnd the relevnt neuromusculr nd structurl ntomy of the re involved nd ny ltertions to the ntomy due to prior surgicl procedures nd disese, especilly when injecting ner the lungs. 2.2 Preprtion nd Dilution Technique Prior to injection, reconstitute ech vcuum-dried vil of with only sterile, preservtive-free 0.9% Sodium Chloride Injection USP. Drw up the proper mount of diluent in the pproprite size syringe (see Tble 1, or for specific instructions for detrusor overctivity ssocited with neurologic condition see Section 2.3), nd slowly inject the diluent into the vil. Discrd the vil if vcuum does not pull the diluent into the vil. Gently mix with the sline by rotting the vil. Record the dte nd time of reconstitution on the spce on the lbel. should be dministered within 24 hours fter reconstitution. During this time period, reconstituted should be stored in refrigertor (2 to 8 C).

5 Tble 1: Dilution Instructions for Vils ( nd 200 Units)** Diluent* Added to 100 Unit Vil 1 ml 2 ml 4 ml 8 ml 10 ml Resulting Dose Units per 0.1 ml 10 Units 5 Units 2.5 Units 1.25 Units 1 Unit Diluent* Added to 200 Unit Vil 1 ml 2 ml 4 ml 8 ml 10 ml Resulting Dose Units per 0.1 ml 20 Units 10 Units 5 Units 2.5 Units 2 Units * Preservtive-free 0.9% Sodium Chloride Injection, USP Only ** For Detrusor Overctivity ssocited with Neurologic Condition Dilution see Section 2.3 Note: These dilutions re clculted for n injection volume of 0.1 ml. A decrese or increse in the dose is lso possible by dministering smller or lrger injection volume - from 0.05 ml (50% decrese in dose) to 0.15 ml (50% increse in dose). An injection of is prepred by drwing into n ppropritely sized sterile syringe n mount of the properly reconstituted toxin slightly greter thn the intended dose. Air bubbles in the syringe brrel re expelled nd the syringe is ttched to n pproprite injection needle. Ptency of the needle should be confirmed. A new, sterile needle nd syringe should be used to enter the vil on ech occsion for removl of. Reconstituted should be cler, colorless, nd free of prticulte mtter. Prenterl drug products should be inspected visully for prticulte mtter nd discolortion prior to dministrtion nd whenever the solution nd the continer permit. 2.3 Bldder Dysfunction Generl Ptients must not hve urinry trct infection (UTI) t the time of tretment. Prophylctic ntibiotics, except minoglycosides, [see Drug Interctions (7.1)] should be dministered 1-3 dys pre-tretment, on the tretment dy, nd 1-3 dys post-tretment to reduce the likelihood of procedure-relted UTI. Ptients should discontinue nti-pltelet therpy t lest 3 dys before the injection procedure. Ptients on nti-cogulnt therpy need to be mnged ppropritely to decrese the risk of bleeding. Approprite cution should be exercised when performing cystoscopy. Overctive Bldder An intrvesicl instilltion of diluted locl nesthetic with or without sedtion my be used prior to injection, per locl site prctice. If locl nesthetic instilltion is performed, the bldder should be drined nd irrigted with sterile sline before injection. The recommended dose is of, nd is the mximum recommended dose. The recommended dilution is /10 ml with preservtive-free 0.9% Sodium Chloride Injection, USP (see Tble 1). Dispose of ny unused sline. Reconstituted (/10 ml) is injected into the detrusor muscle vi flexible or rigid cystoscope, voiding the trigone. The bldder should be instilled with enough sline to chieve dequte visuliztion for the injections, but over-distension should be voided. The injection needle should be filled (primed) with pproximtely 1 ml of reconstituted prior to the strt of injections (depending on the needle length) to remove ny ir. The needle should be inserted pproximtely 2 mm into the detrusor, nd 20 injections of 0.5 ml ech (totl volume of 10 ml) should be spced pproximtely 1 cm prt (see Figure 1). For the finl injection, pproximtely 1 ml of sterile norml sline should be injected so tht the remining in the needle is delivered to the bldder. After the injections re given, ptients should demonstrte their bility to void prior to leving the clinic. The ptient should be observed for t lest 30 minutes post-injection nd until spontneous void hs occurred. Ptients should be considered for reinjection when the clinicl effect of the previous injection hs diminished (medin time until ptients qulified for the second tretment of in double-blind, plcebo-controlled clinicl studies ws 169 dys [~24 weeks]), but no sooner thn 12 weeks from the prior bldder injection. Figure 1: Injection Pttern for Intrdetrusor Injections for Tretment of Overctive Bldder nd Detrusor Overctivity ssocited with Neurologic Condition Detrusor Overctivity ssocited with Neurologic Condition An intrvesicl instilltion of diluted locl nesthetic with or without sedtion, or generl nesthesi my be used prior to injection, per locl site prctice. If locl nesthetic instilltion is performed, the bldder should be drined nd irrigted with sterile sline before injection. The recommended dose is 200 Units of per tretment, nd should not be exceeded. 200 Unit Vil of Reconstitute 200 Unit vil of with 6 ml of preservtive-free 0.9% Sodium Chloride Injection, USP nd mix the vil gently. Drw 2 ml from the vil into ech of three 10 ml syringes. Complete the reconstitution by dding 8 ml of preservtive-free 0.9% Sodium Chloride Injection, USP into ech of the 10 ml syringes, nd mix gently. This will result in three 10 ml syringes ech contining 10 ml (~67 Units in ech), for totl of 200 Units of reconstituted. Use immeditely fter reconstitution in the syringe. Dispose of ny unused sline. 100 Unit Vil of Reconstitute two 100 Unit vils of, ech with 6 ml of preservtive-free 0.9% Sodium Chloride Injection, USP nd mix the vils gently. Drw 4 ml from ech vil into ech of two 10 ml syringes. Drw the remining 2 ml from ech vil into third 10 ml syringe for totl of 4 ml in ech syringe. Complete the reconstitution by dding 6 ml of preservtive-free 0.9% Sodium Chloride Injection, USP into ech of the 10 ml syringes, nd mix gently. This will result in three 10 ml syringes ech contining 10 ml (~67 Units in ech), for totl of 200 Units of reconstituted. Use immeditely fter reconstitution in the syringe. Dispose of ny unused sline. Reconstituted (200 Units/30 ml) is injected into the detrusor muscle vi flexible or rigid cystoscope, voiding the trigone. The bldder should be instilled with enough sline to chieve dequte visuliztion for the injections, but over-distension should be voided. The injection needle should be filled (primed) with pproximtely 1 ml of reconstituted prior to the strt of injections (depending on the needle length) to remove ny ir. The needle should be inserted pproximtely 2 mm into the detrusor, nd 30 injections of 1 ml (~6.7 Units) ech (totl volume of 30 ml) should be spced pproximtely 1 cm prt (see Figure 1). For the finl injection, pproximtely 1 ml of sterile norml sline should be injected so tht the remining in the needle is delivered to the bldder. After the injections re given, the sline used for bldder wll visuliztion should be drined. The ptient should be observed for t lest 30 minutes post-injection. Ptients should be considered for re-injection when the clinicl effect of the previous injection diminishes (medin time to qulifiction for re-tretment in the double-blind, plcebo-controlled clinicl studies ws dys [42-48 weeks] for 200 Units), but no sooner thn 12 weeks from the prior bldder injection. 2.4 Chronic Migrine The recommended dilution is 200 Units/4 ml or /2 ml, with finl concentrtion of 5 Units per 0.1 ml (see Tble 1). The recommended dose for treting chronic migrine is 155 Units dministered intrmusculrly using sterile 30-guge, 0.5 inch needle s 0.1 ml (5 Units) injections per ech site. Injections should be divided cross 7 specific hed/neck muscle res s specified in the digrms nd Tble 2 below. A one inch needle my be needed in the neck region for ptients with thick neck muscles. With the exception of the procerus muscle, which should be injected t one site (midline), ll muscles should be injected bilterlly with hlf the number of injection sites dministered to the left, nd hlf to the right side of the hed nd neck. The recommended re-tretment schedule is every 12 weeks. Digrms 1-4: Recommended Injection Sites (A through G) for Chronic Migrine A. Corrugtor: 5 U ech side D. Temporlis: 20 U ech side E. Occipitlis: 15 U ech side F. Cervicl prspinl: 10 U ech side B. Procerus: 5 U (one site) G. Trpezius: 15 U ech side C. Frontlis: 10 U ech side

6 Tble 2: Dosing by Muscle for Chronic Migrine Hed/Neck Are Recommended Dose (Number of Sites ) Frontlis b Corrugtor b Procerus Occipitlis b Temporlis b Trpezius b Cervicl Prspinl Muscle Group b Totl Dose: Ech IM injection site = 0.1 ml = 5 Units b Dose distributed bilterlly 20 Units divided in 4 sites 10 Units divided in 2 sites 5 Units in 1 site 30 Units divided in 6 sites 40 Units divided in 8 sites 30 Units divided in 6 sites 20 Units divided in 4 sites 155 Units divided in 31 sites 2.5 Upper Limb Spsticity Dosing in initil nd sequentil tretment sessions should be tilored to the individul bsed on the size, number nd loction of muscles involved, severity of spsticity, the presence of locl muscle wekness, the ptient s response to previous tretment, or dverse event history with. In clinicl trils, doses rnging from 75 Units to 400 Units were divided mong selected muscles (see Tble 3 nd Figure 2) t given tretment session. Tble 3: Dosing by Muscle for Upper Limb Spsticity Muscle Biceps Brchii Flexor Crpi Rdilis Flexor Crpi Ulnris Flexor Digitorum Profundus Flexor Digitorum Sublimis Adductor Pollicis Flexor Pollicis Longus Recommended Dose Totl Dosge (Number of Sites) -200 Units divided in 4 sites 12.5 Units-50 Units in 1 site 12.5 Units-50 Units in 1 site 30 Units-50 Units in 1 site 30 Units-50 Units in 1 site 20 Units in 1 site 20 Units in 1 site Dosing in initil nd sequentil tretment sessions should be tilored to the individul ptient bsed on the ptient s hed nd neck position, locliztion of pin, muscle hypertrophy, ptient response, nd dverse event history. The initil dose for ptient without prior use of should be t lower dose, with subsequent dosing djusted bsed on individul response. Limiting the totl dose injected into the sternocleidomstoid muscle to or less my decrese the occurrence of dysphgi [see Wrnings nd Precutions (5.2, 5.5, 5.6)]. The recommended dilution is 200 Units/2 ml, 200 Units/4 ml, /1 ml, or 100 Units/2 ml with preservtive-free 0.9% Sodium Chloride Injection, USP, depending on volume nd number of injection sites desired to chieve tretment objectives (see Tble 1). In generl, no more thn 50 Units per site should be dministered. An ppropritely sized needle (e.g., guge) my be used for superficil muscles, nd longer 22 guge needle my be used for deeper musculture. Locliztion of the involved muscles with electromyogrphic guidnce my be useful. Clinicl improvement generlly begins within the first two weeks fter injection with mximum clinicl benefit t pproximtely six weeks post-injection. In the double-blind, plcebo-controlled study most subjects were observed to hve returned to pre-tretment sttus by 3 months post-tretment. 2.7 Primry Axillry Hyperhidrosis The recommended dose is 50 Units per xill. The hyperhidrotic re to be injected should be defined using stndrd stining techniques, e.g., Minor s Iodine-Strch Test. The recommended dilution is /4 ml with 0.9% preservtive-free sterile sline (see Tble 1). Using 30 guge needle, 50 Units of (2 ml) is injected intrdermlly in 0.1 to 0.2 ml liquots to ech xill evenly distributed in multiple sites (10-15) pproximtely 1-2 cm prt. Repet injections for hyperhidrosis should be dministered when the clinicl effect of previous injection diminishes. Instructions for the Minor s Iodine-Strch Test Procedure: Ptients should shve underrms nd bstin from use of over-the-counter deodornts or ntiperspirnts for 24 hours prior to the test. Ptient should be resting comfortbly without exercise, hot drinks for pproximtely 30 minutes prior to the test. Dry the underrm re nd then immeditely pint it with iodine solution. Allow the re to dry, then lightly sprinkle the re with strch powder. Gently blow off ny excess strch powder. The hyperhidrotic re will develop deep blue-blck color over pproximtely 10 minutes. Ech injection site hs ring of effect of up to pproximtely 2 cm in dimeter. To minimize the re of no effect, the injection sites should be evenly spced s shown in Figure 3. Figure 3: Injection Pttern for Primry Axillry Hyperhidrosis Figure 2: Injection Sites for Upper Limb Spsticity Biceps brchii Flexor crpi ulnris Flexor crpi rdilis Flexor digitorum sublimis (flexor digitorum superficilis) Adductor pollicis Flexor digitorum profundus Flexor pollicis longus The recommended dilution is 200 Units/4 ml or /2 ml with preservtive-free 0.9% Sodium Chloride Injection, USP (see Tble 1). The lowest recommended strting dose should be used, nd no more thn 50 Units per site should generlly be dministered. An ppropritely sized needle (e.g., guge) my be used for superficil muscles, nd longer 22 guge needle my be used for deeper musculture. Locliztion of the involved muscles with techniques such s needle electromyogrphic guidnce or nerve stimultion is recommended. Repet tretment my be dministered when the effect of previous injection hs diminished, but generlly no sooner thn 12 weeks fter the previous injection. The degree nd pttern of muscle spsticity t the time of re-injection my necessitte ltertions in the dose of nd muscles to be injected. 2.6 Cervicl Dystoni A double-blind, plcebo-controlled study enrolled ptients who hd extended histories of receiving nd tolerting injections, with prior individulized djustment of dose. The men dose dministered to ptients in this study ws 236 Units (25th to 75th percentile rnge of 198 Units to 300 Units). The dose ws divided mong the ffected muscles [see Clinicl Studies (14.5)]. Ech dose is injected to depth of pproximtely 2 mm nd t 45 ngle to the skin surfce, with the bevel side up to minimize lekge nd to ensure the injections remin intrderml. If injection sites re mrked in ink, do not inject directly through the ink mrk to void permnent tttoo effect. 2.8 Blephrospsm For blephrospsm, reconstituted is injected using sterile, guge needle without electromyogrphic guidnce. The initil recommended dose is 1.25 Units-2.5 Units (0.05 ml to 0.1 ml volume t ech site) injected into the medil nd lterl pre-trsl orbiculris oculi of the upper lid nd into the lterl pre-trsl orbiculris oculi of the lower lid. Avoiding injection ner the levtor plpebre superioris my reduce the compliction of ptosis. Avoiding medil lower lid injections, nd thereby reducing diffusion into the inferior oblique, my reduce the compliction of diplopi. Ecchymosis occurs esily in the soft eyelid tissues. This cn be prevented by pplying pressure t the injection site immeditely fter the injection. The recommended dilution to chieve 1.25 Units is /8 ml; for 2.5 Units it is /4 ml (see Tble 1). In generl, the initil effect of the injections is seen within three dys nd reches pek t one to two weeks post-tretment. Ech tretment lsts pproximtely three months, following which the procedure cn be repeted. At repet tretment sessions, the dose my be incresed up to two-fold if the response from the initil tretment is considered insufficient, usully defined s n effect tht does not lst longer thn two months. However, there ppers to be little benefit obtinble from injecting more thn 5 Units per site. Some tolernce my be found when is used in treting blephrospsm if tretments re given ny more frequently thn every three months, nd is rre to hve the effect be permnent. The cumultive dose of tretment for blephrospsm in 30-dy period should not exceed 200 Units. 2.9 Strbismus is intended for injection into extroculr muscles utilizing the electricl ctivity recorded from the tip of the injection needle s guide to plcement within the trget muscle. Injection without surgicl exposure or electromyogrphic guidnce should not be ttempted. Physicins should be fmilir with electromyogrphic technique. To prepre the eye for injection, it is recommended tht severl drops of locl nesthetic nd n oculr decongestnt be given severl minutes prior to injection. The volume of injected for tretment of strbismus should be between ml per muscle.

7 The initil listed doses of the reconstituted [see Dosge nd Administrtion (2.2)] typiclly crete prlysis of the injected muscles beginning one to two dys fter injection nd incresing in intensity during the first week. The prlysis lsts for 2-6 weeks nd grdully resolves over similr time period. Overcorrections lsting over six months hve been rre. About one hlf of ptients will require subsequent doses becuse of indequte prlytic response of the muscle to the initil dose, or becuse of mechnicl fctors such s lrge devitions or restrictions, or becuse of the lck of binoculr motor fusion to stbilize the lignment. Initil doses in Units Use the lower listed doses for tretment of smll devitions. Use the lrger doses only for lrge devitions. For verticl muscles, nd for horizontl strbismus of less thn 20 prism diopters: 1.25 Units-2.5 Units in ny one muscle. For horizontl strbismus of 20 prism diopters to 50 prism diopters: 2.5 Units-5 Units in ny one muscle. For persistent VI nerve plsy of one month or longer durtion: 1.25 Units-2.5 Units in the medil rectus muscle. Subsequent doses for residul or recurrent strbismus It is recommended tht ptients be re-exmined 7-14 dys fter ech injection to ssess the effect of tht dose. Ptients experiencing dequte prlysis of the trget muscle tht require subsequent injections should receive dose comprble to the initil dose. Subsequent doses for ptients experiencing incomplete prlysis of the trget muscle my be incresed up to two-fold compred to the previously dministered dose. Subsequent injections should not be dministered until the effects of the previous dose hve dissipted s evidenced by substntil function in the injected nd djcent muscles. The mximum recommended dose s single injection for ny one muscle is 25 Units. The recommended dilution to chieve 1.25 Units is /8 ml; for 2.5 Units it is /4 ml (see Tble 1). 3 DOSAGE FORMS AND STRENGTHS Single-use, sterile or 200 Units vcuum-dried powder for reconstitution only with sterile, preservtive-free 0.9% Sodium Chloride Injection USP prior to injection. 4 CONTRAINDICATIONS 4.1 Known Hypersensitivity to Botulinum Toxin is contrindicted in ptients who re hypersensitive to ny botulinum toxin preprtion or to ny of the components in the formultion [see Wrnings nd Precutions (5.4)]. 4.2 Infection t the Injection Site(s) is contrindicted in the presence of infection t the proposed injection site(s). 4.3 Urinry Trct Infection or Urinry Retention Intrdetrusor injection of is contrindicted in ptients with overctive bldder or detrusor overctivity ssocited with neurologic condition who hve urinry trct infection. Intrdetrusor injection of is lso contrindicted in ptients with urinry retention nd in ptients with post-void residul (PVR) urine volume >200 ml, who re not routinely performing clen intermittent self-ctheteriztion (CIC). 5 WARNINGS AND PRECAUTIONS 5.1 Lck of Interchngebility between Botulinum Toxin Products The potency Units of re specific to the preprtion nd ssy method utilized. They re not interchngeble with other preprtions of botulinum toxin products nd, therefore, units of biologicl ctivity of cnnot be compred to nor converted into units of ny other botulinum toxin products ssessed with ny other specific ssy method [see Dosge nd Administrtion (2.1), Description (11)]. 5.2 Spred of Toxin Effect Postmrketing sfety dt from nd other pproved botulinum toxins suggest tht botulinum toxin effects my, in some cses, be observed beyond the site of locl injection. The symptoms re consistent with the mechnism of ction of botulinum toxin nd my include stheni, generlized muscle wekness, diplopi, ptosis, dysphgi, dysphoni, dysrthri, urinry incontinence, nd brething difficulties. These symptoms hve been reported hours to weeks fter injection. Swllowing nd brething difficulties cn be life thretening nd there hve been reports of deth relted to spred of toxin effects. The risk of symptoms is probbly gretest in children treted for spsticity but symptoms cn lso occur in dults treted for spsticity nd other conditions, nd prticulrly in those ptients who hve n underlying condition tht would predispose them to these symptoms. In unpproved uses, including spsticity in children, nd in pproved indictions, symptoms consistent with spred of toxin effect hve been reported t doses comprble to or lower thn doses used to tret cervicl dystoni nd upper limb spsticity. Ptients or cregivers should be dvised to seek immedite medicl cre if swllowing, speech or respirtory disorders occur. No definitive serious dverse event reports of distnt spred of toxin effect ssocited with dermtologic use of / Cosmetic t the lbeled dose of 20 Units (for glbellr lines) or (for severe primry xillry hyperhidrosis) hve been reported. No definitive serious dverse event reports of distnt spred of toxin effect ssocited with for blephrospsm t the recommended dose (30 Units nd below), strbismus, or for chronic migrine t the lbeled doses hve been reported. 5.3 Serious Adverse Rections with Unpproved Use Serious dverse rections, including excessive wekness, dysphgi, nd spirtion pneumoni, with some dverse rections ssocited with ftl outcomes, hve been reported in ptients who received injections for unpproved uses. In these cses, the dverse rections were not necessrily relted to distnt spred of toxin, but my hve resulted from the dministrtion of to the site of injection nd/or djcent structures. In severl of the cses, ptients hd pre-existing dysphgi or other significnt disbilities. There is insufficient informtion to identify fctors ssocited with n incresed risk for dverse rections ssocited with the unpproved uses of. The sfety nd effectiveness of for unpproved uses hve not been estblished. 5.4 Hypersensitivity Rections Serious nd/or immedite hypersensitivity rections hve been reported. These rections include nphylxis, serum sickness, urticri, soft tissue edem, nd dyspne. If such rection occurs, further injection of should be discontinued nd pproprite medicl therpy immeditely instituted. One ftl cse of nphylxis hs been reported in which lidocine ws used s the diluent, nd consequently the cusl gent cnnot be relibly determined. 5.5 Pre-Existing Neuromusculr Disorders Individuls with peripherl motor neuropthic diseses, myotrophic lterl sclerosis or neuromusculr junction disorders (e.g., mystheni grvis or Lmbert-Eton syndrome) should be monitored when given botulinum toxin. Ptients with neuromusculr disorders my be t incresed risk of cliniclly significnt effects including generlized muscle wekness, diplopi, ptosis, dysphoni, dysrthri, severe dysphgi nd respirtory compromise from therpeutic doses of [see Adverse Rections (6.1)]. 5.6 Dysphgi nd Brething Difficulties Tretment with nd other botulinum toxin products cn result in swllowing or brething difficulties. Ptients with pre-existing swllowing or brething difficulties my be more susceptible to these complictions. In most cses, this is consequence of wekening of muscles in the re of injection tht re involved in brething or orophryngel muscles tht control swllowing or brething [see Wrnings nd Precutions (5.2)]. Deths s compliction of severe dysphgi hve been reported fter tretment with botulinum toxin. Dysphgi my persist for severl months, nd require use of feeding tube to mintin dequte nutrition nd hydrtion. Aspirtion my result from severe dysphgi nd is prticulr risk when treting ptients in whom swllowing or respirtory function is lredy compromised. Tretment with botulinum toxins my weken neck muscles tht serve s ccessory muscles of ventiltion. This my result in criticl loss of brething cpcity in ptients with respirtory disorders who my hve become dependent upon these ccessory muscles. There hve been postmrketing reports of serious brething difficulties, including respirtory filure. Ptients with smller neck muscle mss nd ptients who require bilterl injections into the sternocleidomstoid muscle for the tretment of cervicl dystoni hve been reported to be t greter risk for dysphgi. Limiting the dose injected into the sternocleidomstoid muscle my reduce the occurrence of dysphgi. Injections into the levtor scpule my be ssocited with n incresed risk of upper respirtory infection nd dysphgi. Ptients treted with botulinum toxin my require immedite medicl ttention should they develop problems with swllowing, speech or respirtory disorders. These rections cn occur within hours to weeks fter injection with botulinum toxin [see Wrnings nd Precutions (5.2) nd Adverse Rections (6.1)]. 5.7 Pulmonry Effects of in Ptients with Compromised Respirtory Sttus Treted for Spsticity or for Detrusor Overctivity ssocited with Neurologic Condition Ptients with compromised respirtory sttus treted with for upper limb spsticity should be monitored closely. In double-blind, plcebo-controlled, prllel group study in ptients with stble reduced pulmonry function (defined s FEV % of predicted vlue nd FEV 1 /FVC 0.75), the event rte in chnge of Forced Vitl Cpcity 15% or 20% ws generlly greter in ptients treted with thn in ptients treted with plcebo (see Tble 4). Tble 4: Event rte per ptient tretment cycle mong ptients with reduced lung function who experienced t lest 15% or 20% decrese in forced vitl cpcity from bseline t Week 1, 6, 12 post-injection with up to two tretment cycles with or plcebo 360 Units 240 Units 15% 20% 15% 20% 15% 20% Week 1 4% 0% 3% 0% 7% 3% Week 6 7% 4% 4% 2% 2% 2% Week 12 10% 5% 2% 1% 4% 1% Differences from plcebo were not sttisticlly significnt In ptients with reduced lung function, upper respirtory trct infections were lso reported more frequently s dverse rections in ptients treted with thn in ptients treted with plcebo [see Wrnings nd Precutions (5.10)].

8 In n ongoing double-blind, plcebo-controlled, prllel group study in dult ptients with detrusor overctivity ssocited with neurologic condition nd restrictive lung disese of neuromusculr etiology [defined s FVC 50-80% of predicted vlue in ptients with spinl cord injury between C5 nd C8, or MS] the event rte in chnge of Forced Vitl Cpcity 15% or 20% ws generlly greter in ptients treted with thn in ptients treted with plcebo (see Tble 5). Tble 5: Number nd percent of ptients experiencing t lest 15% or 20% decrese in FVC from bseline t Week 2, 6, 12 post-injection with or plcebo 200 Units 15% 20% 15% 20% Week 2 0/12 (0%) 0/12 (0%) 1/11 (9%) 0/11 (0%) Week 6 2/11 (18%) 1/11 (9%) 0/11 (0%) 0/11 (0%) Week 12 0/11 (0%) 0/11 (0%) 0/6 (0%) 0/6 (0%) 5.8 Cornel Exposure nd Ulcertion in Ptients Treted with for Blephrospsm Reduced blinking from injection of the orbiculris muscle cn led to cornel exposure, persistent epithelil defect, nd cornel ulcertion, especilly in ptients with VII nerve disorders. Vigorous tretment of ny epithelil defect should be employed. This my require protective drops, ointment, therpeutic soft contct lenses, or closure of the eye by ptching or other mens. 5.9 Retrobulbr Hemorrhges in Ptients Treted with for Strbismus During the dministrtion of for the tretment of strbismus, retrobulbr hemorrhges sufficient to compromise retinl circultion hve occurred. It is recommended tht pproprite instruments to decompress the orbit be ccessible Bronchitis nd Upper Respirtory Trct Infections in Ptients Treted for Spsticity Bronchitis ws reported more frequently s n dverse rection in ptients treted for upper limb spsticity with (3% t 251 Units-360 Units totl dose), compred to plcebo (1%). In ptients with reduced lung function treted for upper limb spsticity, upper respirtory trct infections were lso reported more frequently s dverse rections in ptients treted with (11% t 360 Units totl dose; 8% t 240 Units totl dose) compred to plcebo (6%) Autonomic Dysreflexi in Ptients Treted for Detrusor Overctivity ssocited with Neurologic Condition Autonomic dysreflexi ssocited with intrdetrusor injections of could occur in ptients treted for detrusor overctivity ssocited with neurologic condition nd my require prompt medicl therpy. In clinicl trils, the incidence of utonomic dysreflexi ws greter in ptients treted with 200 Units compred with plcebo (1.5% versus 0.4%, respectively) Urinry Trct Infections in Ptients with Overctive Bldder increses the incidence of urinry trct infection [see Adverse Rections (6.1)]. Clinicl trils for overctive bldder excluded ptients with more thn 2 UTIs in the pst 6 months nd those tking ntibiotics chroniclly due to recurrent UTIs. Use of for the tretment of overctive bldder in such ptients nd in ptients with multiple recurrent UTIs during tretment should only be considered when the benefit is likely to outweigh the potentil risk Urinry Retention in Ptients Treted for Bldder Dysfunction Due to the risk of urinry retention, tret only ptients who re willing nd ble to initite ctheteriztion post-tretment, if required, for urinry retention. In ptients who re not ctheterizing, post-void residul (PVR) urine volume should be ssessed within 2 weeks post-tretment nd periodiclly s mediclly pproprite up to 12 weeks, prticulrly in ptients with multiple sclerosis or dibetes mellitus. Depending on ptient symptoms, institute ctheteriztion if PVR urine volume exceeds 200 ml nd continue until PVR flls below 200 ml. Instruct ptients to contct their physicin if they experience difficulty in voiding s ctheteriztion my be required. The incidence nd durtion of urinry retention is described below for ptients with overctive bldder nd detrusor overctivity ssocited with neurologic condition who received or plcebo injections. Overctive Bldder In double-blind, plcebo-controlled trils in ptients with OAB, the proportion of subjects who initited clen intermittent ctheteriztion (CIC) for urinry retention following tretment with or plcebo is shown in Tble 6. The durtion of post-injection ctheteriztion for those who developed urinry retention is lso shown. Tble 6: Proportion of Ptients Ctheterizing for Urinry Retention nd Durtion of Ctheteriztion following n injection in double-blind, plcebo-controlled clinicl trils in OAB Timepoint At ny time during complete tretment cycle (N=552) Proportion of Ptients Ctheterizing for Urinry Retention (N=542) 6.5% (n=36) 0.4% (n=2) Durtion of Ctheteriztion for Urinry Retention (Dys) Medin Min, Mx 1, 214 3, 18 Ptients with dibetes mellitus treted with were more likely to develop urinry retention thn those without dibetes, s shown in Tble 7. Tble 7. Proportion of Ptients Experiencing Urinry Retention following n injection in double-blind, plcebo-controlled clinicl trils in OAB ccording to history of Dibetes Mellitus Ptients with Dibetes (N=81) (N=69) Ptients without Dibetes (N=526) (N=516) Urinry retention 12.3% (n=10) 0 6.3% (n=33) 0.6% (n=3) Detrusor Overctivity ssocited with Neurologic Condition In double-blind, plcebo-controlled trils in ptients with detrusor overctivity ssocited with neurologic condition, the proportion of subjects who were not using clen intermittent ctheteriztion (CIC) prior to injection nd who subsequently required ctheteriztion for urinry retention following tretment with or plcebo is shown in Tble 8. The durtion of post-injection ctheteriztion for those who developed urinry retention is lso shown. Tble 8: Proportion of Ptients not using CIC t bseline nd then Ctheterizing for Urinry Retention nd Durtion of Ctheteriztion following n injection in doubleblind, plcebo-controlled clinicl trils Timepoint At ny time during complete tretment cycle 200 Units (N=108) Proportion of Ptients Ctheterizing for Urinry Retention (N=104) 30.6% (n=33) 6.7% (n=7) Durtion of Ctheteriztion for Urinry Retention (Dys) Medin Min, Mx 1, 530 2, 379 Among ptients not using CIC t bseline, those with MS were more likely to require CIC post-injection thn those with SCI (see Tble 9). Tble 9: Proportion of Ptients by Etiology (MS nd SCI) not using CIC t bseline nd then Ctheterizing for Urinry Retention following n injection in double-blind, plcebo-controlled clinicl trils Timepoint At ny time during complete tretment cycle 200 Units (N=86) MS (N=88) 200 Units (N=22) SCI (N=16) 31% (n=27) 5% (n=4) 27% (n=6) 19% (n=3) 5.14 Humn Albumin nd Trnsmission of Virl Diseses This product contins lbumin, derivtive of humn blood. Bsed on effective donor screening nd product mnufcturing processes, it crries n extremely remote risk for trnsmission of virl diseses. A theoreticl risk for trnsmission of Creutzfeldt-Jkob disese (CJD) is lso considered extremely remote. No cses of trnsmission of virl diseses or CJD hve ever been reported for lbumin. 6 ADVERSE REACTIONS The following dverse rections to (onbotulinumtoxina) for injection re discussed in greter detil in other sections of the lbeling: Spred of Toxin Effects [see Wrnings nd Precutions (5.2)] Hypersensitivity [see Contrindictions (4.1) nd Wrnings nd Precutions (5.4)] Dysphgi nd Brething Difficulties [see Wrnings nd Precutions (5.6)] Bronchitis nd Upper Respirtory Trct Infections in Ptients Treted for Spsticity [see Wrnings nd Precutions (5.10)] Urinry Retention in Ptients Treted for Bldder Dysfunction [see Wrnings nd Precutions (5.13)]

9 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, the dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in clinicl prctice. nd Cosmetic contin the sme ctive ingredient in the sme formultion, but with different lbeled Indictions nd Usge. Therefore, dverse rections observed with the use of Cosmetic lso hve the potentil to be observed with the use of. In generl, dverse rections occur within the first week following injection of nd while generlly trnsient, my hve durtion of severl months or longer. Loclized pin, infection, inflmmtion, tenderness, swelling, erythem, nd/or bleeding/bruising my be ssocited with the injection. Needle-relted pin nd/or nxiety my result in vsovgl responses (including e.g., syncope, hypotension), which my require pproprite medicl therpy. Locl wekness of the injected muscle(s) represents the expected phrmcologicl ction of botulinum toxin. However, wekness of nerby muscles my lso occur due to spred of toxin [see Wrnings nd Precutions (5.2)]. Overctive Bldder Tble 10 presents the most frequently reported dverse rections in double-blind, plcebocontrolled clinicl trils for overctive bldder occurring within 12 weeks of the first tretment. Tble 10: Adverse Rections Reported by 2% of treted Ptients nd More Often thn in -treted Ptients Within the First 12 Weeks fter Intrdetrusor Injection, in Double-blind, -controlled Clinicl Trils in Ptients with OAB Adverse Rections Urinry trct infection Dysuri Urinry retention Bcteriuri Residul urine volume* (N=552) 99 (18%) 50 (9%) 31 (6%) 24 (4%) 17 (3%) (N=542) 30 (6%) 36 (7%) 2 (0%) 11 (2%) 1 (0%) * Elevted PVR not requiring ctheteriztion. Ctheteriztion ws required for PVR 350 ml regrdless of symptoms, nd for PVR 200 ml to <350 ml with symptoms (e.g., voiding difficulty). A higher incidence of urinry trct infection ws observed in ptients with dibetes mellitus treted with nd plcebo thn in ptients without dibetes, s shown in Tble 11. Tble 11: Proportion of Ptients Experiencing Urinry Trct Infection following n Injection in Double-blind, -controlled Clinicl Trils in OAB ccording to history of Dibetes Mellitus Ptients with Dibetes (N=81) (N=69) Ptients without Dibetes (N=526) (N=516) Urinry trct infection (UTI) 25 (31%) 8 (12%) 135 (26%) 51 (10%) The incidence of UTI incresed in ptients who experienced mximum post-void residul (PVR) urine volume 200 ml following injection compred to those with mximum PVR <200 ml following injection, 44% versus 23%, respectively. No chnge ws observed in the overll sfety profile with repet dosing during n open-lbel, uncontrolled extension tril. Detrusor Overctivity ssocited with Neurologic Condition Tble 12 presents the most frequently reported dverse rections in double-blind, plcebocontrolled studies within 12 weeks of injection for detrusor overctivity ssocited with neurologic condition. Tble 12: Adverse Rections Reported by 2% of treted Ptients nd More Frequent thn in -treted Ptients Within the First 12 Weeks fter Intrdetrusor Injection in Double-blind, -controlled Clinicl Trils Adverse Rections Urinry trct infection Urinry retention Hemturi 200 Units (N=262) 64 (24%) 45 (17%) 10 (4%) (N=272) 47 (17%) 8 (3%) 8 (3%) The following dverse rections with 200 Units were reported t ny time following initil injection nd prior to re-injection or study exit (medin durtion of 44 weeks of exposure): urinry trct infections (49%), urinry retention (17%), constiption (4%), musculr wekness (4%), dysuri (4%), fll (3%), git disturbnce (3%), nd muscle spsm (2%). In the MS ptients enrolled in the double-blind, plcebo-controlled trils, the MS excerbtion nnulized rte (i.e., number of MS excerbtion events per ptient-yer) ws 0.23 for nd 0.20 for plcebo. No chnge ws observed in the overll sfety profile with repet dosing. Chronic Migrine In double-blind, plcebo-controlled chronic migrine efficcy trils (Study 1 nd Study 2), the discontinution rte ws 12% in the treted group nd 10% in the plcebotreted group. Discontinutions due to n dverse event were 4% in the group nd 1% in the plcebo group. The most frequent dverse events leding to discontinution in the group were neck pin, hedche, worsening migrine, musculr wekness nd eyelid ptosis. The most frequently reported dverse rections following injection of for chronic migrine pper in Tble 13. Tble 13: Adverse Rections Reported by 2% of treted Ptients nd More Frequent thn in -treted Ptients in Two Chronic Migrine Double-blind, -controlled Clinicl Trils Adverse Rections by System Orgn Clss Nervous system disorders Hedche Migrine Fcil presis 155 Units-195 Units (N=687) 32 (5%) 26 (4%) 15 (2%) (N=692) 22 (3%) 18 (3%) 0 (0%) Eye disorders Eyelid ptosis 25 (4%) 2 (<1%) Infections nd Infesttions Bronchitis 17 (3%) 11 (2%) Musculoskeletl nd connective tissue disorders Neck pin Musculoskeletl stiffness Musculr wekness Mylgi Musculoskeletl pin Muscle spsms 60 (9%) 25 (4%) 24 (4%) 21 (3%) 18 (3%) 13 (2%) 19 (3%) 6 (1%) 2 (<1%) 6 (1%) 10 (1%) 6 (1%) Generl disorders nd dministrtion site conditions Injection site pin 23 (3%) 14 (2%) Vsculr Disorders Hypertension 11 (2%) 7 (1%) Other dverse rections tht occurred more frequently in the group compred to the plcebo group t frequency less thn 1% nd potentilly relted include: vertigo, dry eye, eyelid edem, dysphgi, eye infection, nd jw pin. Severe worsening of migrine requiring hospitliztion occurred in pproximtely 1% of treted ptients in Study 1 nd Study 2, usully within the first week fter tretment, compred to 0.3% of plcebo-treted ptients. Upper Limb Spsticity The most frequently reported dverse rections following injection of for dult spsticity pper in Tble 14. Tble 14: Adverse Rections Reported by 2% of treted Ptients nd More Frequent thn in -treted Ptients in Adult Spsticity Double-blind, controlled Clinicl Trils Adverse Rections by System Orgn Clss 251 Units- 360 Units (N=115) 150 Units- 250 Units (N=188) <150 Units (N=54) (N=182) Gstrointestinl disorder Nuse 3 (3%) 3 (2%) 1 (2%) 1 (1%) Generl disorders nd dministrtion site conditions Ftigue 4 (3%) 4 (2%) 1 (2%) 0 Infections nd infesttions Bronchitis 4 (3%) 4 (2%) 0 2 (1%) Musculoskeletl nd connective tissue disorders Pin in extremity Musculr wekness 7 (6%) 0 10 (5%) 7 (4%) 5 (9%) 1 (2%) 8 (4%) 2 (1%) Twenty two dult ptients, enrolled in double-blind plcebo controlled studies, received 400 Units or higher of for tretment of upper limb spsticity. In ddition, 44 dults received 400 Units of or higher for four consecutive tretments over pproximtely one yer for tretment of upper limb spsticity. The type nd frequency of dverse rections observed in ptients treted with 400 Units of were similr to those reported in ptients treted for upper limb spsticity with 360 Units of.

10 Cervicl Dystoni In cervicl dystoni ptients evluted for sfety in double-blind nd open-lbel studies following injection of, the most frequently reported dverse rections were dysphgi (19%), upper respirtory infection (12%), neck pin (11%), nd hedche (11%). Other events reported in 2-10% of ptients in ny one study in decresing order of incidence include: incresed cough, flu syndrome, bck pin, rhinitis, dizziness, hypertoni, soreness t injection site, stheni, orl dryness, speech disorder, fever, nuse, nd drowsiness. Stiffness, numbness, diplopi, ptosis, nd dyspne hve been reported. Dysphgi nd symptomtic generl wekness my be ttributble to n extension of the phrmcology of resulting from the spred of the toxin outside the injected muscles [see Wrnings nd Precutions (5.2, 5.6)]. The most common severe dverse rection ssocited with the use of injection in ptients with cervicl dystoni is dysphgi with bout 20% of these cses lso reporting dyspne [see Wrnings nd Precutions (5.2, 5.6)]. Most dysphgi is reported s mild or moderte in severity. However, it my be ssocited with more severe signs nd symptoms [see Wrnings nd Precutions (5.6)]. Additionlly, reports in the literture include cse of femle ptient who developed brchil plexopthy two dys fter injection of 120 Units of for the tretment of cervicl dystoni, nd reports of dysphoni in ptients who hve been treted for cervicl dystoni. Primry Axillry Hyperhidrosis The most frequently reported dverse rections (3-10% of dult ptients) following injection of in double-blind studies included injection site pin nd hemorrhge, non-xillry sweting, infection, phryngitis, flu syndrome, hedche, fever, neck or bck pin, pruritus, nd nxiety. The dt reflect 346 ptients exposed to 50 Units nd 110 ptients exposed to 75 Units in ech xill. Blephrospsm In study of blephrospsm ptients who received n verge dose per eye of 33 Units (injected t 3 to 5 sites) of the currently mnufctured, the most frequently reported dverse rections were ptosis (21%), superficil punctte kertitis (6%), nd eye dryness (6%). Other events reported in prior clinicl studies in decresing order of incidence include: irrittion, tering, lgophthlmos, photophobi, ectropion, kertitis, diplopi, entropion, diffuse skin rsh, nd locl swelling of the eyelid skin lsting for severl dys following eyelid injection. In two cses of VII nerve disorder, reduced blinking from injection of the orbiculris muscle led to serious cornel exposure, persistent epithelil defect, cornel ulcertion nd cse of cornel perfortion. Focl fcil prlysis, syncope, nd excerbtion of mystheni grvis hve lso been reported fter tretment of blephrospsm. Strbismus Extroculr muscles djcent to the injection site cn be ffected, cusing verticl devition, especilly with higher doses of. The incidence rtes of these dverse effects in 2058 dults who received totl of 3650 injections for horizontl strbismus ws 17%. The incidence of ptosis hs been reported to be dependent on the loction of the injected muscles, 1% fter inferior rectus injections, 16% fter horizontl rectus injections nd 38% fter superior rectus injections. In series of 5587 injections, retrobulbr hemorrhge occurred in 0.3% of cses. 6.2 Immunogenicity As with ll therpeutic proteins, there is potentil for immunogenicity. Formtion of neutrlizing ntibodies to botulinum toxin type A my reduce the effectiveness of tretment by inctivting the biologicl ctivity of the toxin. In long term, open-lbel study evluting 326 cervicl dystoni ptients treted for n verge of 9 tretment sessions with the current formultion of, 4 (1.2%) ptients hd positive ntibody tests. All 4 of these ptients responded to therpy t the time of the positive ntibody test. However, 3 of these ptients developed clinicl resistnce fter subsequent tretment, while the fourth ptient continued to respond to therpy for the reminder of the study. One ptient mong the 445 hyperhidrosis ptients (0.2%), two ptients mong the 380 dult upper limb spsticity ptients (0.5%), no ptients mong 406 migrine ptients, no ptients mong 615 overctive bldder ptients, nd no ptients mong 475 detrusor overctivity ssocited with neurologic condition ptients with nlyzed specimens developed the presence of neutrlizing ntibodies. The dt reflect the ptients whose test results were considered positive or negtive for neutrlizing ctivity to in mouse protection ssy. The results of these tests re highly dependent on the sensitivity nd specificity of the ssy. Additionlly, the observed incidence of ntibody (including neutrlizing ntibody) positivity in n ssy my be influenced by severl fctors including ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, comprison of the incidence of neutrlizing ctivity to with the incidence of ntibodies to other products my be misleding. The criticl fctors for neutrlizing ntibody formtion hve not been well chrcterized. The results from some studies suggest tht injections t more frequent intervls or t higher doses my led to greter incidence of ntibody formtion. The potentil for ntibody formtion my be minimized by injecting with the lowest effective dose given t the longest fesible intervls between injections. 6.3 Post-Mrketing Experience The following dverse rections hve been identified during post-pprovl use of. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. These rections include: bdominl pin; lopeci, including mdrosis; norexi; brchil plexopthy; denervtion/muscle trophy; dirrhe; hyperhidrosis; hypocusis; hypoesthesi; mlise; presthesi; peripherl neuropthy; rdiculopthy; erythem multiforme, dermtitis psorisiform, nd psorisiform eruption; strbismus; tinnitus; nd visul disturbnces. There hve been spontneous reports of deth, sometimes ssocited with dysphgi, pneumoni, nd/or other significnt debility or nphylxis, fter tretment with botulinum toxin [see Wrnings nd Precutions (5.4, 5.6)]. There hve lso been reports of dverse events involving the crdiovsculr system, including rrhythmi nd myocrdil infrction, some with ftl outcomes. Some of these ptients hd risk fctors including crdiovsculr disese. The exct reltionship of these events to the botulinum toxin injection hs not been estblished. New onset or recurrent seizures hve lso been reported, typiclly in ptients who re predisposed to experiencing these events. The exct reltionship of these events to the botulinum toxin injection hs not been estblished. 7 DRUG INTERACTIONS 7.1 Aminoglycosides nd Other Agents Interfering with Neuromusculr Trnsmission Co-dministrtion of nd minoglycosides or other gents interfering with neuromusculr trnsmission (e.g., curre-like compounds) should only be performed with cution s the effect of the toxin my be potentited. 7.2 Anticholinergic Drugs Use of nticholinergic drugs fter dministrtion of my potentite systemic nticholinergic effects. 7.3 Other Botulinum Neurotoxin Products The effect of dministering different botulinum neurotoxin products t the sme time or within severl months of ech other is unknown. Excessive neuromusculr wekness my be excerbted by dministrtion of nother botulinum toxin prior to the resolution of the effects of previously dministered botulinum toxin. 7.4 Muscle Relxnts Excessive wekness my lso be exggerted by dministrtion of muscle relxnt before or fter dministrtion of. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory C. There re no dequte nd well-controlled studies in pregnnt women. should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. When (4, 8, or 16 Units/kg) ws dministered intrmusculrly to pregnnt mice or rts two times during the period of orgnogenesis (on gesttion dys 5 nd 13), reductions in fetl body weight nd decresed fetl skeletl ossifiction were observed t the two highest doses. The no-effect dose for developmentl toxicity in these studies (4 Units/kg) is pproximtely 0.7 times the verge high humn dose for upper limb spsticity of 360 Units on body weight bsis (Units/kg). When ws dministered intrmusculrly to pregnnt rts (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rbbits (0.063, 0.125, 0.25, or 0.5 Units/kg) dily during the period of orgnogenesis (totl of 12 doses in rts, 13 doses in rbbits), reduced fetl body weights nd decresed fetl skeletl ossifiction were observed t the two highest doses in rts nd t the highest dose in rbbits. These doses were lso ssocited with significnt mternl toxicity, including bortions, erly deliveries, nd mternl deth. The developmentl noeffect doses in these studies of 1 Unit/kg in rts nd 0.25 Units/kg in rbbits re less thn the verge high humn dose bsed on Units/kg. When pregnnt rts received single intrmusculr injections (1, 4, or 16 Units/kg) t three different periods of development (prior to implnttion, implnttion, or orgnogenesis), no dverse effects on fetl development were observed. The developmentl no-effect level for single mternl dose in rts (16 Units/kg) is pproximtely 3 times the verge high humn dose bsed on Units/kg. 8.3 Nursing Mothers It is not known whether is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should be exercised when is dministered to nursing womn. 8.4 Peditric Use Bldder Dysfunction Sfety nd effectiveness in ptients below the ge of 18 yers hve not been estblished. Prophylxis of Hedches in Chronic Migrine Sfety nd effectiveness in ptients below the ge of 18 yers hve not been estblished. Spsticity Sfety nd effectiveness in ptients below the ge of 18 yers hve not been estblished. Axillry Hyperhidrosis Sfety nd effectiveness in ptients below the ge of 18 yers hve not been estblished. Cervicl Dystoni Sfety nd effectiveness in peditric ptients below the ge of 16 yers hve not been estblished.

11 Blephrospsm nd Strbismus Sfety nd effectiveness in peditric ptients below the ge of 12 yers hve not been estblished. 8.5 Geritric Use Overll, with the exception of Overctive Bldder (see below), clinicl studies of did not include sufficient numbers of subjects ged 65 nd over to determine whether they respond differently from younger subjects. Other reported clinicl experience hs not identified differences in responses between the elderly nd younger ptients. There were too few ptients over the ge of 75 to enble ny comprisons. In generl, dose selection for n elderly ptient should be cutious, usully strting t the low end of the dosing rnge, reflecting the greter frequency of decresed heptic, renl, or crdic function, nd of concomitnt disese or other drug therpy. Overctive Bldder Of 1242 overctive bldder ptients in plcebo-controlled clinicl studies of, 41.4% (n=514) were 65 yers of ge or older, nd 14.7% (n=182) were 75 yers of ge or older. Adverse rections of UTI nd urinry retention were more common in ptients 65 yers of ge or older in both plcebo nd groups compred to younger ptients (see Tble 15). Otherwise, there were no overll differences in the sfety profile following tretment between ptients ged 65 yers nd older compred to younger ptients in these studies. Tble 15. Incidence of Urinry Trct Infection nd Urinry Retention ccording to Age Group during First -controlled Tretment, -controlled Clinicl Trils in Ptients with OAB Adverse Rections (N=344) <65 Yers 65 to 74 Yers 75 Yers (N=348) (N=169) (N=151) (N=94) (N=86) Urinry trct infection 73 (21%) 23 (7%) 51 (30%) 20 (13%) 36 (38%) 16 (19%) Urinry retention 21 (6%) 2 (0.6%) 14 (8%) 0 (0%) 8 (9%) 1 (1%) Observed effectiveness ws comprble between these ge groups in plcebo-controlled clinicl studies. 10 OVERDOSAGE Excessive doses of (onbotulinumtoxina) for injection my be expected to produce neuromusculr wekness with vriety of symptoms. Symptoms of overdose re likely not to be present immeditely following injection. Should ccidentl injection or orl ingestion occur or overdose be suspected, the person should be mediclly supervised for severl weeks for signs nd symptoms of systemic musculr wekness which could be locl, or distnt from the site of injection [see Boxed Wrning nd Wrnings nd Precutions (5.2, 5.6)]. These ptients should be considered for further medicl evlution nd pproprite medicl therpy immeditely instituted, which my include hospitliztion. If the musculture of the orophrynx nd esophgus re ffected, spirtion my occur which my led to development of spirtion pneumoni. If the respirtory muscles become prlyzed or sufficiently wekened, intubtion nd ssisted respirtion my be necessry until recovery tkes plce. Supportive cre could involve the need for trcheostomy nd/or prolonged mechnicl ventiltion, in ddition to other generl supportive cre. In the event of overdose, ntitoxin rised ginst botulinum toxin is vilble from the Centers for Disese Control nd Prevention (CDC) in Atlnt, GA. However, the ntitoxin will not reverse ny botulinum toxin-induced effects lredy pprent by the time of ntitoxin dministrtion. In the event of suspected or ctul cses of botulinum toxin poisoning, plese contct your locl or stte Helth Deprtment to process request for ntitoxin through the CDC. If you do not receive response within 30 minutes, plese contct the CDC directly t More informtion cn be obtined t 11 DESCRIPTION (onbotulinumtoxina) for injection is sterile, vcuum-dried purified botulinum toxin type A, produced from fermenttion of Hll strin Clostridium botulinum type A, nd intended for intrmusculr, intrdetrusor nd intrderml use. It is purified from the culture solution by dilysis nd series of cid precipittions to complex consisting of the neurotoxin, nd severl ccessory proteins. The complex is dissolved in sterile sodium chloride solution contining Albumin Humn nd is sterile filtered (0.2 microns) prior to filling nd vcuum-drying. The primry relese procedure for uses cell-bsed potency ssy to determine the potency reltive to reference stndrd. The ssy is specific to Allergn s products nd Cosmetic. One Unit of corresponds to the clculted medin intrperitonel lethl dose (LD 50 ) in mice. Due to specific detils of this ssy such s the vehicle, dilution scheme, nd lbortory protocols, Units of biologicl ctivity of cnnot be compred to nor converted into Units of ny other botulinum toxin or ny toxin ssessed with ny other specific ssy method. The specific ctivity of is pproximtely 20 Units/nnogrm of neurotoxin protein complex. Ech vil of contins either of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Humn, nd 0.9 mg of sodium chloride; or 200 Units of Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Humn, nd 1.8 mg of sodium chloride in sterile, vcuum-dried form without preservtive. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action blocks neuromusculr trnsmission by binding to cceptor sites on motor or sympthetic nerve terminls, entering the nerve terminls, nd inhibiting the relese of cetylcholine. This inhibition occurs s the neurotoxin cleves SNAP-25, protein integrl to the successful docking nd relese of cetylcholine from vesicles situted within nerve endings. When injected intrmusculrly t therpeutic doses, produces prtil chemicl denervtion of the muscle resulting in loclized reduction in muscle ctivity. In ddition, the muscle my trophy, xonl sprouting my occur, nd extrjunctionl cetylcholine receptors my develop. There is evidence tht reinnervtion of the muscle my occur, thus slowly reversing muscle denervtion produced by. When injected intrdermlly, produces temporry chemicl denervtion of the swet glnd resulting in locl reduction in sweting. Following intrdetrusor injection, ffects the efferent pthwys of detrusor ctivity vi inhibition of cetylcholine relese Phrmcokinetics Using currently vilble nlyticl technology, it is not possible to detect in the peripherl blood following intrmusculr injection t the recommended doses. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Crcinogenesis Long term studies in nimls hve not been performed to evlute the crcinogenic potentil of. Mutgenesis ws negtive in bttery of in vitro (microbil reverse muttion ssy, mmmlin cell muttion ssy, nd chromosoml berrtion ssy) nd in vivo (micronucleus ssy) genetic toxicologic ssys. Impirment of Fertility In fertility studies of (4, 8, or 16 Units/kg) in which either mle or femle rts were injected intrmusculrly prior to mting nd on the dy of mting (3 doses, 2 weeks prt for mles, 2 doses, 2 weeks prt for femles) to untreted nimls, reduced fertility ws observed in mles t the intermedite nd high doses nd in femles t the high dose. The no-effect doses for reproductive toxicity (4 Units/kg in mles, 8 Units/kg in femles) re pproximtely equl to the verge high humn dose for upper limb spsticity of 360 Units on body weight bsis (Units/kg) Animl Toxicology In study to evlute indvertent peribldder dministrtion, bldder stones were observed in 1 of 4 mle monkeys tht were injected with totl of 6.8 Units/kg divided into the prosttic urethr nd proximl rectum (single dministrtion). No bldder stones were observed in mle or femle monkeys following injection of up to 36 Units/kg (~12X the highest humn bldder dose) directly to the bldder s either single or 4 repet dose injections or in femle rts for single injections up to /kg (~33X the highest humn bldder dose). 14 CLINICAL STUDIES 14.1 Overctive Bldder (OAB) Two double-blind, plcebo-controlled, rndomized, multi-center, 24-week clinicl studies were conducted in ptients with OAB with symptoms of urge urinry incontinence, urgency, nd frequency (Studies OAB-1 nd OAB-2). Ptients needed to hve t lest 3 urinry urgency incontinence episodes nd t lest 24 micturitions in 3 dys to enter the studies. A totl of 1105 ptients, whose symptoms hd not been dequtely mnged with nticholinergic therpy (indequte response or intolerble side effects), were rndomized to receive either of (n=557), or plcebo (n=548). Ptients received 20 injections of study drug (5 units of or plcebo) spced pproximtely 1 cm prt into the detrusor muscle. In both studies, significnt improvements compred to plcebo in the primry efficcy vrible of chnge from bseline in dily frequency of urinry incontinence episodes were observed for t the primry time point of week 12. Significnt improvements compred to plcebo were lso observed for the secondry efficcy vribles of dily frequency of micturition episodes nd volume voided per micturition. These primry nd secondry vribles re shown in Tbles 16 nd 17, nd Figures 4 nd 5.

12 Tble 16: Bseline nd Chnge from Bseline in Urinry Incontinence Episode Frequency, Micturition Episode Frequency nd Volume Voided Per Micturition, Study OAB-1 Dily Frequency of Urinry Incontinence Episodes (N=278) (N=272) Men Bseline Tretment Difference Men Chnge* t Week Men Chnge* t Week Men Chnge* t Week 12** (-2.1, -1.2) Dily Frequency of Micturition Episodes b Men Bseline Men Chnge t Week 12** (-1.5, -0.6) Volume Voided per Micturition b (ml) Men Bseline Men Chnge t Week 12** (17, 43) p-vlue <0.001 <0.001 <0.001 * Lest squres (LS) men chnge, tretment difference nd p-vlue re bsed on n ANCOVA model with bseline vlue s covrite nd tretment group nd investigtor s fctors. Lst observtion crried forwrd (LOCF) vlues were used to nlyze the primry efficcy vrible. LS men chnge, tretment difference nd p-vlue re bsed on n ANCOVA model with bseline vlue s covrite nd strtifiction fctor, tretment group nd investigtor s fctors. ** Primry timepoint Primry vrible b Secondry vrible Tble 17: Bseline nd Chnge from Bseline in Urinry Incontinence Episode Frequency, Micturition Episode Frequency nd Volume Voided Per Micturition, Study OAB-2 Dily Frequency of Urinry Incontinence Episodes (N=275) (N=269) Men Bseline Tretment Difference Men Chnge* t Week Men Chnge* t Week Men Chnge* t Week 12** (-2.5, -1.4) Dily Frequency of Micturition Episodes b Men Bseline Men Chnge t Week 12** (-2.2, -1.3) Volume Voided per Micturition b (ml) Men Bseline Men Chnge t Week 12** (20, 41) p-vlue <0.001 <0.001 <0.001 Figure 4: Men Chnge from Bseline in Dily Frequency of Urinry Incontinence Episodes following intrdetrusor injection in Study OAB-1 Episodes per Dy: Men Chnge From Bseline (± SE) Weeks Post-Tretment ** Tretment (n = 272) 100 U (n = 278) ** : p < Figure 5: Men Chnge from Bseline in Dily Frequency of Urinry Incontinence Episodes following intrdetrusor injection in Study OAB-2 Episodes per Dy: Men Chnge From Bseline (± SE) Weeks Post-Tretment ** Tretment (n = 269) 100 U (n = 275) ** : p < The medin durtion of response in Study OAB-1 nd OAB-2, bsed on ptient qulifiction for re-tretment, ws weeks for the 100 Unit dose group compred to 13 weeks for plcebo. To qulify for re-tretment, t lest 12 weeks must hve pssed since the prior tretment, post-void residul urine volume must hve been less thn 200 ml nd ptients must hve reported t lest 2 urinry incontinence episodes over 3 dys Detrusor Overctivity ssocited with Neurologic Condition Two double-blind, plcebo-controlled, rndomized, multi-center clinicl studies were conducted in ptients with urinry incontinence due to detrusor overctivity ssocited with neurologic condition who were either spontneously voiding or using ctheteriztion (Studies NDO-1 nd NDO-2). A totl of 691 spinl cord injury (T1 or below) or multiple sclerosis ptients, who hd n indequte response to or were intolernt of t lest one nticholinergic mediction, were enrolled. These ptients were rndomized to receive either 200 Units of (n=227), 300 Units of (n=223), or plcebo (n=241). In both studies, significnt improvements compred to plcebo in the primry efficcy vrible of chnge from bseline in weekly frequency of incontinence episodes were observed for (200 Units) t the primry efficcy time point t week 6. Increses in mximum cystometric cpcity nd reductions in mximum detrusor pressure during the first involuntry detrusor contrction were lso observed. These primry nd secondry endpoints re shown in Tbles 18 nd 19, nd Figures 6 nd 7. No dditionl benefit of 300 Units over 200 Units ws demonstrted. * LS men chnge, tretment difference nd p-vlue re bsed on n ANCOVA model with bseline vlue s covrite nd tretment group nd investigtor s fctors. LOCF vlues were used to nlyze the primry efficcy vrible. LS men chnge, tretment difference nd p-vlue re bsed on n ANCOVA model with bseline vlue s covrite nd strtifiction fctor, tretment group nd investigtor s fctors. ** Primry timepoint Primry vrible b Secondry vrible

13 Tble 18: Bseline nd Chnge from Bseline in Weekly Urinry Incontinence Episode Frequency, Mximum Cystometric Cpcity nd Mximum Detrusor Pressure during First Involuntry Detrusor Contrction (cmh 2 O) Study NDO-1 Weekly Frequency of Urinry Incontinence Episodes 200 Units N Men Bseline Tretment Difference* p-vlue* Men Chnge* t Week Men Chnge* t Week 6** (-13.1, -5.3) p<0.001 Men Chnge* t Week Mximum Cystometric Cpcity b (ml) N Men Bseline Men Chnge* t Week 6** (89.1, 158.7) Mximum Detrusor Pressure during First Involuntry Detrusor Contrction b (cmh 2 O) N Men Bseline p<0.001 Men Chnge* t Week 6** * LS men chnge, tretment difference nd p-vlue re bsed on n nlysis using n ANCOVA model with bseline weekly endpoint s covrite nd tretment group, etiology t study entry (spinl cord injury or multiple sclerosis), concurrent nticholinergic therpy t screening, nd investigtor s fctors. LOCF vlues were used to nlyze the primry efficcy vrible. ** Primry timepoint Primry endpoint b Secondry endpoint Tble 19: Bseline nd Chnge from Bseline in Weekly Urinry Incontinence Episode Frequency, Mximum Cystometric Cpcity nd Mximum Detrusor Pressure during First Involuntry Detrusor Contrction (cmh 2 O) in Study NDO-2 Weekly Frequency of Urinry Incontinence Episodes 200 Units N Men Bseline Tretment Difference* p-vlue* Men Chnge* t Week Men Chnge* t Week 6** (-14.5, -3.0) p=0.003 Men Chnge* t Week Mximum Cystometric Cpcity b (ml) N Men Bseline Men Chnge* t Week 6** (101.8, 194.2) Mximum Detrusor Pressure during First Involuntry Detrusor Contrction b (cmh 2 O) N Men Bseline p<0.001 Men Chnge* t Week 6** * LS men chnge, tretment difference nd p-vlue re bsed on n nlysis using n ANCOVA model with bseline weekly endpoint s covrite nd tretment group, etiology t study entry (spinl cord injury or multiple sclerosis), concurrent nticholinergic therpy t screening, nd investigtor s fctors. LOCF vlues were used to nlyze the primry efficcy vrible. ** Primry timepoint Primry endpoint b Secondry endpoint Figure 6: Men Chnge from Bseline in Weekly Frequency of Urinry Incontinence Episodes During Tretment Cycle 1 in Study NDO-1 Episodes/Week: Men Chnge from Bseline (± Std Err) ** Weeks Post-Tretment Tretment (n = 146) 200 U (n = 134) ** p < Figure 7: Men Chnge from Bseline in Weekly Frequency of Urinry Incontinence Episodes During Tretment Cycle 1 in Study NDO-2 Episodes/Week: Men Chnge from Bseline (± Std Err) * Weeks Post-Tretment Tretment (n = 91) 200 U (n = 91) * p < 0.05 The medin durtion of response in study NDO-1 nd NDO-2, bsed on ptient qulifiction for re-tretment ws dys (42-48 weeks) for the 200 Units dose group compred to dys (13-18 weeks) for plcebo. Re-tretment ws bsed on loss of effect on incontinence episode frequency (50% of effect in Study NDO-1; 70% of effect in Study NDO-2) Chronic Migrine ws evluted in two rndomized, multi-center, 24-week, 2 injection cycle, plcebocontrolled double-blind studies. Study 1 nd Study 2 included chronic migrine dults who were not using ny concurrent hedche prophylxis, nd during 28-dy bseline period hd 15 hedche dys lsting 4 hours or more, with 50% being migrine/ probble migrine. In both studies, ptients were rndomized to receive plcebo or 155 Units to 195 Units injections every 12 weeks for the 2-cycle, double-blind phse. Ptients were llowed to use cute hedche tretments during the study. tretment demonstrted sttisticlly significnt nd cliniclly meningful improvements from bseline compred to plcebo for key efficcy vribles (see Tble 20). Tble 20: Week 24 Key Efficcy Vribles for Study 1 nd Study 2 Efficcy per 28 dys Chnge from bseline in frequency of hedche dys Chnge from bseline in totl cumultive hours of hedche on hedche dys * Significntly different from plcebo (p 0.05) (N=341) Study 1 Study 2 (N=338) (N=347) (N=358) -7.8* * * * -95 Ptients treted with hd significntly greter men decrese from bseline in the frequency of hedche dys t most timepoints from Week 4 to Week 24 in Study 1 (Figure 8), nd ll timepoints from Week 4 to Week 24 in Study 2 (Figure 9), compred to plcebo-treted ptients.

14 Figure 8: Men Chnge from Bseline in Number of Hedche Dys for Study 1 Hedche Dys: Men Chnge From Bseline (± Std Err) * * Week 4 Week 8 Week 12 Week 16 * Visit Tretment (n = 338) (n = 341) * : p 0.05 * * Week 20 Week 24 Figure 9: Men Chnge from Bseline in Number of Hedche Dys for Study 2 Hedche Dys: Men Chnge From Bseline (± Std Err) * * * Week 4 Week 8 Week 12 Week 16 Visit * Tretment (n = 358) (n = 347) * : p 0.05 * * Week 20 Week Upper Limb Spsticity The efficcy of for the tretment of upper limb spsticity ws evluted in three rndomized, multi-center, double-blind, plcebo-controlled studies (Studies 1, 2, nd 3). Two dditionl rndomized, multi-center, double-blind, plcebo-controlled studies for upper limb spsticity in dults lso included the evlution of the efficcy of for the tretment of thumb spsticity (Studies 4 nd 5). Study 1 included 126 ptients (64 nd 62 plcebo) with upper limb spsticity (Ashworth score of t lest 3 for wrist flexor tone nd t lest 2 for finger flexor tone) who were t lest 6 months post-stroke. ( totl dose of 200 Units to 240 Units) nd plcebo were injected intrmusculrly (IM) into the flexor digitorum profundus, flexor digitorum sublimis, flexor crpi rdilis, flexor crpi ulnris, nd if necessry into the dductor pollicis nd flexor pollicis longus (see Tble 21). Use of n EMG/nerve stimultor ws recommended to ssist in proper muscle locliztion for injection. Ptients were followed for 12 weeks. Tble 21: Study Mediction Dose nd Injection Sites in Study 1 Muscles Injected Volume (ml) (Units) Number of Injection Sites Wrist Flexor Crpi Rdilis Flexor Crpi Ulnris Finger Flexor Digitorum Profundus Flexor Digitorum Sublimis Thumb Adductor Pollicis Flexor Pollicis Longus injected only if spsticity is present in this muscle The primry efficcy vrible ws wrist flexors muscle tone t week 6, s mesured by the Ashworth score. The Ashworth Scle is clinicl mesure of the force required to move n extremity round joint, with reduction in score cliniclly representing reduction in the force needed to move joint (i.e., improvement in spsticity). Possible scores rnge from 0 to 4: 0 = No increse in muscle tone (none) 1 = Slight increse in muscle tone, giving ctch when the limb ws moved in flexion or extension (mild) 2 = More mrked increse in muscle tone but ffected limb is esily flexed (moderte) 3 = Considerble increse in muscle tone - pssive movement difficult (severe) 4 = Limb rigid in flexion or extension (very severe). Key secondry endpoints included Physicin Globl Assessment, finger flexors muscle tone, nd thumb flexors tone t Week 6. The Physicin Globl Assessment evluted the response to tretment in terms of how the ptient ws doing in his/her life using scle from -4 = very mrked worsening to +4 = very mrked improvement. Study 1 results on the primry endpoint nd the key secondry endpoints re shown in Tble 22. Tble 22: Primry nd Key Secondry Endpoints by Muscle Group t Week 6 in Study 1 (N=64) (N=62) Medin Chnge from Bseline in Wrist Flexor Muscle Tone on the Ashworth Scle -2.0* 0.0 Medin Chnge from Bseline in Finger Flexor Muscle Tone on the Ashworth Scle b -1.0* 0.0 Medin Chnge from Bseline in Thumb Flexor Muscle Tone on the Ashworth Scle c Medin Physicin Globl Assessment of Response to Tretment 2.0* 0.0 Primry endpoint t Week 6 Secondry endpoints t Week 6 * Significntly different from plcebo (p 0.05) injected into both the flexor crpi rdilis nd ulnris muscles b injected into the flexor digitorum profundus nd flexor digitorum sublimis muscles c injected into the dductor pollicis nd flexor pollicis longus muscles Study 2 compred 3 doses of with plcebo nd included 91 ptients [ 360 Units (N=21), 180 Units (N=23), 90 Units (N=21), nd plcebo (N=26)] with upper limb spsticity (expnded Ashworth score of t lest 2 for elbow flexor tone nd t lest 3 for wrist flexor tone) who were t lest 6 weeks post-stroke. nd plcebo were injected with EMG guidnce into the flexor digitorum profundus, flexor digitorum sublimis, flexor crpi rdilis, flexor crpi ulnris, nd biceps brchii (see Tble 23). Tble 23: Study Mediction Dose nd Injection Sites in Study 2 nd Study 3 Muscles Injected low dose (90 Units) Totl Dose mid dose (180 Units) high dose (360 Units) Volume (ml) per site Injection Sites (n) Wrist Flexor Crpi Ulnris 10 Units 20 Units 40 Units Flexor Crpi Rdilis 15 Units 30 Units 60 Units Finger Flexor Digitorum Profundus 7.5 Units 15 Units 30 Units Flexor Digitorum Sublimis 7.5 Units 15 Units 30 Units Elbow Biceps Brchii 50 Units 200 Units The primry efficcy vrible in Study 2 ws the wrist flexor tone t Week 6 s mesured by the expnded Ashworth Scle. The expnded Ashworth Scle uses the sme scoring system s the Ashworth Scle, but llows for hlf-point increments. Key secondry endpoints in Study 2 included Physicin Globl Assessment, finger flexors muscle tone, nd elbow flexors muscle tone t Week 6. Study 2 results on the primry endpoint nd the key secondry endpoints t Week 6 re shown in Tble 24. Tble 24: Primry nd Key Secondry Endpoints by Muscle Group nd Dose t Week 6 in Study 2 low dose (90 Units) (N=21) mid dose (180 Units) (N=23) high dose (360 Units) (N=21) (N=26) Medin Chnge from Bseline in Wrist Flexor Muscle Tone on the -1.5* -1.0* -1.5* -1.0 Ashworth Scle b Medin Chnge from Bseline in Finger Flexor Muscle Tone on the Ashworth Scle c Medin Chnge from Bseline in Elbow Flexor Muscle Tone on the * Ashworth Scle d Medin Physicin Globl Assessment of Response to Tretment 1.0* 1.0* 1.0* 0.0 Primry endpoint t Week 6 Secondry endpoints t Week 6 * Significntly different from plcebo (p 0.05) p=0.053 b Totl dose of injected into both the flexor crpi rdilis nd ulnris muscles c Totl dose of injected into the flexor digitorum profundus nd flexor digitorum sublimis muscles d Dose of injected into biceps brchii muscle

15 Study 3 compred 3 doses of with plcebo nd enrolled 88 ptients [ 360 Units (N=23), 180 Units (N=23), 90 Units (N=23), nd plcebo (N=19)] with upper limb spsticity (expnded Ashworth score of t lest 2 for elbow flexor tone nd t lest 3 for wrist flexor tone nd/or finger flexor tone) who were t lest 6 weeks post-stroke. nd plcebo were injected with EMG guidnce into the flexor digitorum profundus, flexor digitorum sublimis, flexor crpi rdilis, flexor crpi ulnris, nd biceps brchii (see Tble 23). The primry efficcy vrible in Study 3 ws wrist nd elbow flexor tone s mesured by the expnded Ashworth score. A key secondry endpoint ws ssessment of finger flexors muscle tone. Study 3 results on the primry endpoint t Week 4 re shown in Tble 25. Tble 25: Primry nd Key Secondry Endpoints by Muscle Group nd Dose t Week 4 in Study 3 low dose (90 Units) (N=23) mid dose (180 Units) (N=21) high dose (360 Units) (N=22) (N=19) Medin Chnge from Bseline in Wrist Flexor Muscle Tone on the * -0.5 Ashworth Scle b Medin Chnge from Bseline in Finger Flexor Muscle Tone on the * -0.5 Ashworth Scle c Medin Chnge from Bseline in Elbow Flexor Muscle Tone on the * -0.5 Ashworth Scle d Primry endpoint t Week 4 Secondry endpoints t Week 4 * Significntly different from plcebo (p 0.05) b Totl dose of injected into both the flexor crpi rdilis nd ulnris muscles c Totl dose of injected into the flexor digitorum profundus nd flexor digitorum sublimis muscles d Dose of injected into biceps brchii muscle Study 4 included 170 ptients (87 nd 83 plcebo) with upper limb spsticity who were t lest 6 months post-stroke. In Study 4, ptients received 20 Units of into the dductor pollicis nd flexor pollicis longus (totl dose =40 Units in thumb muscles) or plcebo (see Tble 26). Study 5 included 109 ptients with upper limb spsticity who were t lest 6 months post-stroke. In Study 5, ptients received 15 Units (low dose) or 20 Units (high dose) of into the dductor pollicis nd flexor pollicis longus under EMG guidnce (totl low dose =30 Units, totl high dose =40 Units), or plcebo (see Tble 26). The durtion of follow-up in Study 4 nd Study 5 ws 12 weeks. Tble 26: Study Mediction Dose nd Injection Sites in Studies 4 nd 5 Muscles Injected Thumb Adductor Pollicis Flexor Pollicis Longus Study 4 Study 5 Number Volume Volume of Injection Volume low high low high Sites for (Units) (ml) dose dose dose dose Studies (Units) (Units) (ml) (ml) 4 nd The results of Study 4 for the chnge from Bseline to Week 6 in thumb flexor tone mesured by modified Ashworth Scle nd overll tretment response by Physicin Globl Assessment t week 6 re presented in Tble 27. Tble 27: Efficcy Endpoints for Thumb Flexors t Week 6 in Study 4 (N=66) (N=57) Medin Chnge from Bseline in Thumb Flexor Muscle Tone on the modified Ashworth Scle -1.0* 0.0 Medin Physicin Globl Assessment of Response to Tretment 2.0* 0.0 Secondry endpoints t Week 6 * Significntly different from plcebo (p 0.001) injected into the dductor pollicis nd flexor pollicis longus muscles In Study 5, the results of the chnge from Bseline to Week 6 in thumb flexor tone mesured by modified Ashworth Scle nd Clinicl Globl Impression (CGI) of functionl ssessment scle ssessed by the physicin using n 11-point Numeric Rting Scle [-5 worst possible function to +5 best possible function]) re presented in Tble 28. Tble 28: Efficcy Endpoints for Thumb Flexors t Week 6 in Study 5 low dose (30 Units) (N=14) low dose (N=9) high dose (40 Units) (N=43) high dose (N=23) Medin Chnge from Bseline in Thumb Flexor Muscle Tone on * 0.0 the modified Ashworth Scle Medin chnge from Bseline in Clinicl Globl Impression Score * 0.0 by Physicin Secondry endpoint t Week 6 Other endpoint t Week 6 * Significntly different from plcebo (p 0.010) injected into the dductor pollicis nd flexor pollicis longus muscles 14.5 Cervicl Dystoni A rndomized, multi-center, double-blind, plcebo-controlled study of the tretment of cervicl dystoni ws conducted. This study enrolled dult ptients with cervicl dystoni nd history of hving received in n open lbel mnner with perceived good response nd tolerble side effects. Ptients were excluded if they hd previously received surgicl or other denervtion tretment for their symptoms or hd known history of neuromusculr disorder. Subjects prticipted in n open lbel enrichment period where they received their previously employed dose of. Only ptients who were gin perceived s showing response were dvnced to the rndomized evlution period. The muscles in which the blinded study gent injections were to be dministered were determined on n individul ptient bsis. There were 214 subjects evluted for the open lbel period, of which 170 progressed into the rndomized, blinded tretment period (88 in the group, 82 in the plcebo group). Ptient evlutions continued for t lest 10 weeks post-injection. The primry outcome for the study ws dul endpoint, requiring evidence of both chnge in the Cervicl Dystoni Severity Scle (CDSS) nd n increse in the percentge of ptients showing ny improvement on the Physicin Globl Assessment Scle t 6 weeks fter the injection session. The CDSS quntifies the severity of bnorml hed positioning nd ws newly devised for this study. CDSS llots 1 point for ech 5 degrees (or prt thereof) of hed devition in ech of the three plnes of hed movement (rnge of scores up to theoreticl mximum of 54). The Physicin Globl Assessment Scle is 9 ctegory scle scoring the physicin s evlution of the ptients sttus compred to bseline, rnging from 4 to +4 (very mrked worsening to complete improvement), with 0 indicting no chnge from bseline nd +1 slight improvement. Pin is lso n importnt symptom of cervicl dystoni nd ws evluted by seprte ssessments of pin frequency nd severity on scles of 0 (no pin) to 4 (constnt in frequency or extremely severe in intensity). Study results on the primry endpoints nd the pin-relted secondry endpoints re shown in Tble 29. Tble 29: Efficcy Outcomes of the Phse 3 Cervicl Dystoni Study (Group Mens) (N=82) (N=88) Bseline CDSS % CI on Difference Chnge in CDSS t Week (-2.3, 0.3) [,b] % Ptients with Any Improvement on Physicin Globl Assessment Pin Intensity Bseline % 51% (5%, 34%) [] Chnge in Pin Intensity t Week (-0.7, -0.2) [c] Pin Frequency Bseline Chnge in Pin Frequency t Week (-0.5, -0.0) [c] [] Confidence intervls re constructed from the nlysis of covrince tble with tretment nd investigtionl site s min effects, nd bseline CDSS s covrite. [b] These vlues represent the prospectively plnned method for missing dt imputtion nd sttisticl test. Sensitivity nlyses indicted tht the 95% confidence intervl excluded the vlue of no difference between groups nd the p-vlue ws less thn These nlyses included severl lterntive missing dt imputtion methods nd nonprmetric sttisticl tests. [c] Confidence intervls re bsed on the t-distribution. Explortory nlyses of this study suggested tht the mjority of ptients who hd shown beneficil response by week 6 hd returned to their bseline sttus by 3 months fter tretment. Explortory nlyses of subsets by ptient sex nd ge suggest tht both sexes receive benefit, lthough femle ptients my receive somewht greter mounts thn mle ptients. There is consistent tretment-ssocited effect between subsets greter thn nd less thn ge 65. There were too few non-cucsin ptients enrolled to drw ny conclusions regrding reltive efficcy in rcil subsets. In this study the medin totl dose in ptients rndomized to receive (N=88) ws 236 Units, with 25th to 75th percentile rnges of 198 Units to 300 Units. Of these 88 ptients, most received injections to 3 or 4 muscles; 38 received injections to 3 muscles, 28 to 4 muscles, 5 to 5 muscles, nd 5 to 2 muscles. The dose ws divided mongst the ffected muscles in quntities shown in Tble 30. The totl dose nd muscles selected were tilored to meet individul ptient needs.

16 Tble 30: Number of Ptients Treted per Muscle nd Frction of Totl Dose Injected into Involved Muscles Muscle Number of Ptients Treted in this Muscle (N=88) Men % Dose per Muscle Mid-Rnge of % Dose per Muscle* Splenius cpitis/cervicis Sternocleidomstoid Levtor scpule Trpezius Semispinlis Sclene Longissimus * The mid-rnge of dose is clculted s the 25th to 75th percentiles. There were severl rndomized studies conducted prior to the double-blind, plcebocontrolled study, which were supportive but not dequtely designed to ssess or quntittively estimte the efficcy of Primry Axillry Hyperhidrosis The efficcy nd sfety of for the tretment of primry xillry hyperhidrosis were evluted in two rndomized, multi-center, double-blind, plcebo-controlled studies. Study 1 included dult ptients with persistent primry xillry hyperhidrosis who scored 3 or 4 on Hyperhidrosis Disese Severity Scle (HDSS) nd who produced t lest 50 mg of swet in ech xill t rest over 5 minutes. HDSS is 4-point scle with 1 = underrm sweting is never noticeble nd never interferes with my dily ctivities ; to 4 = underrm sweting is intolerble nd lwys interferes with my dily ctivities. A totl of 322 ptients were rndomized in 1:1:1 rtio to tretment in both xille with either 50 Units of, 75 Units of, or plcebo. Ptients were evluted t 4-week intervls. Ptients who responded to the first injection were re-injected when they reported re-increse in HDSS score to 3 or 4 nd produced t lest 50 mg swet in ech xill by grvimetric mesurement, but no sooner thn 8 weeks fter the initil injection. Study responders were defined s ptients who showed t lest 2-grde improvement from bseline vlue on the HDSS 4 weeks fter both of the first two tretment sessions or hd sustined response fter their first tretment session nd did not receive re-tretment during the study. Spontneous resting xillry swet production ws ssessed by weighing filter pper held in the xill over period of 5 minutes (grvimetric mesurement). Swet production responders were those ptients who demonstrted reduction in xillry sweting from bseline of t lest 50% t week 4. In the three study groups the percentge of ptients with bseline HDSS score of 3 rnged from 50% to 54% nd from 46% to 50% for score of 4. The medin mount of swet production (verged for ech xill) ws 102 mg, 123 mg, nd 114 mg for the plcebo, 50 Units nd 75 Units groups respectively. The percentge of responders bsed on t lest 2-grde decrese from bseline in HDSS or bsed on >50% decrese from bseline in xillry swet production ws greter in both groups thn in the plcebo group (p<0.001), but ws not significntly different between the two doses (see Tble 31). Durtion of response ws clculted s the number of dys between injection nd the dte of the first visit t which ptients returned to 3 or 4 on the HDSS scle. The medin durtion of response following the first tretment in treted ptients with either dose ws 201 dys. Among those who received second injection, the medin durtion of response ws similr to tht observed fter the first tretment. In study 2, 320 dults with bilterl xillry primry hyperhidrosis were rndomized to receive either 50 Units of (n=242) or plcebo (n=78). Tretment responders were defined s subjects showing t lest 50% reduction from bseline in xillry sweting mesured by grvimetric mesurement t 4 weeks. At week 4 post-injection, the percentges of responders were 91% (219/242) in the group nd 36% (28/78) in the plcebo group, p< The difference in percentge of responders between nd plcebo ws 55% (95% CI=43.3, 65.9). Tble 31: Study 1 - Study Outcomes Tretment Response 50 Units (N=104) 75 Units (N=110) (N=108) 50-plcebo (95% CI) HDSS Score 55% (57) 49% (54) 6% (6) 49.3% chnge 2 (n) (38.8, 59.7) >50% decrese in xillry swet production % (n) 81% (84) 86% (94) 41% (44) 40% (28.1, 52.0) 75-plcebo (95% CI) 43% (33.2, 53.8) 45% (33.3, 56.1) Ptients who showed t lest 2-grde improvement from bseline vlue on the HDSS 4 weeks fter both of the first two tretment sessions or hd sustined response fter their first tretment session nd did not receive re-tretment during the study Blephrospsm Botulinum toxin hs been investigted for use in ptients with blephrospsm in severl studies. In n open lbel, historiclly controlled study, 27 ptients with essentil blephrospsm were injected with 2 Units of t ech of six sites on ech side. Twenty-five of the 27 ptients treted with botulinum toxin reported improvement within 48 hours. One ptient ws controlled with higher dosge t 13 weeks post initil injection nd one ptient reported mild improvement but remined functionlly impired. In nother study, 12 ptients with blephrospsm were evluted in double-blind, plcebo-controlled study. Ptients receiving botulinum toxin (n=8) improved compred with the plcebo group (n=4). The effects of the tretment lsted men of 12 weeks. One thousnd six hundred eighty-four ptients with blephrospsm who were evluted in n open lbel tril showed clinicl improvement s evluted by mesured eyelid force nd cliniclly observed intensity of lid spsm, lsting n verge of 12 weeks prior to the need for re-tretment Strbismus Six hundred seventy-seven ptients with strbismus treted with one or more injections of were evluted in n open lbel tril. Fifty-five percent of these ptients improved to n lignment of 10 prism diopters or less when evluted six months or more following injection. 16 HOW SUPPLIED/STORAGE AND HANDLING is supplied in single-use vil in the following sizes: NDC Units NDC Vils of hve hologrphic film on the vil lbel tht contins the nme Allergn within horizontl lines of rinbow color. In order to see the hologrm, rotte the vil bck nd forth between your fingers under desk lmp or fluorescent light source. (Note: the hologrphic film on the lbel is bsent in the dte/lot re.) If you do not see the lines of rinbow color or the nme Allergn, do not use the product nd contct Allergn for dditionl informtion t from 7:00 AM to 3:00 PM Pcific Time. Storge Unopened vils of should be stored in refrigertor (2 to 8 C) for up to 36 months. Do not use fter the expirtion dte on the vil. Administer within 24 hours of reconstitution; during this period reconstituted should be stored in refrigertor (2 to 8 C). Reconstituted should be cler, colorless, nd free of prticulte mtter. 17 PATIENT COUNSELING INFORMATION Advise the ptient to red the FDA-pproved ptient lbeling (Mediction Guide) Swllowing, Speking or Brething Difficulties, or Other Unusul Symptoms Advise ptients to inform their doctor or phrmcist if they develop ny unusul symptoms (including difficulty with swllowing, speking, or brething), or if ny existing symptom worsens [see Boxed Wrning nd Wrnings nd Precutions (5.2, 5.6)]. Ability to Operte Mchinery or Vehicles Advise ptients tht if loss of strength, muscle wekness, blurred vision, or drooping eyelids occur, they should void driving cr or engging in other potentilly hzrdous ctivities. Voiding Symptoms fter Bldder Injections After bldder injections for urinry incontinence, dvise ptients to contct their physicin if they experience difficulties in voiding or burning senstion upon voiding. MEDICATION GUIDE Cosmetic (Boe-tox) (onbotulinumtoxina) for Injection Red the Mediction Guide tht comes with or Cosmetic before you strt using it nd ech time it is given to you. There my be new informtion. This informtion does not tke the plce of tlking with your doctor bout your medicl condition or your tretment. You should shre this informtion with your fmily members nd cregivers. Wht is the most importnt informtion I should know bout nd Cosmetic? nd Cosmetic my cuse serious side effects tht cn be life thretening, including: Problems brething or swllowing Spred of toxin effects These problems cn hppen hours, dys, to weeks fter n injection of or Cosmetic. Cll your doctor or get medicl help right wy if you hve ny of these problems fter tretment with or Cosmetic:

17 1. Problems swllowing, speking, or brething. These problems cn hppen hours, dys, to weeks fter n injection of or Cosmetic usully becuse the muscles tht you use to brethe nd swllow cn become wek fter the injection. Deth cn hppen s compliction if you hve severe problems with swllowing or brething fter tretment with or Cosmetic. People with certin brething problems my need to use muscles in their neck to help them brethe. These people my be t greter risk for serious brething problems with or Cosmetic. Swllowing problems my lst for severl months. People who cnnot swllow well my need feeding tube to receive food nd wter. If swllowing problems re severe, food or liquids my go into your lungs. People who lredy hve swllowing or brething problems before receiving or Cosmetic hve the highest risk of getting these problems. 2. Spred of toxin effects. In some cses, the effect of botulinum toxin my ffect res of the body wy from the injection site nd cuse symptoms of serious condition clled botulism. The symptoms of botulism include: loss of strength nd muscle wekness ll over the body double vision blurred vision nd drooping eyelids horseness or chnge or loss of voice (dysphoni) trouble sying words clerly (dysrthri) loss of bldder control trouble brething trouble swllowing These symptoms cn hppen hours, dys, to weeks fter you receive n injection of or Cosmetic. These problems could mke it unsfe for you to drive cr or do other dngerous ctivities. See Wht should I void while receiving or Cosmetic? There hs not been confirmed serious cse of spred of toxin effect wy from the injection site when hs been used t the recommended dose to tret chronic migrine, severe underrm sweting, blephrospsm, or strbismus, or when Cosmetic hs been used t the recommended dose to tret frown lines nd/or crow s feet lines. Wht re nd Cosmetic? is prescription medicine tht is injected into muscles nd used: to tret overctive bldder symptoms such s strong need to urinte with leking or wetting ccidents (urge urinry incontinence), strong need to urinte right wy (urgency), nd urinting often (frequency) in dults when nother type of medicine (nticholinergic) does not work well enough or cnnot be tken. to tret lekge of urine (incontinence) in dults with overctive bldder due to neurologic disese when nother type of medicine (nticholinergic) does not work well enough or cnnot be tken. to prevent hedches in dults with chronic migrine who hve 15 or more dys ech month with hedche lsting 4 or more hours ech dy. to tret incresed muscle stiffness in elbow, wrist, nd finger muscles in dults with upper limb spsticity. to tret the bnorml hed position nd neck pin tht hppens with cervicl dystoni (CD) in dults. to tret certin types of eye muscle problems (strbismus) or bnorml spsm of the eyelids (blephrospsm) in people 12 yers nd older. is lso injected into the skin to tret the symptoms of severe underrm sweting (severe primry xillry hyperhidrosis) when medicines used on the skin (topicl) do not work well enough. Cosmetic is prescription medicine tht is injected into muscles nd used to improve the look of moderte to severe frown lines between the eyebrows (glbellr lines) in dults for short period of time (temporry). Cosmetic is prescription medicine tht is injected into the re round the side of the eyes to improve the look of crow s feet lines in dults for short period of time (temporry). You my receive tretment for frown lines nd crow s feet lines t the sme time. It is not known whether is sfe or effective in people younger thn: 18 yers of ge for tretment of urinry incontinence 18 yers of ge for tretment of chronic migrine 18 yers of ge for tretment of spsticity 16 yers of ge for tretment of cervicl dystoni 18 yers of ge for tretment of hyperhidrosis 12 yers of ge for tretment of strbismus or blephrospsm Cosmetic is not recommended for use in children younger thn 18 yers of ge. It is not known whether nd Cosmetic re sfe or effective to prevent hedches in people with migrine who hve 14 or fewer hedche dys ech month (episodic migrine). It is not known whether nd Cosmetic re sfe or effective for other types of muscle spsms or for severe sweting nywhere other thn your rmpits. Who should not tke or Cosmetic? Do not tke or Cosmetic if you: re llergic to ny of the ingredients in or Cosmetic. See the end of this Mediction Guide for list of ingredients in nd Cosmetic. hd n llergic rection to ny other botulinum toxin product such s Myobloc, Dysport, or Xeomin hve skin infection t the plnned injection site re being treted for urinry incontinence nd hve urinry trct infection (UTI) re being treted for urinry incontinence nd find tht you cnnot empty your bldder on your own (only pplies to people who re not routinely ctheterizing) Wht should I tell my doctor before tking or Cosmetic? Tell your doctor bout ll your medicl conditions, including if you: hve disese tht ffects your muscles nd nerves (such s myotrophic lterl sclerosis [ALS or Lou Gehrig s disese], mystheni grvis or Lmbert-Eton syndrome). See Wht is the most importnt informtion I should know bout nd Cosmetic? hve llergies to ny botulinum toxin product hd ny side effect from ny botulinum toxin product in the pst hve or hve hd brething problem, such s sthm or emphysem hve or hve hd swllowing problems hve or hve hd bleeding problems hve plns to hve surgery hd surgery on your fce hve wekness of your forehed muscles, such s trouble rising your eyebrows hve drooping eyelids hve ny other chnge in the wy your fce normlly looks hve symptoms of urinry trct infection (UTI) nd re being treted for urinry incontinence. Symptoms of urinry trct infection my include pin or burning with urintion, frequent urintion, or fever. hve problems emptying your bldder on your own nd re being treted for urinry incontinence re pregnnt or pln to become pregnnt. It is not known if or Cosmetic cn hrm your unborn bby. re brest-feeding or pln to brestfeed. It is not known if or Cosmetic psses into brest milk.

18 Tell your doctor bout ll the medicines you tke, including prescription nd nonprescription medicines, vitmins nd herbl products. Using or Cosmetic with certin other medicines my cuse serious side effects. Do not strt ny new medicines until you hve told your doctor tht you hve received or Cosmetic in the pst. Especilly tell your doctor if you: hve received ny other botulinum toxin product in the lst four months hve received injections of botulinum toxin, such s Myobloc (rimbotulinumtoxinb), Dysport (bobotulinumtoxina), or Xeomin (incobotulinumtoxina) in the pst. Be sure your doctor knows exctly which product you received. hve recently received n ntibiotic by injection tke muscle relxnts tke n llergy or cold medicine tke sleep medicine tke nti-pltelets (spirin-like products) nd/or nti-cogulnts (blood thinners) Ask your doctor if you re not sure if your medicine is one tht is listed bove. Know the medicines you tke. Keep list of your medicines with you to show your doctor nd phrmcist ech time you get new medicine. How should I tke or Cosmetic? or Cosmetic is n injection tht your doctor will give you. is injected into your ffected muscles, skin, or bldder. Cosmetic is injected into your ffected muscles. Your doctor my chnge your dose of or Cosmetic, until you nd your doctor find the best dose for you. Your doctor will tell you how often you will receive your dose of or Cosmetic injections. Wht should I void while tking or Cosmetic? nd Cosmetic my cuse loss of strength or generl muscle wekness, or vision problems within hours to weeks of tking or Cosmetic. If this hppens, do not drive cr, operte mchinery, or do other dngerous ctivities. See Wht is the most importnt informtion I should know bout nd Cosmetic? Wht re the possible side effects of nd Cosmetic? nd Cosmetic cn cuse serious side effects. See Wht is the most importnt informtion I should know bout nd Cosmetic? Other side effects of nd Cosmetic include: dry mouth discomfort or pin t the injection site tiredness hedche neck pin eye problems: double vision, blurred vision, decresed eyesight, drooping eyelids, swelling of your eyelids, nd dry eyes. urinry trct infection in people being treted for urinry incontinence pinful urintion in people being treted for urinry incontinence inbility to empty your bldder on your own nd re being treted for urinry incontinence. If you hve difficulty fully emptying your bldder fter getting, you my need to use disposble self-ctheters to empty your bldder up to few times ech dy until your bldder is ble to strt emptying gin. llergic rections. Symptoms of n llergic rection to or Cosmetic my include: itching, rsh, red itchy welts, wheezing, sthm symptoms, or dizziness or feeling fint. Tell your doctor or get medicl help right wy if you re wheezing or hve sthm symptoms, or if you become dizzy or fint. Tell your doctor if you hve ny side effect tht bothers you or tht does not go wy. These re not ll the possible side effects of nd Cosmetic. For more informtion, sk your doctor or phrmcist. Cll your doctor for medicl dvice bout side effects. You my report side effects to FDA t FDA Generl informtion bout nd Cosmetic: Medicines re sometimes prescribed for purposes other thn those listed in Mediction Guide. This Mediction Guide summrizes the most importnt informtion bout nd Cosmetic. If you would like more informtion, tlk with your doctor. You cn sk your doctor or phrmcist for informtion bout nd Cosmetic tht is written for helthcre professionls. Wht re the ingredients in nd Cosmetic? Active ingredient: botulinum toxin type A Inctive ingredients: humn lbumin nd sodium chloride Revised: 08/2015 This Mediction Guide hs been pproved by the U.S. Food nd Drug Administrtion. Mnufctured by: Allergn Phrmceuticls Irelnd subsidiry of: Allergn, Inc Dupont Dr. Irvine, CA Allergn. All rights reserved. mrks owned by Allergn, Inc. Ptented. See: Myobloc is registered trdemrk of Solstice Neurosciences, Inc. Dysport is registered trdemrk of Ipsen Biophrm Limited Compny. Xeomin is registered trdemrk of Merz Phrm GmbH & Co KGA US US US14 APC38OA15

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